Scientific Program

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Show Only CME Accredited Sessions

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    MS20 - Innovative and Evolving Strategies in Diagnosis and Management of Stage I NSCLC

    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Moderators:
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      MS20.01 - Robotic and Innovative Surgery

      15:15 - 15:30  |  Presenting Author(s): Waël C. Hanna

      • Abstract

      Abstract not provided

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      MS20.02 - The Future of Stereotactic Ablative Radiotherapy (SABR)

      15:30 - 15:45  |  Presenting Author(s): Billy W Loo

      • Abstract

      Abstract not provided

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      MS20.03 - Immunotherapy and Surgery: Neoadjuvant or Adjuvant? Is It Safe?

      15:45 - 16:00  |  Presenting Author(s): Jamie E Chaft

      • Abstract

      Abstract not provided

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      MS20.04 - Prediction of Clinical Outcome in NSCLC Using Integrative Genomics: Implications for Adjuvant Chemotherapy

      16:00 - 16:15  |  Presenting Author(s): Phillippe Broet

      • Abstract

      Abstract not provided

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      MS20.05 - Beyond Surgery - Support of the Surgical Patient

      16:15 - 16:30  |  Presenting Author(s): Kate Kuhns

      • Abstract

      Abstract not provided

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      MS20.06 - Less Is More: Segmentectomy in the Management of Early Stage NSCLC

      16:30 - 16:45  |  Presenting Author(s): Shun-ichi Watanabe

      • Abstract

      Abstract not provided

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    MS21 - Giants in Thoracic Oncology

    • Type: Mini Symposium
    • Track:
    • Moderators:
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      MS21.01 - Surgery and its Evolution

      15:15 - 15:25  |  Presenting Author(s): Paul Emile Van Schil

      • Abstract

      Abstract not provided

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      MS21.02 - Chemotherapy through the 21st Century

      15:25 - 15:35  |  Presenting Author(s): David H Johnson

      • Abstract

      Abstract not provided

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      MS21.03 - Revolution in Radiation

      15:35 - 15:45  |  Presenting Author(s): Ben Slotman

      • Abstract

      Abstract not provided

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      MS21.04 - Targeted Therapy - The Second Revolution

      15:45 - 15:55  |  Presenting Author(s): Frances A Shepherd

      • Abstract

      Abstract not provided

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      MS21.05 - Quality of Life - Are we Paying Enough Attention?

      15:55 - 16:05  |  Presenting Author(s): Richard J Gralla

      • Abstract

      Abstract not provided

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      MS21.06 - Immunotherapy - Sequence or Combination?

      16:05 - 16:15  |  Presenting Author(s): Roy S. Herbst

      • Abstract

      Abstract not provided

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      MS21.07 - The Growing Role of Biomarkers in Treatment Selection: “The Tissue is the Issue”

      16:15 - 16:25  |  Presenting Author(s): Fred R. Hirsch

      • Abstract

      Abstract not provided

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      MS21.08 - Where will we be in 10 years?

      16:25 - 16:35  |  Presenting Author(s): Paul A. Bunn, Jr.

      • Abstract

      Abstract not provided

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      MS21.09 - Discussion

      16:35 - 17:00

      • Abstract

      Abstract not provided

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    OA12 - Novel Therapies in MET, RET and BRAF

    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Moderators:
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      OA12.01 - Phase II Data for the MET Inhibitor Tepotinib in Patients with Advanced NSCLC and MET Exon 14-Skipping Mutations

      15:15 - 15:25  |  Presenting Author(s): Enriqueta Felip  |  Author(s): Hiroshi Sakai, Jyoti Patel, Leora Horn, Remi Veillon, Frank Griesinger, Rolf Bruns, Jürgen Scheele, Paul K. Paik

      • Abstract

      Background

      A subset (3%) of NSCLCs harbor mutations of the MET proto-oncogene that cause MET exon 14 skipping (METex14) and accumulation of active MET lacking a juxtamembrane domain. We report interim data from a single-arm phase II trial (NCT02864992) investigating the efficacy and safety of the potent, selective tyrosine-protein kinase MET inhibitor tepotinib in patients with METex14-skipping mutation-positive (METex14+) NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Recruitment of ≤120 adult patients with advanced METex14+ NSCLC without EGFR-activating mutations or ALK rearrangements is ongoing. METex14+ mutations are identified in FPE tumor (T) material and/or plasma (L; 60 patients each, overlap anticipated) by a central laboratory. Patients receive tepotinib 500mg QD until disease progression, intolerable toxicity, or withdrawal. Primary endpoint: objective response rate (ORR). Secondary endpoints include safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty-one patients have been treated to date; data are available for 34 (median age 73.5 years; 23 male; 24/8 Caucasian/Asian; prior lines of therapy: 0, n=12; 1, n=11; 2, n=10; 3, n=1; stage IVA, n=4; stage IV, n=29; stage IIIB, n=1). Treatment is ongoing in 24 patients. Based on investigator assessment, 13/22 (59.1%) evaluable patients responded: 1 had a confirmed complete response; 12 had a confirmed partial response (PR); 3 (13.6%) had stable disease for ≥12 weeks (SD). Based on independent review, 9/22 (40.9%) had a confirmed PR; 5 (22.7%) had SD. Duration of response >12 months in 2 patients. Twenty (58.8%) patients have experienced tepotinib-related treatment-emergent adverse events (TRTEAEs), including serious TRTEAEs in 3 (8.8%): pneumonia =1, generalized oedema=1, interstitial lung disease=1, and grade ≥3 TRTEAEs in 6 (17.6%): generalized oedema=1, pneumonia=1, ALT increased=1, AST increased=1, amylase increased=2, gamma GT increased=1, lipase increased=1, hyperkalemia=1; no TRTEAEs were grade ≥4 or led to death. Five (14.7%) patients have died.

      0022_figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tepotinib 500mg QD has promising activity in METex14+ NSCLC, with a favorable safety profile.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA12.02 - Updated Antitumor Activity of Crizotinib in Patients with MET Exon 14-Altered Advanced Non-Small Cell Lung Cancer

      15:25 - 15:35  |  Presenting Author(s): Alexander Drilon  |  Author(s): Jeffrey W. Clark, Jared Weiss, Sai-Hong Ignatius Ou, Ross Camidge, Ben J Solomon, Gregory A. Otterson, Liza Villaruz, Gregory J Riely, Rebecca Heist, Geoffrey I. Shapiro, Danielle A. Murphy, Sherry C. Wang, Tiziana Usari, Sherry Li, Keith D. Wilner, Paul K. Paik

      • Abstract

      Background

      MET exon 14 alterations occur in ~3% of non-squamous non-small cell lung cancer (NSCLCs) and 20–30% of sarcomatoid lung carcinomas. Here we present updated antitumor activity for crizotinib in patients with advanced NSCLC whose tumors are positive for MET exon 14 alterations (hereafter MET exon 14-positive NSCLC), including updated biomarker analyses in circulating tumor DNA (ctDNA).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with MET exon 14-positive NSCLC by local molecular profiling were treated with 250 mg crizotinib BID in an expansion cohort of the ongoing PROFILE 1001 study (NCT00585195). Responses were based on derived investigator assessment per RECIST v1.0. Prospective plasma profiling for MET exon 14 alterations in plasma ctDNA was performed (PlasmaSELECT-R64; Personal Genome Diagnostics, Boston, MA).

      4c3880bb027f159e801041b1021e88e8 Result

      As of Jan 31, 2018, 69 patients (65 response-evaluable) with MET exon 14-positive NSCLC had been treated. Median age was 72 y (range: 34, 91). Tumor histology was: 84% adenocarcinoma, 9% sarcomatoid adenocarcinoma, 4% squamous cell carcinoma and 3% adenosquamous carcinoma. 61% were former-smokers, 38% never-smokers and 1% a current smoker. Median duration of treatment was 7.4 mo (95% CI: 5.5, 9.1), with 29% of patients ongoing. Confirmed responses were 3 CRs and 18 PRs (ORR, 32% [95% CI: 21, 45]); 29 patients had SD as their best overall response (Figure).

      crizo cmet ex14 waterfall_4may2018-v3.jpg

      Median time to response was 7.6 weeks (range: 3.7, 16.3). Median DOR was 9.1 mo (95% CI: 6.4, 12.7). Median PFS was 7.3 mo (95% CI: 5.4, 9.1). MET exon 14 alterations were detected in ctDNA from 18/37 (49%) patients with analyzable samples.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In patients with MET exon 14-positive advanced NSCLC, crizotinib treatment led to objective responses that were rapid and durable, with CRs in some cases. Plasma ctDNA profiling detected MET exon 14 alterations in a subset of patients who harbor MET exon 14 alterations by tumor testing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      Crizotinib was registered for ALK+ NSCLC in 2013 and recently for ROS1+ stage IV NSCLC. To generate high evidenced-based knowledge and to prevent off-label use, the French National Cancer Institute (INCa) launched the AcSé Program: equal access to tumor molecular diagnosis including an exploratory phase II trial. AcSé allows nationwide safe and controlled access to crizotinib off-label.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Biomarkers were identified with INCa molecular genetic platforms. Patients with amplification [amp] MET or mutation [mut] MET or translocation [tlc] ROS1 advanced NSCLC and not eligible for any other trial, were proposed crizotinib 250 mg BID. Tumor response was evaluated every 2 months (mo) using RECIST v1.1. The primary endpoint was the objective response rate (ORR) at 2 mo (complete + partiale response). A two-stage Simon design was applied to each cohort. Median and 95% confidence interval (CI) was estimated through Kaplan-Meier for progression-free survival (PFS), overall survival (OS), and response duration. Response duration was the delay between CR/PR and first progression/death or last follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      From 08/2013 to 03/2018, 5407 patients from 186 centers entered the biomarker program. Tumor alterations found in patients were: ROS1 tlc in 77/4050; MET amp (≥6 copies/diploid genome) in 251/4171; MET mut in 76/1007.

      Overall, 90 patients (median age, 63 years [30–92]) received crizotinib 250 mg BID.

      #12937.jpg

      73 grade ≥3 adverse events (AEs) or SAE were reported in 70/90 patients. Grade ≥3 AEs were: hematologic toxicities (23%) including neutropenia (11%), and general disorders (16%) including fatigue (10%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study confirms the excellent response rate of crizotinib in the ROS1+ population. Response rate in the MET mut population is comparable to the MET amp population. In addition, the response rate to crizotinib in the MET mut population is lower than that in the PROFILE 1001 study. The tolerance profile is good as previously reported.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA12.04 - Discussant - OA 12.01, OA 12.02, OA 12.03

      15:45 - 16:00  |  Presenting Author(s): Mark M. Awad

      • Abstract

      Abstract not provided

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      OA12.05 - Vemurafenib in Patients Harboring V600 and Non V600 BRAF Mutations: Final Results of the NSCLC Cohort from the AcSé Trial.

      16:00 - 16:10  |  Presenting Author(s): Julien Mazieres  |  Author(s): Laure Montané, Fabrice Barlesi, Bruno Coudert, Pierre Jean Souquet, Josiane Otto, Radj Gervais, Denis Moro-Sibilot, Isabelle Monnet, Etienne Brain, Olivier Huillard, Gilles Quéré, Didier Debieuvre, Elisabeth Fabre, Marion Jaffro, Samia Collot, Gilbert Ferretti, Céline Tiffon, Céline Mahier - Ait Oukhatar, Jean-Yves Blay

      • Abstract

      Background

      BRAF mutations are found in 2-3% of NSCLC. BRAF inhibitors reportedly have antitumor activity. The French National Cancer Institute (INCa) launched a program giving nationwide access to vemurafenib for cancer patients with BRAF-mutated tumors and supported molecular screening. We herein report the NSCLC cohort results.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      BRAF mutational status was assessed on INCa molecular genetic centers by direct sequencing or NGS. Patients with mutated BRAF (V600E and others mutations) progressing after ≥1 standard treatment were proposed vemurafenib 960 mg BID. Objective Response Rate (ORR) was assessed using RECIST v1.1 every 8 weeks. A sequential Bayesian approach was planned to allow early stopping using an inefficacy bound for ORR of 10%. If no early stopping occurred, the treatment was considered worthy for further evaluation if there was a 90% probability that the estimated ORR is ≥30%, the efficacy bound.

      4c3880bb027f159e801041b1021e88e8 Result

      From 10/2014 to 10/2017, 118 NSCLC patients were enrolled: 101 with BRAF V600E and 17 with other potentially activating mutations (4 G466, 4 G469, 1 G596, 5 K601, and 3 N581). Median age was 68 years (range 34–85), 71% smokers, 48% females, 100% non-squamous histology, and 20% with ECOG PS 2. Most frequent grade ≥3 adverse events (AEs) were asthenia (9% of patients), epidermoid carcinoma (6%), dermatitis (5%), and increased GGT (5%). Three toxic deaths were reported: 1 nausea and vomiting leading to dehydration, 1 pneumonia, and 1 neutropenic sepsis.

      #12936.jpg

      Nine patients were still on treatment at the cut-off date, 106 had stopped vemurafenib (65 PD, 26 AEs, 3 deaths, 1 doctor’s decision, 11 patient’s decisions).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Vemurafenib provided reasonable response rate and extended PFS in pretreated NSCLC patients with BRAF V600E mutations but was not effective in those with other BRAF mutations. These results emphasize the need of integrating BRAF V600E in routine biomarkers screening.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA12.06 - Mutational Landscape of BRAF V600E Positive Lung Cancer Patients Following BRAF Directed Therapy Failure

      16:10 - 16:20  |  Presenting Author(s): Anastasios Dimou  |  Author(s): Terry L. Ng, Anna Chalmers, Michael E. Devitt, Anh Le, Vikas Malhotra, Vasu Malhotra, Richard Hall, Thereasa Rich, Wallace Akerley, Jun Zhang, Dara L. Aisner, Ross Camidge, Robert C. Doebele

      • Abstract

      Background

      BRAF V600E mutation is identified as molecular drivers in 1-2% of lung adenocarcinomas and predicts response to combination BRAF and MEK inhibitors. Little is known about molecular mechanisms of acquired resistance to these therapies for lung cancer patients with BRAF V600E mutations, partially due to a lack of representative cancer models.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified patients with BRAF V600E mutated lung cancer who were progressing after initial response to a BRAF/MEK inhibitor combination in 5 academic institutions in the US. Potential molecular mechanisms of resistance were explored by comparing pre- and post-therapy results from comprehensive tissue and/or the Guardant360 and FoundationACT plasma-based next generation sequencing assays.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 6 patients. Prior to treatment with a BRAF/MEK inhibitor combination, four patients had received at least one line of chemotherapy and immune checkpoint inhibitor monotherapy, one had received chemotherapy only and one was treatment naïve. Five patients received dabrafenib/trametinib and one vemurafenib/cobimetinib combination. All 6 patients achieved a partial response. Progression free survival (PFS) ranged from 3 to 15 months (median 9.5 months). At the time of progression, all patients had the BRAF V600E mutation re-identified in their samples. Additionally, there was one patient with a new AKT1 E17K and a new KRAS G12A mutation, one patient with a new VHL R167Q mutation and one patient with a new TP53 splice site indel mutation at the time of progression. Another two patients had AKT1 E17K mutations that were present prior to BRAF/MEK inhibitor therapy. They both had oligoprogression, one in lymph nodes and one in the brain after 5.2 and 3 months, respectively; both continued on dabrafenib and trametinib combination therapy after radiation treatment to the progressing sites. Interestingly, co-occurrence of AKT1 E17K and BRAF V600E mutations is rare in the TCGA data, but was identified in three of six patients in our case series. Finally, we have established a BRAF V600E positive lung adenocarcinoma cell line from a TKI naïve patient for further functional studies of drug resistance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Comprehensive molecular testing can identify potential resistance mechanisms following progression of BRAF V600E positive lung cancer to TKI therapy. AKT1 mutations were common as co-alterations in BRAF V600E mutated lung adenocarcinoma before and after targeted therapy and may contribute to drug resistance. The development of patient-derived cell line models may assist in the identification and validation of drug resistance mechanisms, and may help devise strategies to overcome drug resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA12.08 - Discussant - OA 12.05, OA 12.06, OA 12.07

      16:30 - 16:45  |  Presenting Author(s): Thomas Newsom-Davis

      • Abstract

      Abstract not provided

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    P2.01 - Advanced NSCLC (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
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      P2.01-01 - The Impact of Anlotinib on Brain Metastases of NSCLC: Post-Hoc Analysis of a Phase III Randomized Control Trial (ALTER0303)

      16:45 - 18:00  |  Presenting Author(s): Wenhua Liang  |  Author(s): Yi Zhao, Yalei Zhang, Xi Han, Xinyun Yang, Jianxing He, Kai Li, Baohui Han, - On Behalf Of The Alter0303 Investigators

      • Abstract

      Background

      Few evidence has measured the intracranial impact of multitargeted VEGFR-TKIs. Anlotinib hydrochloride, which targets VEGFR, PDGFR, FGFR and c-Kit, has been shown to significantly prolong PFS and OS compared with placebo as second/third-line treatment for NSCLC in a randomized, double-blind, phase Ⅲ trial (NCT02388919). Herein we sought to analyze anlotinib’s effect in managing brain metastases (BM) and its brain-associated toxicities.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The PFS/OS of anlotinib versus placebo in those with and without BM records at baseline were calculated and compared respectively. In addition, time to brain progression (TTBP), a direct indicator of intracranial control, was also compared between anlotinib and placebo. All calculations were adjusted for confounding factors, including stage, histology, driver mutation type, etc.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 437 patients (294 receiving anlotinib; 143 receiving placebo) were included. 97 cases (22.2%) were recorded to have BM at baseline. There were more BM cases among younger patients and those with adenocarcinoma. Both of the benefit magnitude from anlotinib over placebo were similar between BM and non-BM group in terms of PFS (BM: HR 0.19, 0.11-0.34; non-BM: HR 0.29, 0.22-0.37; interaction P=0.691) and OS (BM: HR 0.71, 0.44-1.16; non-BM: HR 0.67, 0.51-0.89: interaction P=0.789). More specifically, anlotinib was associated with significantly longer TTBP (HR 0.11, 95% CI 0.03-0.41, P=0.001; Figure1) despite all confounders, indicating a 90% reduction of brain progression risk from anlotinib. Interestingly, anlotinib was also associated with more neural toxicities (18.4% vs. 8.4%, P=0.007) and psychological symptoms (49.3% vs. 35.7%, P=0.008) compared with placebo, especially headache (P=0.01), brain edema (P=0.04) but not infarction or cerebral hemorrhage. The above results were all confirmed both in intention-to-treat and per-protocol population.

      figure 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Anlotinib can benefit NSCLC patients with brain metastases and is highly potent in managing intracranial lesions. Its special effect on brain metastases and cerebral tissues merits further investigation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-02 - Osimertinib for EGFR-Positive Advanced NSCLC with Brain Metastases: Preliminary Analysis of an Open-Label, Two-Arm, Phase 2 Study

      16:45 - 18:00  |  Presenting Author(s): Nir Peled  |  Author(s): Ofer Rotem, Anna Belilovski Rozenblum, Hovav Nechushtan, Lilach Chen, Elizabeth Dudnik, Alona Zer, Shlomit Yust-Katz, Ilan Shelef, Laila C. Roisman, Edna Inbar

      • Abstract

      Background

      Osimertinib is an EGFR tyrosine-kinase inhibitor (TKI) selective for both EGFR TKI sensitizing and Thr790Met resistance mutations. While intracranial activity of osimertinib was observed in EGFR-mutant NSCLC in larger trials, a study focusing on patients with brain metastases was not reported yet.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This phase 2, open-label, two-arm study enrolled patients with EGFR-mutant, advanced NSCLC and at least one asymptomatic brain metastasis. Treatment-naïve (arm A) and Thr790Met-positive patients who progressed on EGFR-TKI therapy (arm B) received osimertinib 80 mg QD. Dose escalation (160 mg QD) was performed in cases of intracranial progression without symptomatic systemic progression. The primary endpoint was intracranial metastasis response. The trial is ongoing (NCT02736513 at ClinicalTrials.gov) and here we present a preliminary analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Between May 31, 2016, and November 30, 2017 (data cutoff), 20 patients started osimertinib (arm A=15, arm B=5). Median duration of follow-up was 43 weeks. Intracranial response was achieved in 11 (73%; 95% CI 45%-92%) of 15 arm A and in four (80%; 95% CI 28%-99%) of five arm B patients. Dose escalation was performed in four cases (arm A=2, arm B=2), with one continuous response (25%, 95% CI 5%-70%). Ten of 15 patients (67%) in arm A and one of five patients (20%) in arm B continue responding to osimertinib 80 mg at data cutoff. Median intracranial PFS (80 mg) was not available for arm A (95% CI 232 days–NA), and was 510 days in arm B (95% CI 161–not available). Toxic effects were similar to previous reported data.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib shows equal intracranial and systemic activity with minor side-effects in EGFR-mutant NSCLC as first-line, as well as in previously treated Thr790Met-positive patients. It might therefore be a reasonable treatment for these patient populations and defer brain radiotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-03 - Quality of Life Outcomes for FDA-Approved Agents in Advanced Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Hamzeh Albaba  |  Author(s): Andrea Bezjak, Natasha B Leighl

      • Abstract

      Background

      Symptom control and quality of life (QoL) improvement are among the most important goals of systemic therapy in advanced NSCLC, but they are not required for regulatory approval. We reviewed published QoL data for agents approved for use in advanced NSCLC by the United States Food and Drug Administration (FDA) and explore their potential uses in the era of precision medicine.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Through systematic review, we identified 19 agents approved by the FDA for the treatment of advanced NSCLC between 1999 and 2017. Clinical trials associated with regulatory approval of these agents were identified. QoL results were abstracted from study publications, in addition to trial characteristics (phase, sponsor).

      4c3880bb027f159e801041b1021e88e8 Result

      46 trials were identified supporting the FDA approval of the 19 agents. Of these, 33 (72%) were phase 3 randomized trials (including 3 cooperative group studies) and 13 (28%) were early phase (I/II) trials. QoL data were reported for 27 trials (59%), including all cooperative group trials. Another 5 (11%) measured QoL but results were not published. The remaining 13 (24%) trials did not measure QoL, 8/13 are phase III, 3/13 phase II and 2 phase I. In trials that reported QoL outcomes, better global QoL and cancer-related symptoms were identified in 17/33 (51%) and 18/33 (55%), respectively. Time to symptom deterioration was reported in 18 (55%) studies, with all but one showing benefit for the approved agent. The remaining studies reported no significant difference in QoL between study treatment arms. All studies reporting improved QoL parameters also reported improved response rates. In trials demonstrating OS and PFS improvement, 3/14 and 10/21 reported better QoL outcomes, respectively. ORR was higher in 26 trials, and it was associated with improvement in QoL in 12/26. Of 12 early phase trials leading to drug approval based on response rate and duration, 6 reported improved QoL outcomes. Three have not yet reported QoL data and 3 did not measure QoL.

      8eea62084ca7e541d918e823422bd82e Conclusion

      QoL is clearly associated with response rate but improved QoL or symptom control was only demonstrated in17/33 (51%) and 18/33 (55%) of studies supporting regulatory approval. QoL may be a clinically relevant endpoint for drug approval based on early phase trials of agents with high response rates and should be given further consideration by pharmaceutical sponsors and regulators in this era of precision medicine.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-04 - Reducing Time to Molecular Diagnosis for Advanced NSCLC in the Context of a Reference Testing Center

      16:45 - 18:00  |  Presenting Author(s): Alla'a Ali  |  Author(s): Gurdip Singh Tamber, Sophie Camilleri-Broet, Victor Cohen, Jonathan David Spicer, Hangjun Wang, George Chong, Majed Munazzit, Caroline Rousseau, Warren Sateren, Myriam Fernandez, Goulnar Kasymjanova, Scott Owen, Alan Spatz, Leon Van Kempen, Jason S Agulnik

      • Abstract

      Background

      Testing for mutation of the epidermal growth factor receptor (EGFR) gene is required for treatment of patients with advanced non-small cell lung cancer (NSCLC). First-line treatment with an EGFR tyrosine kinase inhibitor (TKI) in NSCLC patients with an activating EGFR mutation significantly impacts survival. Within the Rossy Cancer Network, the McGill University Health Centre (MUHC) has a supra-regional designation to perform all thoracic surgeries, while the Jewish General Hospital (JGH) is the reference testing center for specialized molecular pathology services. Significant differences in time to TKI therapy were noted between these centers. Our objective was to identify contributing factors to reduce network-wide delays.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We used the JGH molecular pathology database to identify all specimens tested for EGFR between 2015 and 2016 and mapped the process steps from diagnostic procedure to start of TKI therapy. We identified process differences and initiated reflex testing at the MUHC; EGFR testing was ordered reflexively by pathologists for all non-squamous NSCLC biopsies and other specimens from known or suspected advanced stage NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      Implementation of reflex testing led to a 13-day reduction from pathology report to EGFR request (Figure 1, BàC). We subsequently identified that MUHC time from molecular results to start of TKI therapy was twice that of the JGH (24 vs 12 mean days). This was due to an additional step requiring integration of faxed molecular results into the patients’ electronic health record.

      process map for egfr testing.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      We applied lean strategies to reduce time to initiation of targeted therapy. Within our network and in the context of a reference testing center, we identified two critical components that significantly contributed to delays in treatment planning: (i) absence of reflex testing and (ii) unlinked information technology systems. As Quebec moves towards specialized testing centers, it is important to be cognisant of their impact on timely treatment.

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      P2.01-05 - Adenocarcinoma of the Lung: The Woman’s Cancer?

      16:45 - 18:00  |  Presenting Author(s): Noor Asaad Alsaadoun  |  Author(s): Amanda Gibson, Adrijana D’silva, Anifat A. Elegbede, Michelle L Dean, Emeka K Enwere, Shannon Mary Otsuka, Roxana A. Tudor, Gwyn Bebb

      • Abstract

      Background

      We previously observed a significant interaction between sex and age-standardized incidence rates of Non-small cell lung cancer (NSCLC) patients showing higher rates of Adenocarcinoma (ADC) in women, from the systematic review of published studies within the last 20 years. Our analysis showed disparities across gender over time, and the main effect of gender on incidence rates is significant (p= 0.01). This study aimed to replicate observed sex-related disparities in published records using a 15-year retrospective analysis of a local large-scale database of NSCLC patients diagnosed in Southern Alberta, Canada.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We extracted data from the Glans-Look Lung Cancer Database, a comprehensive clinical and demographic database of all lung cancer patients diagnosed in southern Alberta from 1999-2015. We assessed the impacts of gender on NSCLC risks and mortality. Clinical data e.g. smoking history, histology and NSCLC stage were collected and analyzed using chi-square test, and smoking history and tumor stage were stratified for the analysis. The Kaplan-Meier analysis was conducted to compare gender-based post diagnosis survival and disease progression. Statistical significance was 95% confidence level (p < 0.05).

      4c3880bb027f159e801041b1021e88e8 Result

      Among 7738 lung cancer patients, 95.6% (3743/7738) were NSCLC: 52% male and 48% female. Significant gender-based differences were observed in histology (p=0.00). SCC and ADC were the most frequent histology in both genders. However, ADC was commoner in women (49% vs 41%), while SCC was commoner in men (27% vs 17%). Relative changes of ADC rate over 15 years have increased significantly among women compared to men (58% vs 32%, P<0.02). The risk of developing NSCLC was greatly elevated with cigarette consumption in both genders; however, ADC in never smokers was higher in women (18%) compared to men (8%). Among ADC, smoking history and gender both showed a significant effect on survival, where mOS for never-smokers females exceeded that of never-smokers males [20 months vs 14 months, 95%CI, P=0.00]. The same trend was also seen in smokers [13 months vs 7 months, 95%CI, P=0.021]. In addition, the OS among male ADC cases was significantly lower than women of all tumor stages (P=0.00), but these disparities were insignificant across genders with SCC (P=0.46).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Similar to what we observed in our systematic review, gender influences the clinical course of NSCLC regardless of smoking history or stage in Southern Alberta. Identifying the cause of the increase in ADC rate over 15 years in women and higher prevalence of NSCLC in never smoking women warrants aggressive research strategies.

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      P2.01-06 - HSP72 Expression Associates with Survival in EGFR Mutated NSCLC

      16:45 - 18:00  |  Presenting Author(s): Idoroenyi Amanam  |  Author(s): Paul Frankel, Stephanie Mach, Emily Dickinson, Li Zheng, Binghui Shen, Karen L. Reckamp

      • Abstract

      Background

      Heat shock protein 72 (HSP72) was observed to be important for editing DNA replication errors and repairing base damage. EGFR mediates HSP72 Y41 stability via phosphorylation. EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy inhibited phosphorylation of HSP72 leads to its degradation with suppression of polymerase α (Polα) and a resultant increase in overall mutation rate in EGFR mutant lung cancer cells. Our primary objective was to determine if baseline HSP72 expression is a prognostic biomarker for NSCLC patients with EGFR mutant NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort of patients was identified with known EGFR mutation positive NSCLC and available tissue from the City of Hope Comprehensive Cancer Center seen between 2008 and 2016. Immunohistochemical (IHC) analysis was performed to analyze HSP72 levels. A chi-square test for categorical data and multivariate logistic regression analyses was used to study the relation between HSP72 expression and the other clinical and demographic data.

      4c3880bb027f159e801041b1021e88e8 Result

      48 patients with EGFR mutated NSCLC and available tissue were identified. The median age was 64 range (39-84) with 50% Asian (n = 24), Caucasian 38% (n = 18), and African American 8% (n = 4) and other 4% (n = 2). Most patients were Stage IV at initial diagnosis (n = 41, 85%), other were Stage IB (n = 2), Stage IIB (n = 1), Stage IIIA (n = 1) and Stage IIIB (n = 3). HSP72 expression was 0 in 16 patients, 1 in 15 patients, 2 in 9 patients and 3 in 8 patients. Median survival of HSP72 0, 1, 2,3 were 28.3, 42.4, 41.2, and 107.7 months respectively (p < 0.02, log-rank test). In univariate Cox regression analysis, HSP72 expression of 3 compared to others correlated with an HR of 0.23 (95% CI 0.07-0.77). When stratifying by stage (Stage IV vs all others), the HR associated with an HSP72 expression of 3 was 0.22 (95% CI 0.05-0.97), and the signal for HSP72 was also significant when stratifying by stage and considering HSP72 score as either a continuous marker or as the four categories (0,1,2,3). There was no relationship noted in the change in HSP72 values as tumors transformed from T790M- to T790M+, and no relationship related to L858R or exon 19 deletions.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In EGFR mutated NSCLC, high levels of HSP72 expression are associated with improved survival. Further investigations are evaluating mechanisms of increased DNA damage following EGFR TKI therapy and association with the development of resistance.

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      P2.01-07 - Safety and Efficacy of LATTICE Radiotherapy in Voluminous Non-Small Cell Lung Cancer: A Retrospective Study of 10 Patients Over 7 Year Period

      16:45 - 18:00  |  Presenting Author(s): James Melotek  |  Author(s): Beatriz E Amendola, Naipy C Perez, Ian Qureshi, Marco A Amendola, Xiaodong Wu

      • Abstract

      Background

      Lattice radiotherapy (LRT) is a novel technique of delivering heterogeneous doses of radiation for the management of voluminous tumors which are not amenable to surgical resection. Built from the conventional 2-dimensional GRID, LRT utilizes the power of new technology in the field of radiation therapy to implement 3-dimensional dosimetry plans. LRT allows delivery of higher doses of radiation to small spheres, also called vertices, in the interior of the bulky tumors limiting the exposure of surrounding healthy tissue to unacceptably high doses of radiation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ten patients with non-small cell lung cancer (NSCLC): Nine males and 1 female, with ages from 49 to 87 with a median of 70 who presented with bulky, unresectable primary tumors were treated with LRT during a 7-year period. Follow-up ranged from 4 to 73 months with a median of 10 months. All patients received one initial LRT fraction of 18 Gy in the lattice vertices and 3 Gy in the tumor periphery. All patients continued treatment with conventional radiation given in 25 to 33 daily fractions of 1.8 Gy to 2 Gy each. Image guided radiation therapy IGRT with CBCT and Volumetric Arc Therapy technique were used in all patients.

      4c3880bb027f159e801041b1021e88e8 Result

      There was no associated morbidity or mortality to the addition of LRT in these patients. There was a significant decrease in tumor volume from the time of planning CT to the last f treatment imaging.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this early experience, LRT appears to be a safe and effective modality of treatment for bulky NSCLC. LRT should be considered for non-surgical patients presenting with voluminous tumors. It is postulated that this technique induces changes in the tumor microenvironment leading to a more effective tumor control. More research is needed to elucidate the mechanisms by which LRT is effective in the reduction of tumor size.

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      P2.01-08 - Conversion Surgery for Locally Advanced Lung Adenocarcinoma Harboring Driver Gene Mutation After TKI Followed by Cytotoxic Agent

      16:45 - 18:00  |  Presenting Author(s): Masaya Aoki  |  Author(s): Tadashi Umehara, Go Kamimura, Takuya Tokunaga, Toshiyuki Nagata, Aya Harada Takeda, Naoya Yokomakura, Kota Kariatsumari, masakazu Yanagi, Masami Sato

      • Abstract

      Background

      The optimal treatment of locally advanced non-small cell lung cancer including stage IIIA still remains controversial. For lung adenocarcinoma harboring driver gene mutation, it has been reported that tyrosine kinase inhibitor (TKI) shows great tumor response and downstaging. Moreover, some reports showed its usefulness of salvage surgery after TKI treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between January 2016 and April 2017, we performed surgical resection for five non-small cell lung cancer patients who underwent TKI followed by platinum agent and pemetrexed treatment at Kagoshima University Hospital. All patients were diagnosed as having c-stageIIIA (three patients with c-T2aN2M0 and each one patient with c-T4N1M0 and c-T3N2M0) lung adenocarcinoma harboring driver gene mutation (four patients with EGFR mutation and one patient with EML4-ALK rearrangement) by preoperative examinations (Computed Tomography, 18F-fluorodeoxyglucose Positron Emission Tomography, brain Magnetic Resonance Imaging and bronchoscopic examination). Because these patients initially had locally advanced tumor burden or mediastinal lymph nodes metastasis, one-stage radical surgery would not have been feasible. Therefore, these patients received TKI administration for less than six months, followed by two cycles of platinum agent and pemetrexed treatment before the operation. After the operation, three patients received two or four cycles platinum agent and pemetrexed treatment, however, the other two patients did not receive additional treatment. We obtained informed consent from all the patients before the beginning of treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      In all patients, the effect on tumor response of TKI followed by platinum agent and pemetrexed treatment was shown. In addition, the complete resection was confirmed microscopically. None of these patients experienced disease flare after stopping TKI administration. The exon 20 T790M mutation gene was not found in all resected specimens with EGFR mutation. There were no postoperative major complications and mortality. Brain metastasis appeared in one patient who did not receive postoperative chemotherapy six months after the operation. This patient was managed successfully with gamma knife radiotherapy. All the five patients are now under follow-up treatment with no local recurrence.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conversion Surgery after TKI followed by platinum agent and pemetrexed treatment can become feasible and useful strategy for locally advanced lung adenocarcinoma harboring driver gene mutation.

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      P2.01-09 - Targetable Genomic Alterations in KRAS Mutant Lung Adenocarcinoma by Targeted Next Generation Sequencing

      16:45 - 18:00  |  Presenting Author(s): Edurne Arriola  |  Author(s): Sergi Clave, Max Hardy-Werbin, Alvaro Taus, Pedro Rocha, Imane Chaib, Enric Carcereny, Marta Salido, Alba Dalmases, Beatriz Bellosillo

      • Abstract

      Background

      KRAS mutant (m) non-small cell lung cancer (NSCLC) represents 25% of cases. Despite the common mutation, biological and clinical behaviour of this disease is diverse. The aim of our study was to analyze co-occurring genomic alterations in advanced KRASm lung by next-generation sequencing (NGS) and compare them to a KRAS wild-type (WT) population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced lung adenocarcinoma patients treated with a platinum doublet with KRAS mutation by Sanger were submitted to targeted NGS with the Oncomine Solid Tumor kit (DNA) and compared to a KRAS WT population of clinically similar patients. Association with outcome of the genomic alterations was evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      32 KRASm patients and 18 WT patients were analyzed. The most frequent KRAS mutation was p.Gly12Cys (45%), followed by p.Gly12Val (24%). TP53 mutation was observed in 55% of KRASm tumors and 60% of WT cases (Table 1). Mutations in STK11 were found in 10% of cases in the KRAS mutant cohort while none in the WT. 3 out of the 4 cases of STK11 mutations coexisted with TP53 mutations. FGFR3, SMAD4 and DDR2 mutations were more frequently found in cases with KRAS mutations, although at low frequencies. Neither KRAS nor TP53 mutations had an impact in OS. We then selected the KRAS mutant cohort and evaluated the impact of co-mutations. TP53 or STK11 did not significantly affect OS of KRAS mutant patients.

      Table 1. Co-ocurring alterations in KRAS mutant and WT tumors

      Mutations/CNG

      KRAS mutant % (N: 38)

      KRAS WT % (N: 15)

      TP53 mut

      55%*

      60%*

      STK11 mut

      10%**

      0%

      FGFR3 mut

      13%

      6%

      SMAD4 mut

      8%

      0%

      DDR2 mut

      5%

      0%

      MYC mut

      5%

      6%

      KRAS CNG

      8%

      6%

      8eea62084ca7e541d918e823422bd82e Conclusion

      KRASm lung adenocarcinoma is genomically diverse. NGS provides biologically relevant information and druggable targets in this subset of patients.

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      P2.01-10 - Prognostic Impact of Longitudinal Monitoring of Radiomic Features in Patients with Advanced Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): So Hyeon Bak  |  Author(s): Hyunjin Park, Insuk Sohn, Ho Yun Lee, Seung Hak Lee, Myung-Ju Ahn

      • Abstract

      Background

      Tumor growth dynamics varies substantially in non-small cell lung cancer (NSCLC). We aimed to develop novel biomarkers reflecting longitudinal change of radiomic features in NSCLC and evaluate prognostic power of those.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Fifty-three patients with advanced NSCLC included in this retrospective study. Measurable lesions on baseline and follow-up computed tomography (CT) were segmented and 23 radiomic features were extracted. All three variables reflecting patterns of longitudinal change were extracted: the area under the curve (AUC), beta value, and AUC2. We constructed models for predicting survival using multivariate cox regression, and identified the performance of these models.

      4c3880bb027f159e801041b1021e88e8 Result

      In volume, AUC2 showed an excellent correlation with pattern of longitudinal volume change (r = 0.848, p < 0.000), and showed a significant difference in overall survival time (p = 0.035). In multivariate regression analysis, kurtosis of positive pixel values (p < 0.000), and surface area (p = 0.001) on baseline CT, and AUC2 of density (p < 0.000), skewness of positive pixel values (p = 0.003), and entropy at inner (p = 0.001) were found to be associated with overall survival time, and the area under the receiver operating characteristics curves were 0.922, and 0.771 at 1 year, and 3 years of follow-up.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Longitudinal change of radiomic tumor features would be prognostic biomarkers in patients with advanced NSCLC.

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      P2.01-11 - Characteristics of Non-Small Cell Lung Cancer: Differences by Sex and Hormonal Status in a Hispanic Population

      16:45 - 18:00  |  Presenting Author(s): Feliciano Barron  |  Author(s): Vianey Rodriguez-Lara, Laura-Alejandra Ramírez-Tirado, Diana Flores, Zyanya Lucia Zatarain-Barrón, Oscar Arrieta

      • Abstract

      Background

      Non-small Cell Lung Cancer (NSCLC) appears to be a different disease between women and men. Clinical features and lung cancer behavior by sex and particularly by hormonal status has been poorly approached. We describe the differences in NSCLC by sex and by hormonal status among women in a Hispanic population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective study among NSCLC patients from the National Cancer Institute of Mexico. We assessed clinic-pathological (tobacco, wood smoke and asbestos exposure, histology, disease stage, ECOG, Body Index Mass, Metastases sites) and molecular characteristics (EGFR and KRAS mutation profile). Overall survival (OS) according to sex and hormonal status were estimated using the Kaplan-Meier method and compared using the Log-rank test. Multivariate cox-proportional analysis was performed adjusting for clinical and statistically relevant features.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 1,104 patients 52.7% were men and 47.3% were women. Compared to men, women were more likely to be non-smokers (68% vs. 23%, p<0.001), reported higher frequencies of wood-smoke exposure (50% vs 28.2%, p<0.001), and of EGFR-sensitizing mutations (38.8% vs 18.7%, p<0.001), had a better ECOG performance (<2) (76.2% vs 69.9%, p=0.020) and showed a higher frequency of BMI ³25 (48.4% vs 41.5% p=0.003). Likewise, women, showed better OS (p=0.021) compared to men as well as overweight patients (vs. normal or obese patients) (p=0.045), non-smokers (p=0.002) and patients with lower ECOG status (p=0.006). Differences were found also when considering hormonal status. Postmenopausal women showed higher wood-smoke exposure (52.5% vs 41.7%, p=0.037) and wood-smoke exposure index (113.2% vs 50.6%, p=0.006) as well as tobacco smoking exposure index (19.8 vs 10.2, p=0.017) compared to premenopausal younger women who exhibited higher frequencies of exposure to asbestos (16.7% vs 7.0%, p=0.001) compared to postmenopausal. OS was better in postmenopausal women compared to premenopausal (31.1 vs 19.4 months, p=0.046). No differences were found between premenopausal and postmenopausal women stratified by EGFR mutation status regarding their clinic-pathological and molecular characteristics, neither in the OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results support the differences in lung cancer presentation by sex and also by hormonal status. It is important to highlight that wood-smoke exposure and tobacco consumption were associated with hormonal status. Furthermore, premenopausal women (which showed a younger age at diagnosis) showed a worse OS regardless of other molecular features (e.g. EGFR, KRAS) which highlights the need of investigating in detail hormonal profiles when considering the clinical approach of NSCLC diagnosis and treatment.

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      P2.01-12 - Ramucirumab+Docetaxel Usage Following Rapid Disease Progression in Real World Advanced Non-Small Cell Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Marta Batus  |  Author(s): Cliff Molife, Jeffrey Melson Clarke, Victoria Jennifer Stefaniak, Katherine B Winfree, Zhanglin L Cui, Yimei Han, Mahesh K Tawney, Philip Bonomi

      • Abstract

      Background

      In the Phase III REVEL study, the overall treatment effect of ramucirumab+docetaxel (ram+doc) in patients with rapid disease progression (RDP), defined as disease progression ≤ 12 weeks after start of prior platinum-based chemotherapy, was consistent with that observed in the intent-to-treat population. This real-world, retrospective study described baseline characteristics, treatment patterns, and clinical outcomes among RDP patients subsequently treated with ram+doc in the United States.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced non-small cell lung cancer (aNSCLC) patients receiving ram+doc as 2nd line or 3rd line therapy between March 2015 - May 2017 after platinum-based chemotherapy, with ≥ 3 months of potential follow-up, were identified in the Flatiron Health EHR-derived database. Analyses were conducted for RDP and non-RDP patients. Overall survival (OS) was measured from start of 1st line therapy. Real-world progression-free survival (rwPFS) and time-to-progression (rwTTP) were measured from start of ram+doc. OS, rwPFS, and rwTTP were estimated using Kaplan-Meier method.

      4c3880bb027f159e801041b1021e88e8 Result

      Baseline characteristics were generally similar across RDP (n=49) and non-RDP (n=123) patients with respect to age, gender, and race. Non-RDP patients more often had stage IV disease at diagnosis and non-squamous histology. Among patients with ECOG performance status (PS) reported (n=101, 58.7%), a higher proportion of RDP patients had ECOG PS > 2 (18.4%) than non-RDP patients (9.8%). The majority of patients received ram+doc as 3rd line therapy and the median duration of ram+doc treatment was similar for RDP and non-RDP patients. The most frequently administered chemotherapy regimen prior to ram+doc was carboplatin+pemetrexed for RDP patients and carboplatin+pemetrexed+bevacizumab for non-RDP patients.

      RDP was associated with shorter median OS (13.2 [95% CI: 10.3 - 15.8] vs. 21.6 [95% CI: 17.1-24.1] months, log-rank P < 0.01) whereas median rwPFS (3.0 [1.8 - 4.1] vs. 3.6 [2.9 - 4.1] months, log-rank P = 0.74) and median rwTTP (4.6 [95% CI: 3.5 - 7.9] vs. 5.5 [95% CI: 4.1 - 7.4] months, log-rank P = 0.81) on ram+doc were similar between the RDP vs. non-RDP groups, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      While this real-world cohort shows that RDP correlates with poorer OS, similar rwPFS and rwTTP were observed with ram+doc among aNSCLC patients with RDP vs. non-RDP. This study did not assess the effects of ram+doc vs. other subsequent treatments in patients with RDP. Further research is needed to identify RDP risk factors and to aid in development of optimal treatments for aNSCLC patients with the most aggressive disease.

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      P2.01-13 - Number, Rather Than Location of Metastases, Dictates Outcome in Stage IV, M1b, Non-Small Cell Lung Cancer  

      16:45 - 18:00  |  Presenting Author(s): Amanda Jane Williams Gibson  |  Author(s): Haocheng Li, Adrijana D'Silva, Roxana A. Tudor, Anifat A. Elegbede, Shannon Mary Otsuka, Gwyn Bebb, Winson Y Cheung

      • Abstract

      Background

      To assess the impact of location versus number of extra-pulmonary metastatic sites (EPMS) on survival in stage IV non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A large scale, multi-year retrospective analysis was conducted on patients with a new diagnosis of stage IV, M1b (AJCC 7th edition) NSCLC between 1999-2013. Demographic, clinical, histopathological, treatment and outcome data was extracted from the Canadian institutional Glans-Look Lung Cancer Database. We assessed the impact of location and number of EPMS and identified correlates of overall survival using the Kaplan-Meier method and Cox regression.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 2,065 NSCLC patients with EPMS were identified. Median age was 67 (IQR 58-75) years, 52% were male, and 78% reported a history of smoking. 60% had one EPMS, and 40% had two or more EPMS. Among those with only one EMPS, most frequent organ involvement included bone (40%), brain (32%), liver (13%) and adrenal (10%). Median overall survival (mOS) was worst in those with liver metastasis and best in those with adrenal metastasis (2.0 vs. 5.2 months, p=0.015). However, outcomes based on organ site involvement did not retain prognostic significance in multivariable analysis after controlling for other measured confounders. Compared to patients with one EPMS, individuals with ≥ 2 EPMS experienced worse outcomes (mOS 3.9 vs 2.9 months, p<0.001), and were associated with worse prognosis in Cox regression analysis (HR 1.5, 95%CI 1.3-1.7, p<0.001). A statistically and clinically significant inverse relationship persisted between increasing number of EMPS sites and mOS. Those patients who received systemic anti-cancer therapy or surgical resection of metastatic disease (received by 25% and 3% of total cohort respectively) demonstrated the most improved mOS, regardless of number or location of EMPS (10.0 vs 2.0 months, p<0.001, and 9.0 vs 3.0 months, p<0.001, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We conclude that number, rather than location of EPMS is a prognostic factor in patients with stage IV M1b NSCLC. A simple count of metastatic sites at diagnosis may be of clinical value in in the management and advanced care planning for patients with metastatic NSCLC. Of note, this could assist in identification of patients who would benefit from either more aggressive treatment or best supportive care, and may be an important consideration in future clinical trial design. Overall, this study reinforces the need to advance efforts to determine and mitigate the factors predisposing patients to develop metastatic disease, and develop initiatives to reduce the number of patients presenting with advanced disease.

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      P2.01-14 - Preferred and Achieved Goals of Patients with Metastatic Lung Cancer and Their Oncologists in End-of-Life Therapy

      16:45 - 18:00  |  Presenting Author(s): Annemarie Becker  |  Author(s): Adinda Mieras, Roeline Pasman, Bregje Onwuteaka-Philipsen

      • Abstract

      Background

      Systemic therapy with chemotherapy, immunotherapy or targeted therapy are possible treatments for patients with metastatic lung cancer (stage IV NSCLC). This palliative treatment might prolong survival and reduce symptoms but frequently causes side-effects which may decrease their quality of life (QOL). Little is known about patients’ and oncologists’ goals before starting a new therapy. Therefore, we studied the goals patients and their oncologists have before starting a new treatment for stage IV NSCLC and to what extent these goals are achieved.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with stage IV NSCLC were prospectively studied in three hospitals between November 2016 and April 2018. At the start of systemic therapy patients and their oncologists were asked to complete a questionnaire about their treatment goals. These open questions were coded by the investigators. After treatment patients and oncologists were asked to what extent the goals they mentioned before were achieved. The data collection has not been finished yet. Now we report the preliminary results of 240 patients and their oncologists on predefined goals and of 90 patients (whose treatment was finished) and oncologists on achieved goals.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients and oncologists most often mentioned improvement in QOL (49%;74%), a decrease in tumor size (44%;68%) and life prolongation (43%;50%) as treatment goals. 19% of the patients mentioned cure as a treatment goal. According to patients life prolongation and improvement in QOL were achieved in 56% and 51% respectively. According to oncologists this was only 35% and 32% respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients and oncologists mention improvement in QOL, decrease in tumor growth and life prolongation most often as treatment goals. It can be questioned whether the 19% of the patients who mentioned cure as a treatment goal think this is a realistic goal or that it is more a sign of hope. After treatment, patients were more optimistic about the treatment effects than their oncologists.

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      P2.01-15 - A Radiologist-Led Training Workshop for MR Based Normal Tissue and Tumour Delineation for Lung Cancer Radiotherapy.

      16:45 - 18:00  |  Presenting Author(s): Sean Brown  |  Author(s): Michael Dubec, Hannah Bainbridge, David Catharina Petrus Cobben, Ferry Lalezari, Fiona McDonald, Hamid Sheikh, Corine Van Es, Marcel Van Herk, Corinne Faivre-Finn

      • Abstract

      Background

      A potential benefit of MR-image guided radiotherapy (MRIgRT) in lung cancer is the reduction of treatment related uncertainties through improved soft tissue contrast. However, this benefit may be obscured by inter-observer variation in gross tumour volume (GTV) and organ at risk (OAR) contouring. A radiologist led workshop was organised to provide training in such contouring on MR.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Planning CT, PET-CT and MRI were acquired in four lung cancer patients. MR sequences included 3D radial gradient echo, T2 DIXON Turbo Spin Echo (TSE), and T2 TSE with and without fat-sat. Data sets were local rigidly registered and imported into the so-called “Big Brother” contouring software.

      The radiologist led teaching on OAR and GTV contouring used an MR lung atlas (produced by this group). Seven radiation oncologists contoured the brachial plexus (BP), heart, proximal bronchial tree, oesophagus and GTV. This was followed by a multi-disciplinary group discussion (oncologists, radiologists and physicists) on the contouring challenges and subsequently contours were reviewed and the atlas adjusted.

      4c3880bb027f159e801041b1021e88e8 Result

      The BP and heart were the most difficult OARs to contour and showed the largest inter-observer variation. Following contour review and discussion between radiologist and oncologists updates to atlas and protocols were made. The GTV was found to be most challenging at the soft tissue interfaces and requires further work (Figure 1).

      contours.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      This early work demonstrates the need for radiologist-led training in OAR and GTV contouring in lung cancer patients using MR images. This will be especially important for the integration of MR into treatment planning and an MRIgRT adaptive workflow. We have arranged future workshops in order to provide further training and to assess inter-observer variation in OAR and GTV contouring using MR on more cases.

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      P2.01-16 - Dynamic ctDNA Monitoring Revealed Novel Resistance Mechanisms and Response Predictors of Osimertinib Treatment in East Asian NSCLC Patients

      16:45 - 18:00  |  Presenting Author(s): Jianhua Chang  |  Author(s): Zhihuang Hu, Dongmei Ji, Shannon Chuai, Weina Shen, Junning Cao, Jialei Wang, Xianghua Wu

      • Abstract

      Background

      Advanced NSCLC patients, harboring EGFR T790M, exhibit marked diversity in tumor behavior and response to AZD9291, yet a discriminable molecular profile remains elusive. In addition, although EGFRC797S was involved in 30% of AZD9291 resistance cases in Western patients, mechanisms for the rest patients remain unclear, especially for the East Asian population. We utilized circulating tumor DNA (ctDNA) profiling to conduct dynamic monitoring in patients undergoing AZD9291, thus characterizing mutational heterogeneity and genomic evolution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Longitudinal plasma samples were collected before, during and post of the AZD9291 treatment in Chinese NSCLC patients with acquired T790M mutation. A ctDNA panel, spanning 160KB of human genome, was used to perform capture-based targeted sequencing that comprises critical exons and introns of 168 genes. The EGFR mutation abundance and dynamic changes of allele fraction (AF) were analyzed with progression-free survival (PFS) after AZD9291 treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 61 samples were collected longitudinally from 14 patients, of which 9 have experienced progressive disease (PD). Six patients exhibited a rebound of ctDNA prior to radiographic PD, suggesting the potential of ctDNA in early detection of PD. Several acquired mutations were detected with the AZD9291 resistance, including newly identified EGFR G796S, L792H/F/R/V, V802F, V843I mutations, expect for the previously reported RB1 and EGFR C797S, L718Q mutations. Patients with a higher ratio of T790M and EGFRactivating mutation at baseline had a significantly longer PFS (9.6m vs 4.5m, p=0.008). A lower ratio of EGFRactivating mutation AF compared to baseline at first follow-up was significantly correlated with a longer PFS (8.5m vs 5.0m, p=0.027). Furthermore, patients harboring other known driver mutations in addition to T790M at baseline had an inferior PFS (4.9m vs 7.8m, P=0.039).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Several novel resistance mechanisms were identified by ctDNA monitoring in the East Asian patients treated with AZD9291. Relative AF of T790M, changes of AF after treatment and the presence of concurrent driver mutations at baseline could predict clinical benefit of AZD9291 treatment.

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      P2.01-17 - MALAT1-Mir-101-SOX9 Feedback Loop Modulates the Chemo-Resistance of Lung Cancer Cell to DDP via Wnt Signaling Pathway

      16:45 - 18:00  |  Presenting Author(s): Wei Chen

      • Abstract

      Background

      Cisplatin (DDP)-based chemotherapy is a standard strategy for lung cancer, while chemo-resistance remains a major therapeutic challenge. Recent evidence highlights the crucial regulatory roles of long non-coding RNAs (lncRNA) in tumor biology. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has important roles in regulating the proliferation, invasion and migration of lung cancer cell.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      1. Tissue samples, cell lines and reagents

      2. RNA extraction and SYBR green quantitative PCR analysis

      3. MTT assay and BrdU incorporation assay

      4. Western blot analysis

      5. RNA immunoprecipitation

      6. Chromatin immunoprecipitation (ChIP)

      7. Luciferase reporter assay

      8. Statistical analysis

      4c3880bb027f159e801041b1021e88e8 Result

      High MALAT1 expression in lung cancer was related to poorer clinicopathologic features in this study. MALAT1 knockdown alone was sufficient to amplify DDP-induced repression of cell viability. MALAT1 knockdown could also sensitized DDP-resistant lung cancer cells (A549/DDP and H1299/DDP) to DDP. Further assays indicated that MALAT1 acted as a competing endogenous RNA to upregulate SOX9 expression by sponging miR-101 in DDP-resistant cancer cells, through Wnt signaling pathway. Moreover, SOX9 could bind to the promoter of MALAT1 to activate its transcription.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Taken together, MALAT1, miR-101 and SOX9 form a feedback loop to enhance the chemo-resistance of lung cancer cell to DDP; this MALAT1-miR-101-SOX9 feedback loop plays an important role in the chemo-resistance of lung cancer cell to DDP and may serve as a potential target for cancer treatment.

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      P2.01-18 - Differential Molecular Mechanisms Associated with Dramatic and Gradual Progression in NSCLC Patients with Intrathoracic Dissemination

      16:45 - 18:00  |  Presenting Author(s): Ying Chen  |  Author(s): Bao Hua, Wei Li, Chao Zhang, Wen-Fang Tang, Ao Wang, Xue Wu, Jing-Hua Chen, Jian Su, Yang W. Shao, Yi-Long Wu, Wen-Zhao Zhong

      • Abstract

      Background

      Lung cancer is a highly heterogeneous disease with diverse clinical outcomes. The pleural cavity is a frequent metastasis site of proximal lung cancer. Better understanding of its underlining molecular mechanisms associated with dramatic and gradual progression of pleural metastasis in patients with non-small cell lung cancer (NSCLC) is essential for prognosis, intervention and new therapy development.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed whole-exome sequencing (WES) of matched primary lung adenocarcinoma and pleural metastatic tumors from 26 lung cancer patients with dramatic progression (DP, n=13) or gradual progression (GP, n=13). Somatic alterations at both genome-wide level and gene level were detected. Kaplan-Meier survival analysis and multivariate Cox regression models were applied to analyze the association between different somatic alterations and clinical parameters.

      4c3880bb027f159e801041b1021e88e8 Result

      We first analyzed the differences in somatic alterations between AP and RP group in the primary tumors, and identified higher somatic copy number alteration (SCNA) level in DP group compared to GP group, which is significantly (p=0.016) associated with poorer progression-free survival (PFS). More specifically, patients with chromosome 18q loss in the primary tumor showed a trend (p=0.107) towards poorer PFS. PTEN (p=0.002) and GNAS (p=0.002) mutations are enriched in the primary tumors of DP group, and are associated with poorer PFS. Furthermore, pleural metastatic tumors harbor a relatively higher level of mutation burden (p=0.105) and significantly increased SCNA (p=0.035) compared to the primary tumors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC patients in the attenuated progression group have more stable genomes. High level of genomic instability, GNAS and PTEN mutations, as well as chromosome 18q loss are associated with rapid progression.
      scna&survival.jpg

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      P2.01-19 - Radiomics Features of Contrast Enhanced CT as Prognostic Factors in Resectable Adenocarcinoma of Lung

      16:45 - 18:00  |  Presenting Author(s): Jooae Choe  |  Author(s): Sang Min Lee, Joon Beom Seo, Se Hoon Choi

      • Abstract

      Background

      To identify radiomics features as prognostic factors in patients with adenocarcinoma of lung and assess its incremental value to the traditional staging system and clinical-pathologic risk factors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Total 1085 patients who underwent surgery for lung adenocarcinoma were enrolled in this study (from March 2010 to December 2014, training cohort: n = 749; from January 2015 to February 2016, temporal validation cohort: n = 336). A subset of 80/94 reproducible radiomics features including shape, first order statistics and texture features were identified reproducible and selected for analysis. A radiomics signature to predict (overall survival, OS and recurrence free survival, RFS) was generated by using the least absolute shrinkage and selection operator, or LASSO in training cohort. Association between the radiomics signature and prognosis was explored. Prognostic models incorporating radiomics signature alone and combined clinical-pathologic risk factors including staging system, age, sex, smoking status and adenocarcinoma subtype were tested in the temporal validation cohort.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: The radiomics signatures (constructed from 5 features identified from LASSO) were significantly associated with OS and RFS. Compared with traditional staging, the radiomics signature resulted in better performance for the estimation of OS (C-index for radiomic signature vs TNM staging = 0.726 vs 0.689 in training set, 0.798 vs 0.766 in validation set) and RFS (0.760 vs 0.722 in training set, 0.773 vs 0.751 in validation set) in both training and validation cohorts. The combined model of radiomic signature and clinical-pathologic risk factors showed a significant improvement of predictive performance over the TNM staging system in both training and validation cohorts (OS, C-index = 0.774 in training set and 0.857 in validation set; RFS, C-index = 0.796 in training set and 0.837 in validation set; for all, p < 0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Contrast enhanced CT-based radiomics provided improved prognostic prediction in resectable lung adenocarcinoma, which might enable a step forward precision medicine and affect personalized postoperative treatment strategies.

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      P2.01-20 - FLT-PET for Detection of Relapse Following Radiotherapy for Lung Cancer. Preliminary Results

      16:45 - 18:00  |  Presenting Author(s): Tine Nøhr Christensen  |  Author(s): Seppo W Langer, Klaus Richter Larsen, Gitte Fredberg Persson, Annemarie G Amtoft, Helle Hjorth Johannesen, Sune Høgild Keller, Andreas Kjaer, Barbara Malene Fischer

      • Abstract

      Background

      Differentiation of relapse from radiation induced changes of the normal lung tissue following radiotherapy for lung cancer is challenging. CT and 18F-fluorodeoxyglucose (FDG) PET/CT has low specificity due to radiation induced changes; and invasive procedures might be unfeasible due to small size, difficult location, or poor lung function. 18F-fluorothymidine (FLT) is a PET tracer that correlates with proliferation. FLT-PET is more specific than FDG-PET and does not accumulate in inflammatory tissue. The aim of this study is to investigate if FLT-PET is a key to better diagnosis of relapse in this difficult situation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients who had received definitive radiotherapy for lung cancer and who were suspected for having a relapse were included in this prospective clinical study. Patients underwent FDG-PET/CT and FLT-PET/low dose CT within 3 weeks.

      PET scans were evaluated visually on a 5-level scale, and the worst graded lung lesion in each patient was selected for semi-quantitative measurements. Reference standard was a retrospective expert analysis based on histology, subsequent imaging, conference decisions, and treatment within 6 months after inclusion. Descriptive statistics and diagnostic accuracy tests were conducted.

      4c3880bb027f159e801041b1021e88e8 Result

      We present the results from the first 18 patients. All patients had been treated with definitive radiotherapy (66 Gy in 24 or 33 fractions), and 17 patients had concomitant or sequential chemotherapy. FLT-PET was performed 34-541 days after radiotherapy.

      7 patients had no evidence of relapse during the follow up period. 11 patients were diagnosed with relapse based on positive biopsy (3), further progression on CT within 6 months (4), further metabolic progression on FDG-PET/CT and cytology suspicious for malignancy (1), progression on the initial FDG-PET/CT and treatment with response (1), or disseminated disease/bone metastases (2).

      Maximum standardized uptake value (SUVmax) of FDG and FLT were higher in the lesions with relapse. Mean FDG SUVmax in lesions with relapse vs benign lesions was 13.7 vs 4.9 (range: 4.0-18.0 vs 3.3-6.7). Mean FLT SUVmax in lesions with relapse vs benign lesions was 4.1 vs 2.7 (range: 1.8-6.3 vs 1.7-3.3).

      Sensitivity; specificity; positive predictive value (PPV); and negative predictive value of FDG-PET/CT vs FLT-PET were100%;57%;85%;100% vs 73%;100%;100%;78%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      With a PPV of 100% FLT-PET is a promising non-invasive tool for diagnosing relapse after radiotherapy with the potential to obviate invasive procedures in some patients. Further validation is needed.

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      P2.01-21 - Antigen Cascade Triggering Correlates with Prolonged Survival in Advanced NSCLC Patients Undergone PD-1 Blockade with Nivolumab.

      16:45 - 18:00  |  Presenting Author(s): PIERPAOLO Correale  |  Author(s): Rocco Giannicola, Graziella D'Arrigo, Pierpaolo Pastina, Valerio Nardone, Cirino Botta, Vito Barbieri, Giovanni Tripepi, Marika Monoriti, Luigi Pirtoli, Rita Saladino, Antonia Falzea, Pierosandro Tagliaferri

      • Abstract

      Background

      Programmed-cell-death receptor-1 (PD-1) blockade by Nivolumab mAb is a promising treatment for metastatic (m) NSCLC patients, which may yield dramatic improvement in benefit and survival. It acts by rescuing the antitumor activity of PD-1-inactivated tumor-infiltrating-lymphocytes, residual of a pre-existing immune-reaction naturally occurring or consequential to prior radio/chemo-therapy. T-cell rescue is indispensable for the immediate response to the treatment, however, in order to obtain a prolonged effect on patients’ survival continuous immune-priming able to supply fresh immune-effectors with antitumor activity, appears to be indispensable. We have thus investigated, whether Nivolumab treatment is also able to promote antigen cascade and cross-priming measured as occurrence of auto-antibody and auto-immunity and whether these effects are predictive of positive outcome in mNSCLC patients

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a multi-institutional retrospective study including ninety-eight mNSCLC patients who received Nivolumab therapy (3mg/kg every 15 days) between September 2015 and March 2018. These patients had received at least a previous line of platinum-based doublet +/- bevacizumab. Log-rank test and Mantel-Cox analysis were carried-out to correlate patients’ PFS and OS with different parameters including baseline and post-treatment levels of inflammatory markers (CPR, ESR, LDH); ANA, ENA, ASMA auto-antibodies (AAbs); hormone-profiling; Th1, Th2, Th17 cytokines; regulatory-T-cells, different CTL subsets, and natural killers.

      4c3880bb027f159e801041b1021e88e8 Result

      We recorded a PFS and OS of 12.5 [95%CI:9.9-15.0] and 15.3 [95%CI:12.8-17.9] months, respectively, not correlated to histology, number of previous chemotherapy lines, radiotherapy, or TKI use. A better outcome was found in males (OS, HR=2.3, 95%CI: 1.1-4.8, P=0.028), in those who presented autoimmunity signs (PFS: 17.2 vs. 6.7 months; HR=0.30, 95% CI: 0.15-0.57, p<0.001; OS:20.8 vs. 9.7 days; HR=0.24, 95% CI: 0.11-0.50, p<0.001) and those who showed early rise (within thirty days) of one (score 1, HR=0.235, 95% CI: 0.084-0.654. P=0.018) or more AAbs (score 2 HR= 0.22, 95% CI: 0.081-0.624, P= 0.001). Finally, Cox analysis revealed a predictive role for treatment-related early increase in eosinophil cell counts (OS, HR: 0.68, 95% CI: 0.57-0.81, P=0.031).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Antigen cascade triggering measured as early occurrence of ANA ENA, ASMA AABs and subsequently, self-limiting autoimmunity is strongly predictive of longer survival in mNSCLC patients receiving treatment with Nivolumab. Additionally, the occurrence of AAbs strongly supports the occurrence of Nivolumab- dependent antigen cascade and cross-priming. These results offers a strong rationale to design future perspective trials in NSCLC patients.

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      P2.01-22 - Increased Incidence, Morbidity and Mortality Rates for Lung Cancer in Women in Brazil Between 2000 and 2014

      16:45 - 18:00  |  Presenting Author(s): Guilherme Jorge Costa  |  Author(s): Maria Júlia Gonçalves De Mello, Carlos Gil Ferreira, Anke Bergmann, Luiz Claudio Santos Thuler

      • Abstract

      Background

      Introduction: Lung cancer is the principal cause of death from cancer worldwide. However, little is known of its epidemiological and histological profile and of the incidence and mortality rates in Brazil according to sex. Objectives: To evaluate the incidence, morbidity and mortality rates of lung cancer in Brazil from 2000 to 2014, as well as the epidemiological and histological profile of the disease.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: An analytical, cross-sectional study was conducted using three types of sources of secondary data: population-based cancer registries, hospital-based cancer registries and the national mortality database.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: The incidence rate in women increased from 7.92/100,000 in 2000 to 9.12/100,000 in 2012, while mortality increased from 6.02/100,000 in 2000 to 8.29/100,000 in 2014. In men, the incidence decreased from 23.40/100,000 in 2000 to 18.47/100,000 in 2012 and mortality also fell from 16.12/100,000 to 15.11/100,000 in 2014. There was a reduction in the male-to-female ratio from 2.54 in 2000 to 1.46 in 2014. Women tended to be younger (p<0.001), black (p<0.001), non-smokers (p<0.001), to have adenocarcinoma or small-cell lung cancer (p<0.001), and to have metastatic disease (p<0.001). In addition, the time between diagnosis and the start of cancer treatment was longer in women (p<0.001). In relation to treatment, women were more likely to have undergone chemotherapy, surgery or surgery in combination with chemotherapy (p<0.001) and to have response to the initial treatment (p<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      An increase was found in the incidence and mortality rates of lung cancer in women in Brazil.

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      P2.01-23 - Baseline Plasma Biomarkers Predict Long-Term Responses to ALK-TKIs in ALK+ Advanced Non-Small Cell Lung Cancer (NSCLC)

      16:45 - 18:00  |  Presenting Author(s): Mathilde Couetoux Du Tertre  |  Author(s): Maud Marques, Luisa Izzi, Lise Tremblay, Nicole Bouchard, Rasvan Diaconescu, Normand Blais, Cyrla Hoffert, Archana Srivastava, Suzan McNamara, Gerald Batist, Victor Cohen, Jason S Agulnik

      • Abstract

      Background

      Median progression free survival (PFS) for ALK tyrosine kinase inhibitors (ALK-TKIs) range from 10.9-25.7 months (mos)[1],[2],[3],[4]. While most ALK+ NSCLC patients develop resistance to ALK-TKIs within 1-2 years, a subset of patients experience a response >2 years. Given the lack of proteogenomic markers predicting long-term responses to ALK-TKIs, we conducted whole-exome sequencing (WES) and proteomic profiling to define molecular determinants that could predict a long-term ALK-TKI response, help guide the sequentiality of therapies and optimize treatment strategies.

      [1]Soria, J.C. et al. Lancet389,917–929 (2017)

      [2]Peters, S. et al. N. Engl. J. Med.377, 829-838(2017)

      [3]Kim, D.-W. et al.J. Clin. Oncol.35,2490–2498 (2017)

      [4]Solomon, B. J. et al.N. Engl. J. Med.371,2167–2177 (2014).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Twenty-four patients with advanced ALK+ NSCLC were enrolled in our study. WES was performed on primary and post-treatment metastatic tissue to identify genomic aberrations and ALK fusions. MRM-MS was used to analyze 327 protein candidates in plasma collected from patients at baseline.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were categorized into 3 groups based on duration of response: long-term responders [LR; PFS ≥24 mos (n=8)], normal responders [R; 3 < PFS < 24 mos (n=10)] and non-responders [NR;PFS <3 mos (n=6)]. At data cutoff (30 April 2018), median PFS was 1.6 mos for NR, 11.7 mos for R and 37.1 mos for LR. Two LR remain on treatment and have experienced a PFS > 37.4 mos. Despite detecting novel ALK fusion partners, multiple somatic mutations and copy number aberrations by WES, we could not define a genomic signature predictive of a long-term response to ALK-TKIs from our small cohort. However, MRM-MS identified 15 proteins differentially regulated between LR and NR, including SODE, F13A, LYAM1, FCGBP, PGBM and LUM. Differences in protein levels were further pronounced between LR and NR. To determine whether our protein signature can discriminate according to response groups, we performed principal component and hierarchical clustering analyses. Both analyses successfully segregated LR from R and NR. Moreover, we used our set of 15 proteins to generate single-sample Gene Set Enrichment Analysis scores which distinguished LR from R and NR as distinct groups.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Targeted proteomic profiling of baseline plasma from ALK+ NSCLC patients identified a protein signature that may predict a long-term response or resistance to ALK-TKIs. A collaboration is in development to confirm the validity of this protein signature in a larger cohort, and with next-generation ALK-TKIs.

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      P2.01-24 - MLPH Activates CDC42/PAK1 Signaling to Promote Epithelial–Mesenchymal Transition via TGF-β in Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Chunhua Wei, Ling Peng, Fan Tong, Chunjin Xiong

      • Abstract

      Background

      Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). Therefore, a better understanding of molecularmechanisms underlying NSCLC development and progression could provide helpful insights for NSCLC prevention and effective treatment. Melanophilin (MLPH) is a protein coding gene encoding a member of the exophilin subfamily of Rab effector proteins. Recently, MLPH was reported to be associated with cancers, however, to date, the role of MLPH in lung cancer has never been studied.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RNA-Sequencing was performed to identify differentially expressed genes- MLPH in lung tissues of NSCLC patients with and without BM, then the expression of MLPH was further examined in the serum of BM+ and BM- patients. To study the role of MLPH in the initiation and progression of NSCLC, we examined MLPH levels in NSCLC cells and tissues and analyzed the relationship between MLPH levels and patient survival. Then we knocked down MLPH in NSCLC cells. We used cell counting kit-8 assay, wound healing assay, transwell assay, flow cytometry analysis, Phalloidin staining, xenografted tumor model and brain metastasis model to determine the effects of MLPH on the proliferation, migration, invasion, EMT, tumorigenesis and brain metastasis of NSCLC. Western blot analysis was used to explore the underlying mechanism.

      4c3880bb027f159e801041b1021e88e8 Result

      In this study, we found that MLPH was up-regulated in NSCLC tissues and cells. Patients with high levels of MLPH expression had significantly shorter survival than those with low MLPH expression. In NSCLC cell lines, shRNA-mediated depletion of MLPH inhibited the proliferation, lead to apoptosis, induced G0/G1 arrest and suppressed cell migration, invasion, EMT, tumorigenesis and brain metastasis. Mechanistically, we identified TGF-β as a key downstream effector of MLPH. More importantly, MLPH silencing attenuated CDC42/PAK1 signaling activation at least in part through the downregulation of TGF-β.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Together, our findings demonstrated that MLPH positively modulated the CDC42/PAK1 signaling pathway via TGF-β to promote EMT and metastasis, suggesting MLPH as a potential oncogenic biomarker and a promising therapeutic target in the treatment of NSCLC and brain metastasis.

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      P2.01-25 - MicroRNA-330-3p Promotes Brain Metastasis of Non-Small Cell Lung Cancer by Activating MAPK/MEK/ERK Signaling Through GRIA3

      16:45 - 18:00  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Chunhua Wei, Qian Cai, Xican Gao, Fan Tong

      • Abstract

      Background

      Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with NSCLC. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. MicroRNAs (miRNAs) play an essential role in the development of NSCLC. We investigated miRNAs that serve as biomarkers to differentiate NSCLC patients with and without BM, and explored the underlying mechanism.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Logistic regression was conducted in 122 NSCLC patients (60 without BM, 62 with BM) to examine the association between miRNAs and BM. Stable over-expression and knock-down of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay.

      4c3880bb027f159e801041b1021e88e8 Result

      High serum miR-330-3p was an independent risk for BM. Tissue miR-330-3p was also higher in subjects with BM (P=0.003). Migration and invasiveness were increased by over-expressing miR-330-3p using a lentivirus, and decreased by miR-330-3p knockdown in both cell lines. In nude mice receiving NSCLC cells, either subcutaneously or into the brain, tumor growth was faster in mice receiving cells permanently expressing exogenous miR-330-3p, and slower in cells expressing the anti-miR-330-3p sequence. Bioinformatics analysis, followed by microarray analysis of A549 cells over-expressing miR-330-3p and luciferase reporter assay suggested the glutamate receptor GRIA3 as a target of miR-330-3p. Experiments using selective kinase inhibitors suggested that GRIA3 is regulated by miR-330-3p via MAPK/MEK/ERK signaling pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      miR-330-3p promotes NSCLC brain metastasis possibly in part via the MAPK/MEK/ERK pathway and GRIA3, and might be a potential target for the further research of NSCLC brain metastasis.

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      P2.01-26 - Association of Base Excision Repair Gene Polymorphisms with Response to Chemotherapy of Advanced Non Small-Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Xu Wang  |  Author(s): Jie Dong, Jiuwei Cui

      • Abstract

      Background

      Base excision repair (BER) plays an important role in the maintenance of genome integrity and anti-cancer drug resistance. This study aims to explore the role of BER genes polymorphisms in response to chemotherapy of advanced non small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      During the period from November 2009 to January 2016, a total of 152 patients diagnosed with IIIB or IV stage NSCLC in the First Hospital of Jilin University were admitted into our study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G, PARP1 T2444C polymorphisms of all the patients were detected by the mass spectrometry. And the relationship between BER genes polymorphisms and the response of platinum-based chemotherapy is analyzed by Logistic regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Logistic regression model shows that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype (OR: 5.216, 95%CI: 1.568-17.352, P= 0.007) and TC genotype (OR: 2.692, 95%CI: 1.007-7.198, P=0.048) is significantly higher than that of TT wild type, as well as the genotype of TC together with CC (OR: 3.178, 95%CI:1.229-8.219, P = 0.017). There is no relationship between G28152A, MUTYH G972C, XRCC1 HOGG1 C1245G gene polymorphism and chemosensitivity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PARP1 2444 mutation allele C might be associated with the decreased sensitivity to platinum based chemotherapy in advanced NSCLC. Our findings may be helpful towards designing individualized cancer treatment.

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      P2.01-27 - MR, CT and Cone-Beam CT for Lymph Node Visualisation in Locally-Advanced Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Sean Brown  |  Author(s): Michael Dubec, Ahmed Salem, David Catharina Petrus Cobben, Marcel Van Herk, Corinne Faivre-Finn

      • Abstract

      Background

      The largest benefit of MR-guided radiotherapy in lung cancer may be on-board visualisation of malignant lymph nodes (LNs). In this study, we assessed whether MR images were suitable for LN visualisation for treatment adaptation. We hypothesised that MR would outperform CT and Cone-Beam-CT (CBCT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CT, CBCT and MR images were acquired in four lung cancer patients with malignant LNs, confirmed using PET-CT and/or endobronchial ultrasound-guided biopsies. A total of 15 LNs from mediastinal and hilar nodal stations were assessed. Imaging datasets included: (1) CT planning scan with IV contrast; (2) MR1 (within 1 week of CT); (3) Mid-treatment CBCT (without contrast); and (4) MR2 (day of CBCT). MR sequences included: Turbo Spin Echo (TSE), TSE with fat-sat and 3D radial gradient echo. The images were randomised and independently scored by four thoracic radiation oncologists according to whether the malignant LN in each nodal station was visualised well enough to permit contouring. Scores were: not visible (1), unclear (2), clear (3) and very clear (4). Scores 3 and 4 were designated as ‘suitable for contouring’.

      4c3880bb027f159e801041b1021e88e8 Result

      As shown in figure 1, there was no significant difference in the number of LNs deemed suitable for contouring on CT (87%) compared to MR1 (82%). A significant difference was found between CBCT (10%) and MR2 (80%).

      picture11.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      MR did not out-perform CT with contrast for malignant LN visualisation, possibly due to greater observer familiarity with CT. MR was significantly better than CBCT, likely due to superior soft tissue contrast. These findings support the use of MR-guided radiotherapy in locally-advanced lung cancer for adaptive planning or treatment verification. The greater variation in MR scores between oncologists (especially between sequences) could be due to lack of experience with thoracic MR. Future research will optimise MR for this task and assess LN localisation on a larger dataset.

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      P2.01-28 - Gender and Systemic Treatment Patterns: Impacts on the Overall Survival of Stage IV NSCLC 2010 – 2014 Diagnoses

      16:45 - 18:00  |  Presenting Author(s): Anifat A. Elegbede  |  Author(s): Haocheng Li, Adrijana D'Silva, Amanda Jane Williams Gibson, Roxana A. Tudor, Michelle Dean, Shannon Mary Otsuka, Gwyn Bebb

      • Abstract

      Background

      Our previous work reports only ~25% systemic treatment uptake in stage IV non-small cell lung cancer (NSCLC) patients and proposed the availability of more tolerable regimen as one way of improving survival for NSCLC patients. The current study followed-up with the systemic treatment trend in stage IV NSCLC patients from 2010 to 2014, the era where effective and tolerable targeted agents such as EGFR- tyrosine kinase inhibitors (TKIs) and ALK inhibitors are available, to determine changes in clinical and treatment patterns impacting NSCLC survival over time.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using the Glans-Look Lung Research (GLR) database, we defined the clinical features of stage IV NSCLC patients from 2010 to 2014, determined the impact of systemic treatment patterns and uptake rates on overall survival (OS).The findings were summarized with descriptive statistics (Fisher’s Exact tests) and Kaplan Meier survival curves using SPSS. Statistical significance was set at p value < 0.05 and 95% confidence intervals.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 470 patients diagnosed between the year 2010 – 2011, and 724 in 2012 – 2014, 26% and 33% received 1st line systemic treatment respectively. Overall, there was increased use of EGFR and ALK targets (18% in 2010 – 2011 versus 34% in 2012 – 2014 of all 1st line therapy) and a 13% decrease in platinum-based doublet (PBD) uptake over the years, (p = 0.001). This pattern of change was similar for patients ≤70 years versus >70 (p < 0.001). However, for female patients, PBD use remain constant despite the increased targeted agents uptake, (p = 0.001). The median OS was slightly better for female in the subsequent years, 7 (95% CI: 6 – 8) versus 4 (95% CI: 3 – 5) months, p = 0.036. In EGFR/ALK mutation positive patients who received 1st line TKIs, a non-statistically significant lower OS was observed in 2012 – 2014 compared to the previous years (p = 0.188). No significant difference in the OS between the year groups for patients with no actionable mutation treated with 1st line PBD (p = 0.393).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In stage IV NSCLC, systemic treatment uptakes slightly increased with targeted agents, however this may not add up to overall survival benefits for the disease. Targeted agents may confer more benefits to female patients. Outcome results from multivariate analysis will be presented and discussed.

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      P2.01-29 - <sub>Economic Analysis of Osimertinib in Previously Untreated EGFR-Positive Advanced Non-Small Cell Lung Cancer</sub>

      16:45 - 18:00  |  Presenting Author(s): Doreen Anuli Ezeife  |  Author(s): Veronica Kirk, Peter Coyte, Nancy Nixon, Rebecca Hancock-Howard, Natasha B Leighl

      • Abstract

      Background

      Osimertinib doubles progression-free survival (PFS) in previously untreated EGFR-positive advanced non-small cell lung cancer (NSCLC) patients, with remarkable intracranial response rates. However, its cost-effectiveness has not been established. We assessed the cost-effectiveness of first-line osimertinib from the perspective of the Canadian public health care payer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A remaining lifetime Markov model was used to project the outcomes and costs of 2 treatment pathways, osimertinib or current standard-of-care (SoC) first-line EGFR TKI gefinitib or afatinib, in previously untreated EGFR-mutant advanced NSCLC patients from the health care system perspective. Clinical, health preference and cost input estimates were informed from the available literature, including second-line osimertinib after SoC failure in those with EGFR T790M mutant cancer. Model outcomes included costs (in 2017 Canadian dollars), quality-adjusted life-years (QALYs), and the incremental cost per QALY gained. The model was fully probabilistic to assess parameter uncertainty.

      4c3880bb027f159e801041b1021e88e8 Result

      Osimertinib was associated with a gain of 0.70 quality-adjusted life-years (QALYs) at an incremental cost of $58,619 vs SoC (incremental cost-effectiveness ratio [ICER]: $83,164/QALY gained). Unadjusted LY gain was 0.95. Osimertinib had a 7% probability of being cost-effective at a willingness-to-pay threshold of $50,000/QALY, and a 77% probability at a threshold of $100,000/QALY. Deterministic sensitivity analysis showed that health utilities and cost of osimertinib had the largest impact on ICER results.

      8eea62084ca7e541d918e823422bd82e Conclusion

      First-line osimertinib use in patients with advanced EGFR mutant lung cancer was found to involve a trade-off between improved PFS, QALYs and LYs versus increased cost.

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      P2.01-30 - Applicability of Lung-molGPA Index in Non-Small Cell Lung Cancer Patients with Different Gene Alterations and Brain Metastases

      16:45 - 18:00  |  Presenting Author(s): Yun Fan  |  Author(s): Kaiyan Chen, Yanjun Xu, Zhiyu Huang, Xiaoqing Yu, Haiyang Wang

      • Abstract

      Background

      The Lung-molGPA was based on the original Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) by incorporating recently reported gene alteration data for non-small cell lung cancer (NSCLC) patients with brain metastases (BM). However, the prognostic prediction value of DS-GPA and Lung-molGPA models remains undetermined, especially in patients with different molecule types.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 1184 NSCLC patients with BM analyses for clinical factors and outcomes were identified at Zhejiang Cancer Hospital, China. All prognostic factors were weighted for significance by hazard ratios. The applicability of DS-GPA and Lung-molGPA were reappraised in NSCLC patients with BM and various genetic profiles. Additionally, a modified Lung-molGPA, was newly developed for mutant NSCLC patients.

      4c3880bb027f159e801041b1021e88e8 Result

      molgpa-分型.pngThe NSCLC patients in the present study had a median survival of 14.0 months from the time of BM diagnosis. Both DS-GPA and Lung-molGPA models could predict the outcomes (P<0.001), while Lung-molGPA model appeared to exhibit better accurate prediction. Furthermore, Lung-molGPA scores performed a discrimination capability in patients with gene variations (3.5-4.0 vs 2.5-3.0 vs 1.5-2.0 vs 0-1.0=62.0 vs 32.0 vs 17.7 vs 3.2 months, P<0.001). However, no significant difference was reached in wild-type patients (P=0.133). Regarding to the oncogene-positive NSCLC patients with BM, a modified Lung-molGPA index had been established derived from the prognostic factors with the C-index of 0.73 (95% CI: 0.73-0.80) to accurately calculate the survival probability (P<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In an era of precision medicine, Lung-molGPA could precisely predict the prognosis of mutant NSCLC patients with BM, while not work in wild-type patients.

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      P2.01-31 - Updated EGFR Mutation Frequency in 1,689 NSCLC Brazilian Patients – A National-Wide Study

      16:45 - 18:00  |  Presenting Author(s): Carlos Gil Ferreira  |  Author(s): Mariano Zalis, Mauro Zukin, Gilberto Castro Jr, Clarissa Mathias, Carolina Kawamura Haddad, Vladmir CC de Lima, Luiz H. Araujo, Clarissa Baldotto, Ana Caroline Zimmer Gelatti, Carolina Bustamante, Marcelo Graziano Custodio, Giuliana Montenegro, Alessandra Souza, Marcelo Reis

      • Abstract

      Background

      EGFR mutation status is crucial to improving therapeutic results in advanced NSCLC, due to the development of highly effective EGFR-TKIs. Recent local data suggest that EGFR mutation frequency is lower in Brazil ( 22%-33%) than in Asia and higher than in North America and Europe. We intended to describe the EGFR mutation frequency in a large national-wide Brazilian population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This retrospective analysis evaluated a database composed of samples collected between January and August 2017, from all Brazilian regions. Tumor tissue samples of patients with advanced NSCLC were submitted, at discretion of attending physicians, for EGFR mutation testing. EGFR exons 18 to 21 were analyzed by cobas®, NGS, or other non-specified test. Unfortunately, smoking status data was not available and was not included in this analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      1,689 tests were included. Table-1 demonstrates EGFR mutation rates according to test used. Mean age (±SD) was 64.5 (±11.3) for female and 66.0 (±11.1) for male population. From all detected mutations, exon 19 deletion was the most frequent (49.2%), followed by L858R (25.6%), exon 20 insertion (8.4%), T790M (4,7%), and G719X (3.0%). Patients with multiple EGFR variants (more than one EGFR mutation) corresponded to 10.3% of cases. Among different Brazilian geographic macro-regions, EGFRm rate was 33.3% in North (36 tests only), 25.1% in Northeast (307 tests), 30.9% in Central-West (175 tests), 25.8% in Southeast (841 tests), and 20.6% in the South (330 tests) region.

      Table1 – EGFR mutation rate divided by gender and EGFR mutation detection method.

      cobas®

      NGS

      Other

      Overall

      Female

      58/183

      (31.7%)

      223/586

      (38.1%)

      25/159

      (15.7%)

      306/928

      (33.0%)

      Male

      25/167

      (15.0%)

      89/447

      (19.9%)

      9/147

      (6.1%)

      123/761

      (16.2%)

      Overall

      83/350

      (23.7%)

      312/1,033

      (30.2%)

      34/306

      (11.1%)

      429/1689

      (25.4%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings confirm that EGFR mutation rate among Brazilian is higher than observed in Western countries, women have a higher EGFR mutation rate than men, and detection rate using NGS is higher than cobas®. Frequency of EGFR mutation was lower in South region, what could be explained by a higher smoking rate (not evaluated in this study) and a larger Caucasian population.

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      P2.01-32 - Economic Evaluation of Diagnostic Platforms for T790M Detection in Post EGFR-TKI NSCLC in Brazil

      16:45 - 18:00  |  Presenting Author(s): Carlos Gil Ferreira  |  Author(s): Marcelo Graziano Custodio, Giuliana Montenegro, Rosangela Caetano, Luciene Bonan

      • Abstract

      Background

      50% of acquired resistance to first or second-generation EGFR-TKIs NSCLC treatment is attributed to T790M mutation. Clinical trials demonstrated superior efficacy of osimertinib versus chemotherapy in second line setting. Nevertheless, the required molecular testing to identify T790M mutation is a challenge considering difficulties related to tissue re-biopsies. Nowadays, availability of noninvasive ctDNA techniques permits safer and faster molecular diagnostic. In Brazil, there are some commercially available tests presenting different accuracy rates. Our objective was to compare current T790M ctDNA tests cost-effectiveness, under local perspective.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The population is NSCLC post first-line EGFR-TKI progression. Decision tree model started with cfDNA evaluation (RT-PCR based kit, Digital Droplet PCR, or NGS). Due to ctDNA methods intermediate sensitivity, tumor sample analysis is recommended if plasma result is negative. Strategies were a combination of cfDNA tests and RT-PCR based kit or NGS for tumors re-biopsies. Prevalence of T790M mutation, test accuracy, proportion of unknown or unfeasible samples were used to calculate each branch. Tissue re-biopsies complications and costs were also considered. The model was analyzed from a healthcare-payer perspective based on Brazilian private sector.

      4c3880bb027f159e801041b1021e88e8 Result

      Plasma ddPCR then tissue biopsy NGS (if plasma negative) was the most effective, with cost-effective ratio of US$ 3,855.43 per positive T790M detected. Its cost was higher than the second most effective strategy (plasma-NGS + tissue NGS). Incremental cost-effectiveness ratio between both was US$ 21,193.66 per additional positive case detected. All strategies using RT-PCR based kit for plasma and/or tissue were dominated.

      table.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      In terms of costs and effectiveness, the best algorithms to detect more T790M positive cases are combination of ctDNA (ddPCR or NGS) and NGS test for tumor re-biopsy. ddPCR use followed by NGS permits identification of 5% more T790M mutations than the dominated methods. This study is an effort to optimize expenditures and integrate diagnostics discussions in Brazilian health system.

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      P2.01-33 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1 Containing Therapy (HUDSON)

      16:45 - 18:00  |  Presenting Author(s): Patrick M Forde  |  Author(s): John V Heymach, Michael Thomas, Keunchil Park, Benjamin Besse, Mark M. Awad, Glenwood Goss, Naiyer A Rizvi, Helen J Ambrose, Philip John Jewsbury, Barbara Koetz, Si-Houy Lao-Sirieix, Peter G Mortimer, Sabina I Patel, Kris Sachsenmeier, Wolfram Brugger

      • Abstract

      Background

      Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line NSCLC. However, the majority of patients do not respond or have non-durable responses to anti-programmed cell death-1/programmed cell death-ligand 1 (anti-PD-1/PD-L1) containing therapy (primary resistance) or progress during anti-PD-1/PD-L1 containing therapy (acquired resistance). HUDSON addresses the urgent need to identify treatments and understand ICI resistance for this emerging ICI-resistant population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      HUDSON is a multi-centre, international multi-arm umbrella study that will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in NSCLC patients who have progressed following standard-of-care platinum and ICI-based therapies. HUDSON is a platform study that consists of two groups; a biomarker matched and a biomarker non-matched group. Within the biomarker matched group, different cohorts will test 1) homologous recombination repair (HRR) defects and 2) LKB1 aberration for response to durvalumab and olaparib (PARP inhibitor), 3) ATM deficiency for response to durvalumab and AZD6738 (ATR inhibitor) and 4) RICTOR amplification for response to durvalumab and vistusertib (mTORC1/2 inhibitor). In the biomarker non-matched group, cohorts will test durvalumab in combination with either i) olaparib, ii) AZD9150 (STAT3 inhibitor) or iii) AZD6738, in patients with primary and acquired resistance to a prior ICI. Allocation to a cohort is informed by the tumour molecular profile according to a pre-specified assignment algorithm. New cohorts will be added as new translational hypotheses are established. Translational research will be performed on serial peripheral blood samples (including ctDNA) and tumour biopsies. HUDSON enrols ICI-resistant patients in a signal searching manner. Biomarker matched and non-matched groups will be opened simultaneously, and all eligible patients can be allocated a treatment option irrespective of their tumour profile. Enrolment is ongoing, clinical trial information: NCT03334617.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-34 - Prognostic Value of Neutrophil to Lymphocyte Ratio for Metastatic NSCLC Patients Treated with Immunotherapy and Ramucirumab Plus Docetaxel.

      16:45 - 18:00  |  Presenting Author(s): Marta Batus  |  Author(s): Ibtihaj Fughhi, Philip Bonomi, Mary Jo Fidler, Sanjib Basu, Jeffrey Borgia

      • Abstract

      Background

      High NLR has been associated with inferior OS in metastatic NSCLC patients. We previously demonstrated a significant relationship between a high NLR at baseline and at follow-up and poorer OS in patients with metastatic NSCLC. Case series suggest potentially improved benefits of cytotoxic chemotherapy administration post immunotherapy but little is known about whether high NLR is associated with inferior outcomes in patients receiving salvage ramucirumab plus docetaxel (RD). We evaluated the potential predictive value of NLR in pts with metastatic NSCLC who received at least one cycle of immunotherapy and treated with RD regimen.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective analysis of patients with metastatic NSCLC who received at least one cycle of nivolumab or pembrolizumab and treated with RD regimen between April 2015 and May 2017. Patient demographics including NLR, RD and immunotherapy starting dates, and date of progression were recorded. Associations between NLR and both PFS and OS were assessed using Mann-Whitney-Wilcoxon tests. Cutoffs of NLR of 5.0 (based on published data) were analyzed for differences in median OS and PFS.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 62 patients analyzed, 47% were male, 81% former smoker, 76% Caucasian and 76% patients who were treated with RD regimen also received immunotherapy during their treatment course. For entire cohort, baseline NLR ≤ 5 was associated with superior survival (median OS 20.86 mos for NLR ≤ 5 vs 5.78 mos for NLR >5, p=0.01) and superior PFS (median PFS 6.01 mos for NLR ≤ 5 vs 2.76 mos for NLR >5, p=0.03). Another significant predictor of OS was albumin at baseline (HR= 0.44, p = 0.01) and at 6 weeks (HR= 0.38, (p = 0.01). Patients who received immunotherapy had significantly superior OS than those who did not receive immunotherapy (median not reached vs 7.43 mos, p =0.03) within one-year follow-up.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Low NLRs and higher albumins at baseline & 6 weeks were associated with a prolonged PFS and OS in patients with metastatic NSCLC who were treated with RD regimen. In this small retrospective study, longer OS was observed in pts treated with RD regimen and immunotherapy. Pts who did not receive immunotherapy had shorter OS. Additional data are needed to evaluate the impact of treatment sequence.

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      P2.01-35 - Predicting Risk of Chemotherapy-Induced Severe Neutropenia in Patients with Advanced Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Apar Kishor Ganti  |  Author(s): Xiaowen Cao, Chen Shen, Thomas E. Stinchcombe, Jeffrey Crawford, Herbert Pang, Xiaofei Wang

      • Abstract

      Background

      Neutropenia is associated with the risk of life-threatening infections, chemotherapy dose reductions and delays that may compromise treatment outcomes. The goal of this study was to develop simple prediction model for severe neutropenia in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A lung cancer dataset was assembled using data from existing national cooperative group phase II/III trials conducted between 1991-2010. Chemotherapy trials in patients with stages III and IV non-small cell lung cancer (NSCLC) or extensive small-cell lung cancer (SCLC) were included. We randomly selected 2/3 patients to derive the model, and the remaining were used for validation. Models were built with stepwise logistic regression and lasso regression on imputed data sets. We fitted the model on the imputed training data sets individually to get 10 models with 10 sets of selected predictors. Next we picked the union set and the intersection set of predictors from the models. The variables in the final model were selected by lasso regression, and then fitted into a logistic model. The performance of the model was evaluated by receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC).

      4c3880bb027f159e801041b1021e88e8 Result

      The dataset was randomly separated into training [n=7606 (67%)] and testing sets [n=3746 (33%)]. The final predictive model included: Age (>65 years), gender (male), weight (kg), BMI, insurance status (yes/unknown), stage (IIIB/IV/ESSCLC), number of metastatic sites (1, 2 or ≥3), individual chemotherapy agents (gemcitabine, taxanes), number of chemotherapy agents (2 or ≥3), planned use of growth factors, associated radiation therapy, previous therapy (chemotherapy, radiation, surgery), duration of planned treatment, pleural effusion (yes/unknown), performance status (1, ≥2) and presence of symptoms (yes/unknown).

      wclc figure.jpg

      Figure: ROC Curve for Final model AUC=0.8306

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have developed a relatively simple model with variables that are routinely available prior to treatment, to predict for neutropenia. This model should be validated prospectively.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-36 - Real-World Treatment Patterns in Treatment-Naïve Advanced NSCLC Patients in North America: A Systematic Literature Review

      16:45 - 18:00  |  Presenting Author(s): Yong Yuan  |  Author(s): Aleksandra Gara, Nebibe Varol, Sarah Goring, Tina Li, Mariana Oviedo Ovando, Nadine Hertel, Beata Korytowsky

      • Abstract

      Background

      Clinical practice guidelines in North America for first-line (1L) treatment of advanced NSCLC (aNSCLC) include a range of systemic therapy combinations, with consideration given to patient and disease characteristics. As the aNSCLC treatment landscape evolves, it is relevant to understand which combinations are routine in clinical practice. We aimed to characterize treatment patterns in real-world (RW) practice in the US and Canada.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A systematic literature review of RW observational studies was conducted using EMBASE and MEDLINE (January 2012 to March 2018), alongside searches of conference proceedings (2015 to 2018). Two reviewers assessed eligibility and included studies that described treatment patterns among treatment-naïve patients with aNSCLC. Studies focusing exclusively on sub-populations, e.g. EGFR+ or ALK+ were excluded. Data regarding the study’s sampling frame and the frequency and type of therapies received (1L systemic regimens, other 1L treatment modalities, maintenance therapy, subsequent lines of systemic therapy) were extracted and validated.

      4c3880bb027f159e801041b1021e88e8 Result

      From 4600 abstracts, 18 studies met inclusion criteria (n=14 US; n=4 Canada). All studies used a retrospective design; patient sample sizes ranged from 147 to 55,189 and study periods ranged from 2000 to 2015. Six studies (n=5 US; n=1 Canada) applied a sampling frame that captured all regimens available in 1L and provided breakdowns by 1L regimen (Figure 1). Eight studies (n=8 US) applied a sampling frame restricted to a pre-defined subset of 1L regimens. Among these, five were restricted to those receiving bevacizumab-based regimens; the remaining three restricted to those on specific platinum doublet regimens. Four studies (n=1 US; n=3 Canada) provided breakdowns only by treatment modality (surgery, radiation, best supportive care or no systemic therapy).

      figure 1. first line treatment regimens.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      The identified studies capture treatment patterns primarily in an era when immunotherapy was unavailable in the 1L setting and reflect the prevalent use of platinum doublets as the mainstay of 1L treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-37 - A Ph 1/2 Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) with Docetaxel in pts with Previously Treated NSCLC

      16:45 - 18:00  |  Presenting Author(s): David E Gerber  |  Author(s): Sawsan Rashdan, Jessica Williams, Penny Currykosky, Farjana Fattah, Jonathan Padro Arroyo, Rebecca Smith, Robert Holt, Rolf Brekken

      • Abstract

      Background

      AXL is a receptor tyrosine kinase expressed on tumor as well as innate immune cells. AXL regulates multiple cellular processes including tumour cell survival, therapy resistance as well as immunosuppression in the tumour microenvironment. AXL overexpression is an independent negative prognostic factor in NSCLC. Bemcentinib (BGB324) is a phase 2, highly selective, orally bioavailable small molecule AXL kinase inhibitor shown to increase efficacy of chemo-, targeted- and immuno-therapies in NSCLC in vivo models. Preclinically, the combination of bemcentinib with docetaxel was shown to be additive in in vivo models of NSCLC.

      In pts with advanced, pre-treated NSCLC, bemcentinib monotherapy led to disease stabilization in 2 out of 8 pts including evidence of tumor reduction. Clinical benefit including partial responses and disease stabilization in excess of 2 years has been observed in a subset of EGFR therapy resistant previously treated NSCLC pts when treated with bemcentinib in combination with erlotinib. In a study combining bemcentinib with pembrolizumab, objective responses have been reported in pts with previously treated NSCLC.

      The BGBIL005 trial (NCT02922777) is an open label, investigator-initiated dose escalation and expansion trial designed to assess the safety, tolerability, preliminary efficacy and biomarkers of bemcentinib in combination with docetaxel in previously treated NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Dose escalation of daily bemcentinib in combination with 60 or 75 mg/m2 q3wks followed a standard 3+3 design in pts with at least one line of prior Pt-based doublet therapy and appropriate targeted therapy if indicated. Tumor responses were assessed per investigator using RECIST v1.1. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in pts pre-dose and at C2D1.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 30th April, 12 patients have been enrolled. The starting dose of 75 mg/m2 docetaxel and 100 mg daily of bemcentinib led to 2 hematological DLTs, thus recruitment is currently ongoing at 60 mg/m2 docetaxel and 100 mg bemcentinib. Confirmed objective responses have been reported at both dose levels. All pts benefitting had received prior immune checkpoint inhibitor (CPI) therapy and some had been refractory to this treatment. Candidate predictive and pharmacodynamic biomarkers have been identified.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of bemcentinib and docetaxel is active in pts with advanced NSCLC who progressed on chemotherapy, targeted therapy (where applicable) as well as CPIs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-38 - Sarcopenia is Associated with Metastatic Burden and is a Negative Prognostic Factor in Metastatic Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Chad Glisch  |  Author(s): Kathleen Monahan, Dhiraj Baruah, Jonathan R Thompson, Ziyan Yin, Aniko Szabo, Jayshil Patel, Smitha P. Menon

      • Abstract

      Background

      Sarcopenia is associated with poor outcomes in patients with solid tumors. Factors affecting sarcopenia in metastatic NSCLC (mNSCLC) are not well defined. We utilized a novel computerized tomography (CT) method to measure muscle composition and evaluate its impact on metastatic disease burden and survival in mNSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a retrospective study of consecutive adults diagnosed with mNSCLC. Demographic features, clinicopathologic variables, radiologic imaging, and outcomes data were collected and analyzed. Total, healthy, and unhealthy muscle were identified at the L3 psoas level using a previously validated novel CT method. Blinded outcomes assessments were conducted. The primary outcome was correlation between healthy muscle percentage and number of metastases. The secondary outcome was the impact of healthy muscle on overall survival. We hypothesized less total healthy psoas muscle would be associated with greater metastatic burden and worse overall survival. Analyses were adjusted for sex, age, BMI, Charlson comorbidity index, ECOG score, total psoas cross-sectional area, and weight-loss. The survival analysis was also adjusted for presence of a targetable mutation.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 242 patients with mNSCLC. Mean age was 65 years. Forty-seven percent were females. Two hundred thirteen (88%) were current or former smokers. Adenocarcinoma was the most common histological subtype (162,67%) followed by squamous (49,20%) and undifferentiated (18,7%). One hundred thirteen (44%) patients had oligometastatic disease, defined as 1-3 lesions, and 142 (56%) had 4 or more lesions. Eighty (33%) had brain metastases and 69 (29%) visceral. Mean ECOG was 1. Mean percentage of healthy psoas was 74% (SD: 14). Multivariate analysis demonstrated that for every 10% increase in healthy muscle, metastatic lesions decreased by 12% (RR=0.88, 95% CI 0.78-0.98, p=0.02). The odds of oligometastatic disease increased by 39% for each 10% increase in healthy muscle (OR=1.39, 95% CI: 1.06-1.79, p=0.014). Reduced percentage of healthy muscle was associated with reduced survival (median OS 8.9, 19.1, 16.3 months for <70%, 70-80%, >80% of healthy muscle, respectively, log-rank test p=0.038). This effect was preserved in the adjusted analysis, with 13% decrease in the hazard of death for every 10% increase in percent healthy muscle (HR=0.87, 95% CI: 0.75-1.0, p=0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Greater healthy muscle at mNSCLC diagnosis is associated with lower metastatic burden and improved survival. Our novel CT method to identify sarcopenia may be useful in mNSCLC prognostication.

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      P2.01-39 - Can Benefit or Futility in Treating Advanced Nsclc Be Determined Early Using the LCSS 3-Item Global Index (3-IGI) PRO?

      16:45 - 18:00  |  Presenting Author(s): Richard J Gralla  |  Author(s): Patricia J. Hollen, Richard Hall, Ryan Gentzler, Haiying Cheng, Balazs Halmos, Jeffrey Crawford, Jane Cerise, Martin Lesser

      • Abstract

      Background

      Background: Early assessment of the effect of treatment for advanced NSCLC can prevent unnecessary exposure to toxic and costly therapy while aiding in decision making to continue or change treatment. In a prior analysis in patients with mesothelioma (Symanowski JCO 2014), a 20% decline from baseline after 2 cycles of chemotherapy in the 3-Item Global Index of the LCSS identified patients unlikely to benefit. The 3-IGI (which evaluates: 1) global distress, 2) patient rated activities, and 3) quality of life, all in single VAS scales) takes less than 2 minutes to assess.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: 164 patients with NSCLC receiving chemotherapy or checkpoint inhibitors were prospectively evaluated with the LCSS at baseline and every 3 weeks using electronic media. Patients were also randomized 1:1 so that their physicians knew the results of the LCSS immediately in half of the patients.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: Patients: Stage IV 92%; first line 73%; female 43%; median PS 1; mean age 63. The LCSS was completed after 2 cycles of treatment and prior to planning for the next cycle (generally 6 weeks after baseline; representing 91% of the 148 patients living). Patients with a 20% decline in the 3-IGI compared with baseline had a median survival of 7.6 months, contrasted to 15.8 months for those without this degree of 3-IGI decline (p = 0.01); 1 year survivals = 26% versus 62%. Even with the marked PRO decline after 2 treatment cycles, patients in the 20% decline group received a median of 2.3 more cycles of the same chemotherapy (median cost = $10,712 per patient). In the 50% of patients for which their physicians knew the ongoing LCSS results, fewer chemotherapy and imaging studies were performed, but the differences were not significant (p = 0.8).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions: Assessing change from baseline with the 3-IGI of the LCSS identifies after only 2 cycles of treatment those patients who have poor response and survival outcomes if continued on the same therapy. This PRO assessment is rapid, easy, and inexpensive. Physicians need to consider the impact of decline on decision options given that even when physicians were aware of the worsening PRO they often did not act on the findings. Patient responses to this validated PRO questionnaire provide valuable information that is not otherwise attainable. Responding to 3-IGI changes can result in better decisions concerning continuing or changing treatment, lessening toxicity, and savings in cost of unhelpful treatment.

      Supported by: NIH/NCI R01 CA157409

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      P2.01-40 - Prognostic Importance of Sarcopeni and Inflammatory Statements in Stage III Non Small Cell Lung Carcinoma

      16:45 - 18:00  |  Presenting Author(s): Serap Akyürek  |  Author(s): Esra Gümüştepe, Yakup Arslan, Emrah Özgür Gökay, Şaban Çakir GÖkÇe

      • Abstract

      Background

      Sarcopenia is characterized by progressive loss of skeletal muscle mass, muscle strength and physical performance. Systemic inflammation is thought to contribute to sarcopenia. Current retrospective evidence suggests that sarcopenia is an independent prognostic value on overall survival(OS).

      In this study, we aimed to investigate the prognostic significance of sarcopenia and inflammatory markers in stage III small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eighty-three patients with stage III NSCLC undergoing definitive chemoradiotherapy in our clinic between April 2014 and August 2017 were evaluated. The cross-sectional area of muscle at the level of the third lumbar vertebra (L3) was measured using of radiotherapy planning CT images. Sarcopenia was defined as a L3 muscle index of less than 55 cm2/m2 for men and of less than 39 cm2/m2 for women as proposed by international consensus of cancer cachexia. Systemic inflammatory markers investigated included serum lactate dehydrogenase (LDH), neutrophil: lymphocyte ratio (NLR), C-reactive protein (CRP), and albumin(alb) . Relations between variables were determined by Pearson Chi Square and FischerExact Test. Risk factors affecting dependent variables were determined by CoxRegresson Analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy-five (90%) of the patients were male and 8 (10%) were female. The number of sarcopenic patients was 52 (62.6%). The mean age was higher in sarcopenic patients (68.3 ± 9.7 vs 63.7 ± 9.4, p = 0.037). There was no statistically significant difference between the groups with and without sarcopenia in the ratio of low albumin level, LDH height, N / L ratio. Mean survival was 18.14 months (2-48 months). In sarcopenic patients, OS was 17.2 months, while non-sarcopenic patients were 19.58 months (p = 0.310). When the effects on general survival were examined, it was found statistically significant that the presence of sarcopenia (p = 0.016), age (p = 0,001), low alb level (p = 0,009), N / L ratio is higher than 4 (p = 0,003). Multivarible Cox regression analyzes showed independent prognostic significance in survival with RT dose (HR (95% CI) = 1,2; p = 0.001), low albumin level (HR (95% CI) = 2.42; p = 0.007) and age (HR(95%CI)=1,03; p=0,044).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our study, the presence of sarcopenia in patients with stage III definitive KTRT NSCLC, as well as the LOW alb ratio and N / L ratio of inflammatory markers was found to be a significant prognostic factor for OS. We aim to investigate the prognostic significance of sarcopenia 'cutoff' value for Turkey with a prospective, multicenter, larger group of patients.

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      P2.01-41 - The Role and Mechanism Of FBW7 Deficiency in Advanced Non-Small Cell Lung Cancer with Docetaxel Resistance  

      16:45 - 18:00  |  Presenting Author(s): Qisen Guo  |  Author(s): Honglu Liang

      • Abstract

      Background

      Lung cancer is one of the most common malignant tumors of human. NSCLC accounts for about 80%-85% of all lung cancer, and 65%-80% of NSCLC patients have been diagnosed at the advanced stage[1]. Because of the existence of drug resistance, many patients have relapsed or progressed soon after chemotherapy, and the resistance always lead to unsuccessful effect.

      Docetaxel is an anti-microtubule chemotherapeutic agent that acts on cellular tubulin, which can prevent the normal physiological accumulation of intracellular microtubules , resulting in the withering of cells[2]. Like other chemotherapeutic drugs, the drug resistance of docetaxel reduces its efficacy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RT-PCR and Western-blot were used to detect the differences of FBW7 expression in docetaxel-resistant cell line SPC-A1/DTX and parental SPC-A1 cells, and the overexpression and interference sequences of FBW7 were constructed. The SPC-A1/DTX and parental SPC-A1 cells were transfected with lentiviral packaging, and the SPC-A1/DTX FBW7 O/E cell line and SPC-A1 FBW7 D/R cell line were screened by monoclonal screening method. RT-PCR and Western-blot were also used to detect the differences of FBW7 expression among SPC-A1/DTX, SPC-A1/DTX FBW7 O/E, SPC-A1 and SPC-A1 FBW7 D/R cell lines. Finally, MTT colorimetric assay and colony formation assay were used to research the effects of regulation of FBW7 on the sensitivity to docetaxel.

      4c3880bb027f159e801041b1021e88e8 Result

      RT-PCR and Western-blot proved that the expression of FBW7 in NSCLC docetaxel-resistant cell line SPC-A1/DTX was significantly lower than that of parental cell line SPC-A1. With lentiviral transfection and monoclonal screening, a SPC-A1 FBW7 D/R cell line with down-regulated FBW7 expression and an SPC-A1/DTX FBW7 O/E cell line with up-regulated FBW7 expression were constructed. The expression of FBW7 in SPC-A1 cell line and SPC-A1/DTX FBW7 O/E cell line was higher than that of SPC-A1/DTX FBW7 O/E cell line and SPC-A1 by RT-PCR and Western-blot. /DTX cell line. Finally, MTT colorimetric assay and colony formation assay showed that SPC-A1 cell line and SPC-A1/DTX FBW7 O/E cell line were more sensitive to docetaxel than SPC-A1 FBW7 D/R cell line and SPC-A1 /DTX cell line.

      8eea62084ca7e541d918e823422bd82e Conclusion

      For non-small cell lung cancer, the sensitivity to docetaxel was higher in cells with high expression of FBW7 than the cells with low expression of FBW7; the loss of FBW7 gene was associated with drug resistance of NSCLC to docetaxel. However, the specific mechanism of FBW7 deletion causing non-small cell lung cancer resistance to docetaxel still needs further study.

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      P2.01-42 - Impact of Tobacco Smoking on Outcomes in Patients with Metastatic Non-Small Cell Lung Cancer in the Era of Targeted Therapy

      16:45 - 18:00  |  Presenting Author(s): Martin Gutierrez  |  Author(s): Antoinette Wozniak, Corey J Langer, Bruno Fang, Giselle Alexandra Suero-Abreu, Andrew D Norden, Keaton D Bedell, James Schaffer, Ann Collins, Eric V Schultz, Brian Stone, Viraj Narayanan, Stuart Lee Goldberg

      • Abstract

      Background

      Prior epidemiological studies have noted differences in the demographic and clinical characteristics among patients with metastatic non-small cell lung cancer (NSCLC) between those with and without exposure to tobacco smoke. Most notably never smokers are more likely to harbor genomic driver mutations and (in the era of targeted therapy) improved survival. Observational databases, capturing real world diagnostic and treatment patterns, can provide insights on outcomes of NSCLC based on smoking history.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The electronic health records (EHR) of patients with de novo stage IV NSCLC diagnosed between January 2013 and December 2016 from 30 cancer centers, contributing to the Cota Observational Cancer Database, from 184 oncologists were reviewed.

      4c3880bb027f159e801041b1021e88e8 Result

      1716 NSCLC pts were identified including 243 (14.2%) never tobacco smokers, 405 (23.6%) active smokers, 1026 (59.8%) former smokers, 7 (0.4%) passive smokers, and 29 (1.7%) not reporting. Never Smokers (NS) were more likely than smokers (S=active and former smokers combined) to be female (NS: 67.4%; S: 47.2%; p<0.0001) with similar ages (NS: 66 yrs; S: 67 yrs), but included more Asians pts (7.4% vs 1%, p<0.0001). Histologic subtypes differed: Squamous NS: 9%; S: 17.8%: (p<0.0001), AdenoCA NS: 73.2%; S: 68% (p=0.1), NOS N: 5.3%; S: 6.1% (p=0.8). Genomic profiling for EGFR/ALK was more common and identified more mutations in the NS cohort. In the non-squamous histologies EGFR testing was NS: 87% with 45.9% mutated; S: 70% with 10.4% mutated (tested p<0.0001; mutated p<0.0001). In the non-squamous histologies ALK testing was NS: 74% with 5.4% translocated ; S: 67% with 1.4% translocated (tested p=0.04; translocated p<0.001). As first line therapy 40% of NS received targeted therapy (11% receiving targeted 2nd line) whereas 4.8% S received 1st line and 1.5% 2nd line targeted therapy. The median overall survival for the NS cohort was 21 months compared to 11 months among S (log-rank p<0.05); with PFS of 9 vs 6 months (p<0.05). Excluding use of targeted therapy in 1st or 2nd line, the median OS for NS was 17 mo; for S was 10 mo (p<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This real world observational study confirms a higher rate of targetable genomic driver mutations among never smoker NSCLC. Despite guidelines recommending universal genomic testing, never smokers are tested at a higher frequency. In the era of targeted therapy (but before the widespread use of immunotherapy) never smoker NSCLC patients experienced improved overall survival with and without targeted treatment compared to individuals with tobacco exposure.

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      P2.01-43 - ADSCaN: A Randomised Phase II Study of Accelerated, Dose Escalated, Sequential Chemo-Radiotherapy in Non-Small Cell Lung Cancer (NSCLC)

      16:45 - 18:00  |  Presenting Author(s): Matthew Hatton  |  Author(s): Claire Lawless, Corinne Faivre-Finn, David Landau, Kathleen Boyd, John D Fenwick, Jason Lester, Elaine McCartney, James Paul, Ann Shaw, Rita Simoes

      • Abstract

      Background

      Lung cancer is the most common cause of cancer mortality in the UK, and NSCLC accounts for approximately 85% of all lung cancers. Most patients present with inoperable disease therefore radiotherapy plays a major role in treatment. However, the majority of patients are not suitable for gold standard treatment (concurrent chemo-radiotherapy) due to performance status and comorbidities. Novel strategies integrating radiotherapy advances and radiobiological knowledge need to be evaluated in patients treated with sequential chemo-radiotherapy. Four separate accelerated dose escalated radiotherapy schedules have been completed in UK (CHART-ED{1}, IDEAL-CRT{2}, I-START{3} and Isotoxic IMRT{4}). ADSCaN will compare these schedules with a UK standard sequential chemo-radiotherapy schedule. A combined randomized phase II screening / ‘pick the winner’ approach will identify the best schedule to take into a randomised phase III study against conventionally fractionated radiotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Suitable patients will have histologically / cytologically confirmed, stage III NSCLC and be able to undergo chemo-radiotherapy treatment. The study will recruit 360 patients; 130 on the standard arm and 60 on each experimental arm. Patients will complete 2-4 cycles of platinum based chemotherapy before being randomised to one of the radiotherapy schedules.

      Logistic / capacity challenges make it impractical for sites to open all experimental trial arms; a novel trial design allows centres to select upfront the experimental arms they are able to participate in and all will offer the standard arm.

      adscan_trial_schema_v5_17jan2017.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      CURRENT STATUS

      CRUK is funding this multicentre study which is being co-ordinated by the CRUK CTU Glasgow. The study opened to recruitment on 22/08/2017 with planned recruitment lasting 3 years 8 months. The study includes a tailored QA programme through the UK RTTQA Group. 20 of the 36 sites expressing interest have started the QA process, 12 have completed with a further 8 expected to complete in the next few months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section Not Applicable

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      P2.01-44 - Prognostic Value of TP53 Hot Exon Mutation in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)

      16:45 - 18:00  |  Presenting Author(s): Yong He  |  Author(s): Renhua Guo, Yutao Liu, Fang Xu, Yubo Wang, Jin Cao, Qingchen Wu, Zhang-Han Han, Jun-Yi Ye, Lu Zhang, Xinru Mao, Zhe Zhang, Jing Liu, Yu Zhang

      • Abstract

      Background

      Numerous studies have revealed either very marginal or no prognostic value of TP53 mutation NSCLC patients. Currently, in clinical settings, all TP53 mutations have been considered equally, without any differentiation between the various types and positions of mutations. However, increasing evidence has triggered us to challenge such practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively investigated the correlation between mutations occurring at hot exons (5-8) and overall survival (OS) in 214 previously tyrosine kinase inhibitor (TKI) treated advanced NSCLC patients. Among them, 184 had 1 line of TKI-treatment and the remaining 30 patients had more than 1 line of TKI-treatment. 115 harbored TP53 mutation; among them 105 patients had concurrent EGFR mutation; 5 had ALK rearrangements; 1 had ROS1 rearrangements; 1 had KRAS and 2 had ERBB2 mutations. 99 patients had wild type (WT) TP53; among them, 92 had EGFR mutation, 4 with ALK-rearrangements, 1 with MET and 1 with BRAF mutation. Fisher’s exact test and the Mann-Whitney test were used to determine if categorical and continuous variables, respectively, differed between TP53 WT and mutant groups.

      4c3880bb027f159e801041b1021e88e8 Result

      The prevalence of TP53 mutation in our cohort is 53.7% (115/214); 28 had mutation on exon 5, 18 on exon 6, 22 on exon 7 and 32 on exon 8. 32 patients had loss of function mutation and 51 patients had disruptive mutation. Our data revealed a positive correlation with N and M stage. Patients harboring TP53 mutation are more likely to diagnose with more advanced N (p=0.018) and M stage (p=0.001). Furthermore, patients with TP53 mutation are more likely to have liver (p<0.001) and bone metastasis (p=0.012). In patients treated with only 1 line of TKI-treatment, although TP53 status had no effect on PFS (p=0.241) and OS (p=0.49) when they were considered collectively, we observed patients with mutation in exon 5 had shorter OS (p=0.029) and mutation in exon 8 had shorter PFS (P=0.003) after controlling for age, gender, stage and histology. Furthermore, within the osimertinib subgroup (N=101), patients harboring mutation in exon 8 had significantly shorter PFS (P=0.007). In patients treated with more than 1 line of treatment, neither TP53 mutation considered collectively, nor hot exon mutations had correlation with PFS or OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study revealed unfavorable prognostic value of mutations in exon 5 and no prognostic value of TP53 if all mutations were considered collectively. Our study adds new dimension to the emerging picture that not all TP53 mutants are equal.

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      P2.01-45 - Mutational and Inflammatory Biomarkers for Lung Cancer Patients with Pleural Effusions

      16:45 - 18:00  |  Presenting Author(s): Balazs Hegedus  |  Author(s): Daniel Valdivia, Henry Paul Koziej, Elena Loscha, Paul Stockhammer, Till Plönes, Khaled Mardanzai, Mohamed Zaatar, Dirk Theegarten, Clemens Aigner

      • Abstract

      Background

      Pleural effusion is often associated with the progression of lung cancer and the treatment options for patients with malignant pleural effusions are rather limited. The estimation of prognosis remains to be challenging and personalized therapeutic strategies require a set of validated biomarkers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      87 lung adenocarcinoma, 27 squamous cell carcinoma and 8 neuroendocrine carcinoma patients with pleural effusions were treated in our department between July 2016 and April 2018. Preoperative C-reactive protein and white blood cell count was collected and their association with clinicopathological parameters and overall survival was calculated. KRAS, EGFR and ALK mutational status was available in advanced lung adenocarcinoma cases. The association of oncogenic mutations with the malignancy of effusion was also analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      39 of the 122 patients had malignant pleural effusions (32%). 64 patients had TNM stage IV disease. Importantly, high CRP (>5 mg/dl, HR: 14.7, CI95% 2.9-73, p=0.0011) but not high WBC (>9000 cells per microliter) was a strong predictor of shorter survival in lung cancer patients with pleural effusions. High CRP remained a significant prognosticator in lung cancer patients with benign effusions (HR: 21.5, CI95% 1.9-242, p=0.013). KRAS mutation was identified in 28% of the lung adenocarcinoma cases. There was a tendency for lower KRAS mutation incidence in the MPE subcohort when compared to BPE cases (16.6% vs 34.6%, p=0.15). Interestingly, 22% of patients had EGFR mutation and EGFR mutations were more frequent in lung cancer patients with malignant effusions when compared to benign effusions (OR 4.8, CI95% 1.2-19.9, p=0.029).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Oncogenic driver mutations may impact the development of malignant effusions in lung adenocarcinoma patients. Furthermore, our study indicates that the routinely available, circulating preoperative C-reactive protein level carries prognostic information. These findings suggest that oncogenic mutations and inflammatory biomarkers can further personalize therapeutic decisions and can contribute to the risk stratification of lung cancer patients with pleural effusions.

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      P2.01-46 - Investigating the Effects of Prior Malignancy on NSCLC Trial Eligibility

      16:45 - 18:00  |  Presenting Author(s): Michael Herman  |  Author(s): Natasha B Leighl, Frances A Shepherd, Geoffrey Liu, Penelope Bradbury

      • Abstract

      Background

      Up to 18% of patients with non-small cell lung cancer (NSCLC) who are candidates for participation in a clinical trial are excluded due to a prior malignancy. Common reasons include the need for another anti-cancer therapy and potential impact on clinical trial endpoints. We evaluated the proportion of trials that exclude patients with a prior history of malignancy, and estimate the potential impact of the prior malignancy from a cohort of NSCLC patients treated with first line systemic therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinical trials of palliative systemic therapy for NSCLC registered on or after January 1st 2014 from clinical trials.gov were reviewed to determine the proportion of trials that included a prior malignancy as an exclusion criterion. Patients with NSCLC and a prior malignancy, treated with first line palliative systemic treatment between January 1st 2010 and January 1st 2016 at the Princess Margaret Cancer Centre (PMCC), Toronto, Canada were identified from a cancer registry. A list of prespecified criteria of ways in which a prior malignancy may impact safety or a clinical trial endpoint was defined. These included: requirement for non-NSCLC anticancer therapies, other cancer detected on imaging, biopsy or tumour markers, disease progression or death from other malignancy, clinician uncertainty as to presence of synchronous other cancers. The proportions of patients with one or more of these criteria were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      66% of 359 clinical trial protocols contained an exclusion criterion for prior malignancy. 112 patients with advanced NSCLC and a prior malignancy were identified at PMCC, the median age was 71, 49% were male, the median time between prior cancer and NSCLC diagnosis was 74 months. 21% of patients were enrolled on a clinical trial. 52(59%) of the 88 patients not enrolled on a clinical trial did not meet any of our predetermined criteria, which may impact safety or a clinical trial endpoint due to other malignancy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A prior history of a malignancy is a common exclusion in NSCLC clinical trials. Preliminary results suggest the majority of patients in our study did not appear to have a complication that would have impacted safety or clinical trial endpoints. Further analyses to explore appropriate exclusion criteria for prior malignancies, which may minimize need to exclude patients from clinical trials, are underway.

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      P2.01-47 - Clinical Outcome After Surgical Resection Of Clinical Single-station N2 Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Kwanyong Hyun  |  Author(s): Samina Park, Hyun Joo Lee, In Kyu Park, Chang Hyun Kang, Young Tae Kim

      • Abstract

      Background

      We set up our treatment protocol performing upfront surgery for non-bulky, single-station clinical N2 (cN2a) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between 2012 and 2016, 129 patients underwent upfront surgery for cN2a disease diagnosed on CT and PET-CT findings. 85 patients underwent preoperative invasive mediastinal staging (IMS group), whereas, in 44, IMS was not performed (Non-IMS group). Survivals were compared with log-rank test. Subgroup analysis for pN2-3 is performed to identify prognostic factors using Cox-regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Pathologic N stages were pN0-1 in 26 patients (20%: 18 IMS, 8 non-IMS), pN2a in 51 (40%: 33 IMS, 18 non-IMS), pN2b in 47 (36%: 29 IMS, 18 non-IMS) and pN3 in 5 (4%: all IMS). The overall 5-year survival was 55.4% with no difference between groups (p=0.19). In pN2-3 patients, 5-year survival was 51.0% and IMS group was better (p=0.05). In a Cox’s regression, non-IMS (HR 1.89, p=0.04), no adjuvant chemotherapy (HR 3.55, p<0.001), extensive burden of metastatic lymph nodes (number of metastatic LN≥13, HR 3.32, p=0.002) were independent risk factors for survival.

      wclc-2018-table.pngwclc-2018-figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      We found significant number of cN2a patients were pN2b-3 even after IMS, but surgery resulted in reasonable survival. This suggests upfront surgery for cN2a disease is a valid option if preoperative IMS and adjuvant chemotherapy are warranted.

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      P2.01-48 - Predictive Factors in NSCLC Patients with Stage IIIB/IV Treated with First Line Platinum-Doublet Chemotherapy

      16:45 - 18:00  |  Presenting Author(s): Sofi Isaksson  |  Author(s): Christel Reuterswärd, Bassam Hazem, Håkan Griph, Jens Engleson, Kajsa Ericson Lindquist, Maria Planck, Johan Staaf

      • Abstract

      Background

      Predictive factors for response to chemotherapy in non-small cell lung cancer (NSCLC) are deficient. We investigate the associations between mutation status and treatment outcome of first line platinum-doublet chemotherapy in a 1.5 years population-based cohort of stage IIIB/IV patients. Furthermore, we will investigate the usefulness of gene expression signatures in predicting chemotherapy response in patients with advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the region of Skåne, Sweden, n= 600 (preliminary) patients with NSCLC stage I-IV (TNM 7th edition) had conclusive results from reflex NGS testing with Illumina TruSightTumor 26-gene panel between January 2015 – June 2016. From this cohort, we include all patients with stage IIIB/IV with first line platinum-doublet treatment not interrupted by other cause than progressive disease (PD) and evaluate their extra-cranial response to treatment by using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 with slight modifications. Patients who received radiotherapy against the primary tumor and/or mediastinum before or concomitant with chemotherapy are excluded.

      4c3880bb027f159e801041b1021e88e8 Result

      So far, 91 patients have been included, 10 (11%) with stage IIIB and 81 (89%) with stage IV. First-line chemotherapy included carboplatin/cisplatin in combination with gemcitabine/pemetrexed/vinorelbine. Bevacizumab were given in addition to chemotherapy in 3 patients. 25 (28%) responded with progressive disease (PD), 27 (30%) with stable disease (SD) and 39 (43%) with partial response (PR). TP53+/KRAS+ tumors were detected in 22 (24%) patients, TP53+/KRAS- in 34 (37%), TP53-/KRAS+ in 21 (23%) and TP53-/KRAS- in 14 (15%). No difference in response to treatment (p=0.6, Fisher’s exact test) or progression-free survival (PFS) (log rank test, p=0.6) according to mutation status was seen, although we observed a weak tendency of worse PFS in TP53+ patients with or without KRAS mutation compared to TP53-/KRAS- patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this population-based Swedish cohort, mutations in KRAS and/or TP53 are not significantly associated with first line chemotherapy response. However, also subtypes of these mutations should probably be considered. Additional analyses of potential predictors of treatment response, in association with other clinicopathological variables, will be presented.

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      P2.01-49 - Comparision of Radiotheraphy Concurrent Weekly Treatment in Locally Advanced Unresectable Non Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Abdurrahman İsikdogan  |  Author(s): Nadiye Akdeniz, Muhammet Ali Kaplan, Zuhat Urakci, Mehmet Kucukoner, Ogur Karhan

      • Abstract

      Background

      Despite concurrent chemoradiotheraphy is standard treatment of unresectable locally advanced non small cell lung cancer (NSCLC),optimal chemotheraphy regimen is still inconclusive. Radiotheraphy concurrent weekly chemotheraphy has been studying and due to less toxicity it is preferred. In this study, we aimed to compare two weekly different regimens in terms of outcome and toxicity .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We screened retrospectively 142 patients with stage III, locally advanced unresectable NSCLC, treated with radiotheraphy concurrent weekly platinum-paclitaxel ( PP) or platinum-docetaxel (PD ) between 2006 and 2017 years.Age, sex, stage, histologic subtype, response rates, survival and toxicity were analyzed. In RT concurrently PP arm 50 mg/m² paclitaxel and 20 mg/m² cisplatin or carboplatin AUC 2; in PD arm 20 mg/m² dosetaxel and 20 mg/m² cisplatin applied. Radiotheraphy applied as weekly 5 fraction/ 60-66 Gy. Treatment response classified progression and clinically responsive which consist of stable response (SR), complete response(CR) and partial response(PR).

      4c3880bb027f159e801041b1021e88e8 Result

      One hundred thirty one (92,3%) patients were man and median age was 62 (25-79). Histologic subtype was squamous cell carcinoma in 77 (54.2%) patients. At diagnosis 53 patients (37,3%) were stage IIIA, 89 (62,7%) patients were stage IIIB and IIIC. There were 102 patients in DP arm whereas 40 patients were in PP arm. Age, gender, stage and histologic subtypes were similar in both groups.There were no statistically significant in clinically response rates between two group (PD 96,1% vs PP 90% , p = 0.15) . Median overall survival (OS) was higher in PP arm than PD arm ( 29 vs 14,4 months ,p=0,018). Progression free survival (PFS) were same in both arms (15,6 vs 15,4 months p=0,522).There were no statistically significant in mucositis and eosophitis( 90% vs 80 %, p=0,418) and vomiting (10% vs 8,8%, p=0,931) in both arms. In PP arm neutropenia (p=0,000) and thrombocytopenia rates were higher (p=0,021). Pulmonary toxicity (p=0,053) and nausea (p=0,056) was higher in PP arm, which is closed to statistical significance. Although deaths due to treatment toxicity were not detected ,progression and other reason related death were more common in PD arm (p<0,001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our study, despite clinical response and PFS were same in both radiotheraphy concurrent regimens in locally advanced unresectable NSCLC, OS was higher in PP arm. There are few study compared this two arms, which show no OS differences. Although it must be supported by prospective studies,OS is beter in PP arm than PD arm.

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      P2.01-50 - Thromboembolism in ROS1 Rearranged Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Nick Pavlakis  |  Author(s): Malinda Itchins, Marliese Alexander, Thomas John, Steven Chuan-Hao Kao, Brett G.M Hughes, Adrian Lee, Sarah A Hayes, Rozelle Harvie, Viive M Howell, Stephen J Clarke, Michael Millward

      • Abstract

      Background

      The risk of thromboembolism (TE) is estimated to be 0.001% per year and hereditary thrombophilia present in 0.2-5% of the general adult population.

      It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) will develop thromboembolism throughout their disease course. In ALK rearranged NSCLC this incidence has been reported to be three to four fold higher at 36%.

      We sought to investigate the incidence in TE in a cohort of the rare ROS1 rearranged molecular subgroup.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Electronic records were reviewed in six tertiary hospitals to identify all patients diagnosed with ROS1 NSCLC. Predefined data were analysed in STATA15 software for Kaplan-Meier (KM) plot and Cox-regression modelling.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty-two patients were identified at data cut (31/1/2018). Median follow up was 10.9 months (mo); 38% had died. Median age was 53 years (31-80); 74% were female; 67% non-Asian and 88% non- smokers and 29% CNS disease during diagnosis.

      Median overall survival (OS) overall was estimated 28.8mo (range: 0.1-180.4mo).

      Thromboembolism incidence was 48% (n=20); 19 venous, 11 with pulmonary embolus (PE). One patient presented with fatal arterial TE (ROS1 diagnosed pre-mortem).

      Median time to TE was 2.3mo. In four patients TE was the harbinger for their diagnosis and two had encountered unprovoked TE prior to diagnosis, one then recurrent TE throughout diagnosis.

      Screening for a thrombophilia (TP) was not mandatory, and tested in n=9/20 cases with TE, one without. A co-occurring TP was identified in 15% (n=3/20); two factor V Leiden; one anti-thrombin III (ATIII) deficiency. Of interest, one patient with TE had factor XII deficiency; one thalassaemia minor and one acute-promyelocytic leukaemia without evidence of disseminated intravascular coagulation.

      Age; race; baseline ECOG; smoking history; treatment received; brain metastases at diagnosis; hereditary thrombophilia and neutrophil to lymphocyte ratio were not predictive of TE in this small cohort.

      Median OS in patients with TE was 21.3mo (0.1-180.4) versus 28.83mo (1.2-63.5) with no TE; hazard ratio 1.16 (95%CI 0.43-3.15, p=0.77).

      The ROS-1 fusion partner was known in two cases, both CD74-ROS1, one encountering TE (PE). Twenty-five have archival tissue available to identify the fusion partner and explore an association with TE.

      8eea62084ca7e541d918e823422bd82e Conclusion

      To the best of our knowledge, this is the first report on the incidence of thrombotic events specifically in ROS1-rearranged NSCLC. In this small cohort intriguingly there was a high incidence of TE and a higher incidence than the general population of hereditary thrombophilia.

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      P2.01-51 - Study of CD26/DPP4 Expression in a Large Series of Non-Small Cell Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Sven Hillinger  |  Author(s): Jae-Hwi Jang, Martina Haberecker, Alessandra Curioni Fontecedro, Florian Janker, Ignacio Gil-Bazo, Ilseon Hwang, Kunyoung Kwon, Walter Weder, Alex Soltermann, Wolfgang Jungraithmayr

      • Abstract

      Background

      Lung cancer is a leading cause of cancer-related death worldwide and the prognosis remains poor CD26/dipeptidyl peptidase 4 (DPP4) is a transmembrane exopeptidase expressed on various hematopoietic but also somatic cells including malignancies of breast, colon, and mesothelioma. We previously found that the activity of CD26/DPP4 in human lung adenocarcinoma is four times higher than in normal lung tissue and the inhibition of CD26/DPP4 decreased the growth of lung tumors in experimental models. These data prompted us to analyze the expression of CD26/DPP4 in samples from lung cancer patients to unravel the role of CD26/DPP4 as a potential therapeutic target to reduce lung cancer burden.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To identify CD26/DPP4, we performed immunohistochemistry (IHC) on multi-organ tissue micro array (TMA) using four different antibodies. We finally selected the antibody produced by Cell Signaling Technology. For the analysis of CD26/DPP4 by IHC, TMAs constructed from the samples of non-small cell lung cancer patients were used. The cohort consisted of 1110 patients (Adenocarcinoma (AC): 567; Squamous carcinoma (SC): 443). Three pathologists independently scored the staining intensity from zero to three in a blinded manner. Lung AC cell lines from tissue (H2347, H522, A549, and Hop62) and pleural malignant effusion (H1437, H460, Mai9, and Gon8) were employed to assess the expression of CD26/DPP4. ELISA was used to quantify CD26/DPP4 from cell lines.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall survival of the patients showed no difference between AC and SC groups. IHC scores revealed AC expressing significantly higher CD26/DPP4 levels vs. normal lung or SC (p=0.035, p<0.0001, respectively). In consistency with our previous findings, early stage cancer (IA) expresses significantly higher levels of CD26 than other stages IIB (p=0.0012), IIIA (p=0.0019), and IV (p=0.02) among AC samples. From our in vitro studies, we found that early stage derived cell line (H2347: stage I) expresses significantly more CD26/DPP4 compared to others (H522: stage II, A549 and HOP62 stage IV). In contrast, metastatic AC cell lines secrete significantly more CD26/DPP4 in culture medium compared to tissue derived cell lines, while the cellular level of CD26/DPP4 was higher in tissue derived cell lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      AC expresses significantly more CD26/DPP4 than SC. Furthermore, the expression of CD26/DPP4 was higher at early stages of AC compared to advanced stages. Human cell line data suggest that metastatic AC secretes CD26/DPP4 more actively than primary cancer. We therefore deem CD26/DPP4 to be a target for inhibition of human AC.

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      P2.01-52 - Identification of Leptomeningeal Metastasis-Specific Exosomal miRNA Signatures in Cerebrospinal Fluids of NSCLC Patients

      16:45 - 18:00  |  Presenting Author(s): Yang W. Shao  |  Author(s): Ben-Yuan Jiang, Yang-Si Li, Xue Wu, Bao Hua, Yan Ding, Jin -Ji Yang, Xu-Chao Zhang, Xue-Ning Yang, Wen-Zhao Zhong, Qing Zhou, Hai-Yan Tu, Cun Yi Gao, Shuyu Wu, Yi-Long Wu

      • Abstract

      Background

      Leptomeningeal metastasis (LM) is a devastating complication with poor prognosis in non-small-cell lung cancer (NSCLC) patients. The confirmed diagnosis of LM usually involves neurological evaluation, MRI imaging, and cytopathology analysis of limited tumor cells from cerebrospinal fluid (CSF). Exosomes are extracellular vesicles in body fluids enriched with microRNAs (miRNAs), which have been implicated to participate in brain metastasis. Here, we aimed to identify LM-specific exosomal miRNA signatures in NSCLC patients to elucidate their potential role in LM mechanism and to predict LM via liquid biopsy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Exosomes prepared from CSF and plasma samples of 39 advanced NSCLC patients with (LM+) or without (LM-) LM as well as 12 non-cancer individuals (NC) were underwent small RNA next-generation sequencing. For patients in the LM+ group, paired plasma samples were taken before (PLM+pre) and upon (PLM+post) LM diagnosis. Exosomal miRNA profiles were subjected for differential expression analysis, pathway enrichment analysis, and signature discovery.

      4c3880bb027f159e801041b1021e88e8 Result

      Unsupervised hierarchical clustering of the miRNA expression profiles clearly separated CSF samples into LM+ and LM free groups (LM- and NC). Interestingly, these samples were stratified based on their LM status only, regardless of their intraparenchymal metastasis status. In total, 247 (185 up and 62 down-regulated) miRNAs were identified differentially presented in the LM+ CSF exosome samples compared to the LM- and NC groups. Top altered miRNAs include dramatically up-regulated miR-200 family and down-regulated miR-144/451 cluster. Predicted gene targets of these top-regulated miRNAs were significantly enriched in Ras/MAPK/PI3K-AKT signaling, endocytosis pathways, and so on. Promisingly, a signature of five CSF exosomal miRNAs (let-7e-5p, miR-28-3p, miR-375, miR-200a-3p, and miR-486-5p) was identified for classification of LM+ patients with 100% sensitivity and 100% specificity. Due to the higher background complexity, we only identified one miRNA (miR-24-3p) was significantly up-regulated and one miRNA (miR-92b-5p) was significantly down-regulated in LM+ patients’ plasma-derived exosomes (PLM+pre and PLM+post) compared with the LM free group (PLM- and PNC). However, a combined signature of seven miRNAs (miR-24-3p, miR-223-3p, miR-340-5p, miR-27a-3p, miR-423-5p, miR-2110 and miR-342-5p) from PLM+pre samples was identified for the prediction of future LM with 81% sensitivity and 76% specificity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC patients with LM present a remarkably distinct CSF exosomal miRNA signature, which may involve in the progression of LM, and can be used as diagnostic biomarkers for LM. Furthermore, the identification miRNA signature in the pre-LM plasma samples suggests the potential use of liquid biopsy to predict LM for better patient care.

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      P2.01-53 - Local Treatment for Oligoprogression/Oligometastases After Failure to Crizotinib for ALK-Rearranged Stage IV Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Tsz Yeung Kam  |  Author(s): Jacky Yu Chung Li, M.Y. Lim, Oscar S.H. Chan, K.C Cheung, Victor Lee

      • Abstract

      Background

      Crizotinib is approved as 1st line treatment for ALK-rearranged stage IV non-small-cell lung cancer (NSCLC). We investigated if local treatment for oligoprogression/metastases (<=5 lesions) while maintaining crizotinib could prolong progression-free survival (PFS) for ALK-rearranged stage IV NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a retrospective review on crizotinib for ALK-rearranged stage IV NSCLC in the real-world setting in 4 public oncology hospitals. All patients who received crizotinib outside clinical trials were reviewed. Patients who developed oligoprogression/metastases following progressive disease to crizotinib were assessed for local treatment (surgery, palliative or radical radiotherapy or combination of surgery and radiotherapy) for these sites while continuing crizotinib until further progressive disease beyond the definition of oligoprogression/metastases. The primary study endpoint is PFS after local treatment for olioprogression/metastases. Secondary endpoints are overall survival and toxicity profiles.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 165 patients were recruited, of which 115 (69.7%) and 50 (30.3%) received it as 1st line treatment and at later lines respectively. Of the 161 (97.6%) patients eligible for tumour response assessment, the objective response rate was 64.5%. After a median follow up of 18.5 months (range 0.6-70.1 months), the median PFS and OS of the whole population were 10.8 and 18.5 months. There was no statistical difference in PFS and OS among those who received crizotinib as 1st line and later lines. Twenty-nine (17.6%) patients developed oligoprogression/oligometastasis following crizotinib. Eighteen (62.1%) received local treatment (surgery – 2 , stereotactic radiosurgery/radiotherapy – 7, intensity-modulated radiation therapy/tomotherapy – 3, palliative radiotherapy – 7), of whom 3 patients received 2 courses of local treatment to different oligoprogressive/oligometastatic sites at oncologists’ discretion while continuing crizotinib until their next date of progressive disease. Median PFS was significantly longer in those who received local treatment (20.9 months [95% CI 11.8-30.1 months] vs. 11.4 months [95% CI 5.1-17.7 months]; p=0.004) than those who did not for their oligoprogression/oligometastases. Median OS was not different between those who received local treatment and those who did not for their oligoprogression/oligometastases (p=0.742). Seventy-one (43.0%) patients received other ALK inhibitors following progression to crizotinib (1 line – 50, 2 lines – 19, 3 lines – 1, and 4 lines – 1). Four (2.4%) patients are still receiving crizotinib without progression. Crizotinib was well-tolerated with only 7.9% grade 3/4 adverse events. No grade >=2 events were reported for local treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Local treatment for oligoprogressive/metastatic diseases could significantly prolong PFS in the real-world setting, which procrastinates the later use of other systemic therapies.

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      P2.01-54 - Predictive Factors for Thromboembolism in Advanced Lung Cancer Patients on Platinum Chemotherapy: A Prospective Study

      16:45 - 18:00  |  Presenting Author(s): Shruti Kate  |  Author(s): Amit Joshi, Kumar Prabhash, Vanita Noronha, Vijay Patil

      • Abstract

      Background

      Advanced lung cancer patients are predisposed to thrombosis due to many factors related to the disease and treatment, apart from the genetic and phenotypic factors. We aimed to determine the incidence of thromboembolic events (TEs) in advanced Non-Small Cell Lung Cancer (NSCLC) patients treated with platinum chemotherapy and study the baseline and treatment attributes predicting the onset of such events.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We evaluated advanced NSCLC patients on platinum chemotherapy for predetermined risk factors for thrombosis at baseline and routine visits. Patients with prior thromboembolism were excluded. The baseline patient characteristics were noted and patients were assigned to Khorana risk group as per the Khorana scores. The duration of follow up was until 4 weeks from the last chemotherapy. TEs occurring between the first dose of chemotherapy and 4 weeks after the last dose were considered as related. Predetermined factors associated with thromboembolism were studied in univariate analysis by chi square test.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 188 patients were screened, out of which 21 patients were excluded and two patients were lost to follow up. The mean age of was 57.5 years (range 30–79). Majority of the patients were male (83.2%) and either current or former smokers (62.3 %). 69.5% of patients had a normal Body mass Index (BMI) while 13.2 % were overweight (BMI 25-29.9 kg/m2) and 1.2 % were class I obese (BMI 30-34.9kg/m2). Majority of the patients (78.1%) belonged to the intermediate Khorana group (Risk score 1-2) while 23.0% belonged to high risk (Khorana score of ≥3) .Of the 165 patients who completed follow up, 67.8% received carboplatin-gemcitabine, 30.3% carboplatin-pemetrexed, 1.2% cisplatin-pemetrexed and 0.6 % carboplatin-paclitaxel. Median duration on platinum was 94 days (range 1-478). TE’s occurred in 4.8% of patients. Three patients developed venous pulmonary thromboembolism and 5 patients developed cerebral infarction, out of which 4 had arterial cerebral infarction and one patient had superior sagittal sinus thrombosis. The majority of events (7 out of 8) occurred within 100 days of starting chemotherapy. None of the presumed risk factors were found to be related to TEs on univariate analysis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite the lower incidence of TEs in our study, exclusion of patients with prior thrombosis suggests de novo thrombosis on platinum chemotherapy .None of the predetermined risk factors for thrombosis were found to be statistically related to the occurrence of TEs, possibly due to the small number of events and sample size.

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      P2.01-55 - Dual-Energy CT Scan to Evaluate Sarcopenia in Lung Cancer in Comparison with Conventional CT Scan

      16:45 - 18:00  |  Presenting Author(s): Eun Young Kim  |  Author(s): Joohwan Park, Yong Saing Kim, Hee Young Lee, Hee Kyung Ahn, Shin Myung Kang

      • Abstract

      Background

      Depletion of skeletal muscle mass (sarcopenia) have been associated with poor prognosis in patients with malignancy. Although CT-determined skeletal muscle index (muscle area/height2, cm/m2) is regarded as a reference standard to evaluate the presence of sarcopenia, it is unclear the agreement of DECT derived images on the quantification of skeletal muscle area (SMA). The purpose of this study to evaluate the agreement of SMA quantification between dual-energy CT (DECT) derived images (virtual non-contrast; VNC and post-contrast weight-average 120kVp images) and conventional non-contrast CT image.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      For a total 128 lung cancer (LCA) patients who underwent DECT at the time of diagnosis, SMA were measured using non-contrast CT, and DECT images (post-processed VNC and weight-average 120kVp). Paired T-test was used to compare the quantification results, and intraclass correlation coefficients (ICC) for the agreement between three scan results.

      4c3880bb027f159e801041b1021e88e8 Result

      The agreement was excellent (ICC=0.991) between three images. However, SMA was significant higher in VNC (mean±SD, 125.2±23.8cm2, p<0.001) and weight-average 120kVP (110.4±22.0cm2, p<0.001) in comparison with non-contrast CT (107.4±22.7cm2). When using recently proposed L1 muscle index cutoff (46 cm/m2 for male, 29 cm/m2 for female) for sarcopenia, the prevalence of CT-determined sarcopenia is significantly decreased using weight-average 120kVp and VNC to 53.1% and 22.7%, compared with 58.6% using non-contrast CT.

      8eea62084ca7e541d918e823422bd82e Conclusion

      DECT derived VNC and weight-average 120kVp images slightly overestimate SMA. Same scan parameter is recommended to minimize measurement error to evaluate sarcopenia.

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      P2.01-56 - Metastases in Residual PET Uptake of Lymph Nodes After Treatment: Added Value of CT Radiomic Approach for Prediction

      16:45 - 18:00  |  Presenting Author(s): Chu Hyun Kim  |  Author(s): Ho Yun Lee, Hong Kwan Kim, Joon Young Choi

      • Abstract

      Background

      Although substantial decrease of FDG uptake on positron emission tomography-computed tomography (PET-CT) holds promise metabolic response, predicting pathologic complete response of lymph nodes still remains challenging. We investigated the potential of CT radiomics features to predict pathologic complete response of lymph nodes showing residual uptake on PET-CT after neoadjuvant concurrent chemoradiotherapy (CCRT) in stage IIIa non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 2004 through 2013, all consecutive patients who underwent neoadjuvant CCRT for stage IIIa NSCLC, post-treatment PET-CT, and curative operation were included. As for all lymph nodes which showed remaining positive FDG uptake on restaging PET-CT, 161 CT Radiomic features from physical, shape, histogram, texture, regional feature categories were extracted. Positive and negative lymph node metastases were compared with respect to clinicopathologic characteristics as well as CT radiomic features using the Pearson χ2 test or the Fisher exact test Multivariate logistic regression was used to explore the predictive model for the the detection of metastatic lymph nodes, for which receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 237 patients undergoing neoadjuvant CCRT for stage IIIa NSCLC, 135 patients (56.9%) showed residual PET uptake on 177 lymph nodes after treatment. Among those 177 lymph nodes, 70 lymph nodes were proven to be malignant (39.5%, 70 of 177). On multivariate analysis, metastatic lymph nodes were significantly tended to be more squamous cell carcinoma than adenocarcinoma (odds ratio [OR] = 0.370, 95% confidence interval [CI] = 0.190 to 0.722; reference of adenocarcinoma, P value = 0.004) and higher entropy-GLCM (OR = 1.437, 95% CI = 1.147 to 1.802, P value = 0.002), where the predictive model for metastasis showed discrimination performance with an area under the receiver operating characteristic curve (AUC) of 0.770 (95% CI = 0.700 to 0.839, P value < 0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Radiomic approach allows for noninvasive detection of lymph node metastases in lymph nodes showing residual PET uptake after treatment in NSCLC patients

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      P2.01-57 - Prognostic Implication of Clinical, Imaging, and Pathologic Parameters in N2(+) Stage IIIA Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Yong Chan Ahn  |  Author(s): Hakyoung Kim, Jin Man Kim, Hongryull Pyo, Jae Myoung Noh, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Yong Soo Choi, Jhingook Kim, Jae Ill Zo, Young Mog Shim, Joungho Han, Seung Hyup Hyun, Joon Young Choi

      • Abstract

      Background

      As a comprehensive study of large scale and long-term clinical outcomes from a single institution, we are trying to analyze any predictive or prognostic factors for survival outcomes in N2(+) NSCLC patients. The purpose of this study is to investigate the efficacy of clinical, imaging (CT and PET-CT), and pathologic parameters, as a prognostic factor in N2(+) NSCLC patients undergoing tri-modality therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed 160 patients with N2(+) NSCLC patients between January 2008 and June 2014. All patients underwent preoperative concurrent chemoradiotherapy (CCRT) (44-45 Gy in 22-25 fractions concurrent with weekly DP chemotherapy) and surgery. Clinical, imaging (CT and PET-CT), and pathologic parameters were analyzed with respects to outcomes.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall pathologic down-staging and pathologic complete response following preoperative CCRT were achieved in 66 (41.3%) and 13 patients (8.1%), respectively. The median follow-up durations of all patients was 43 months (2~106 months). The 5-year rates of disease-free survival (DFS) and overall survival (OS) were 33.3% and 53.0%, respectively. Pathologic N down-staging (HR 2.604; 95% CI 1.418-4.779; p value=0.002) was a significant factor for DFS. Histopathology (HR 0.475; 95% CI 0.242-0.930; p =0.030), GTV of nodal lesion(s) on pre-RT CT (HR 1.066; 95% CI 1.029-1.104; p <0.001), type of surgery (HR 2.985; 95% CI 1.114-7.997; p =0.030), and proportion of viable tumor on cross-section area (HR 0.986; 95% CI 0.973-0.999; p =0.034) were significant factors for OS. Neither tumor volume reduction rate (TVRR) nor SUVmax was significant for DFS or OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In patients with N2(+) NSCLC undergoing tri-modality therapy, we proved that none of the imaging parameters correlated with prognosis, except pretreatment nodal volume. We confirmed that patients with adenocarcinoma showed prominently improved survival and pathologic N down-staging was a most important pathologic parameter as a prognosticator.

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      P2.01-58 - Demographics, Clinical Characteristics and Treatment Sequencing in Stage III Unresectable NSCLC Patients: A Cancerlinq Cohort

      16:45 - 18:00  |  Presenting Author(s): Alyssa B Klein  |  Author(s): Iksha Herr, Sharon Maclachlan, Danielle Potter

      • Abstract

      Background

      To describe the demographics, clinical characteristics and treatment sequencing among a real-world cohort of stage III unresectable non-small cell lung cancer (NSCLC) treated with chemoradiation therapy (CRT) in the US.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Cancerlinq Discovery Database (CLQ), launched by the American Society of Clinical Oncology (ASCO) in 2016, consists of longitudinal, demographically and geographically diverse data aggregated from oncology practice Electronic Health Record (EHR) databases in the US. This retrospective cohort comprises 324 stage III unresectable NSCLC patients who received concurrent, platinum-based chemoradiation between January 1, 2007 and December 31, 2017 (study period). A patient was considered unresectable if s/he did not have surgery within 6 months of the stage III diagnosis date (study index date). A patient’s follow-up period was defined as the time from study index date until the end of the study period, patient death, or loss to follow up, whichever event occured first.

      4c3880bb027f159e801041b1021e88e8 Result

      The cohort was mostly male, white, with a mean age of 66.86 years at index date. Nearly all patients of the cohort (93.57%) had an initial diagnosis of stage III (75.31% IIIA, 2.78% IIIB); 2.47% had an initial stage I diagnosis and 4.00% had an initial diagnosis of stage II. The most common histology was squamous cell carcinoma (46.61%), followed by adenocarcinoma (41.05%). Curation related to clinical characteristics (eg ECOG status, smoking status and other comorbidities) are ongoing, so they are largely missing at this time. During the mean follow-up time of 26.64 months, the cohort received 1.60 lines of therapy (LOT). The most common treatment sequence during the follow-up period consisted of platinum therapy +CRT (82.72%); almost 10% of patients received platinum therapy +CRT, followed by immuno-oncology (IO) therapy. Approximately 38.30% of patients progressed to line of therapy 2 (LOT2) and 29.84% progressed to line of therapy 3 (LOT3), with nearly 18% of patients receiving IO therapy during LOT2 or LOT3.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This exploratory analysis of a stage III unresectable NSCLC cohort is descriptive in nature and suggests that the CLQ Discovery Database can be used to construct generalizable cancer cohorts. Future analyses will focus on validation of CLQ as a real-world data source, using findings from other retrospective, observational studies conducted by AstraZeneca as a benchmark.

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      P2.01-59 - The Cost of Lung Cancer in the County of Gävleborg – Sweden

      16:45 - 18:00  |  Presenting Author(s): Hirsh Koyi  |  Author(s): Johan Isaksson, Nikolaos Melas, Eva Brandén

      • Abstract

      Background

      Lung cancer is the leading cause of cancer morbidity and mortality, both of which imply that its burden may be high upon the health services and society. The purpose of this study is to present an economic analysis of the actual care costs of lung cancer which will allow comparison with, and verification of, cost estimates that were developed through modelling and opinion.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A chart review was conducted of incident cases of all patients with newly diagnosed lung cancer during 2015 in the Department of Respiratory Medicine, Gävle Hospital. Cases were censored at two years from the date of diagnosis. Data was retrospectively collected from patient charts. This data included patient characteristics, tumour characteristics, treatment details, adverse events, survival and resource use. Relevant clinical and health utilization data were collected. Health utilization data included hospital and institutional outpatient (ie, ambulatory clinic) costs. The present analysis was performed from the economic perspective of the health care institution.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of more than 13 000 health service events were captured. Laboratory tests, diagnostic imaging and ambulatory visits constituted 86% of the service events while patient admissions and therapy constituted 76% of the costs. The vast majority of overall costs occurred just before, or within, three months of diagnosis. The cost for imaging was 344042 USD and for diagnostic procedures was 204272 USD. The total cost for chemotherapy was 651879 USD.

      More data will be presented during the conference.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results agree with the literature that the majority of lung cancer case costs are realized around the date of diagnosis (ie, early phase). The present study illustrates Swedish health care system lung cancer case costs based on actual care received .The majority of the costs occurred soon after diagnosis. These results gave an assessment of all persons treated, the course of the treatment and, thus, is an accurate assessment of costs for policy-making purposes.

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      P2.01-60 - Clinical Utility of Circulating Tumor Cell (CTC) Analysis Using Target Selector™ in Metastatic NSCLC Chemotherapy Patients

      16:45 - 18:00  |  Presenting Author(s): Lara Kujtan  |  Author(s): Cecile Rose T Vibat, Veena M. Singh, Kevin F Kennedy, Anuj Shrestha, Sheshadri Madhusudhana, Jacob Smeltzer, Ashiq Masood, Janakiraman Subramanian

      • Abstract

      Background

      Over half of lung cancer patients present with advanced stage disease at diagnosis. Liquid biopsy is emerging as a minimally invasive and cost-effective means of cancer biomarker evaluation to select appropriate treatment and monitor disease burden. CTC enumeration may have prognostic and predictive potential for patients receiving chemotherapy. Here we describe interim results of a prospective study analyzing blood CTCs from treatment-naïve patients with histologically confirmed metastatic non-small cell lung cancer (NSCLC) who are candidates for systemic cytotoxic chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Venous blood samples were obtained for CTC analysis before administration of chemotherapy on treatment days (D) 1, 8, 22 and 43, and at disease progression. Blood was collected in Biocept CEE-Sure™ blood collection tubes, and samples were processed at Biocept's CLIA-certified, CAP-accredited laboratory. Biocept’s Target Selector™ CTC platform uses an antibody capture cocktail and microfluidic channel for CTC capture and biomarker analysis. Study objectives include determining the proportion of patients with D1 CTC detection, and CTC correlation to time to progression and overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-three patients have been enrolled so far in this ongoing study: 16 (69.5%) adenocarcinoma, 7 (30.4%) squamous cell carcinoma. Fifteen patients progressed on initial therapy to date, with a median time to progression of 110 days. Of 22 patients with blood collections at D1 (treatment start), 14 (63.6%; 10 adenocarcinoma, 4 squamous) had detectable CTCs. For patients with detectable D1 CTCs, CTC count at D8 decreased in 13/14 (92.9%; 9 adenocarcinoma, 4 squamous) subjects, and was unchanged in 1 individual (7.1%; adenocarcinoma). Patients with 1-5 CTCs at D1 had a mean time to progression of 140.75 days; patients with >5 CTCs at D1 had a mean time to progression of 101.83 days (p=0.17). Among patients with undetectable CTCs at D1, CTCs remained undetectable in 4/8 (50%; all adenocarcinoma) and increased in 2/8 (25%; one each of adenocarcinoma and squamous) of subjects; CTCs were not collected at D8 for 2 individuals.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Implementation of Biocept’s TargetSelector™ enables the highly sensitive detection of CTCs in the clinical setting. CTCs are detectable in the majority of patients with metastatic NSCLC. In subjects with detectable CTCs prior to chemotherapy, CTC count declines within a week after starting chemotherapy in >90% patients. Preliminary data suggest that CTC enumeration may have prognostic and predictive potential for patients receiving chemotherapy. Further data from this ongoing study may provide additional insight into the role of CTC analysis applied to clinical practice.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-61 - Body Mass Index over Time is Associated with Overall Survival in Advanced NSCLC Patients Treated with Immunotherapy.

      16:45 - 18:00  |  Presenting Author(s): Stephanie Labomascus  |  Author(s): Ibtihaj Fughhi, Philip Bonomi, Andrew McDonald, Marta Batus, Mary Jo Fidler, Sanjib Basu, Jeffrey Borgia

      • Abstract

      Background

      Cachexia has been associated with inferior outcomes for patients with stage III/IV NSCLC (aNSCLC). This study evaluates the potential relationship between baseline and longitudinal body mass index (BMI) with progression free survival (PFS) and overall survival (OS) in aNSCLC patients on nivolumab or pembrolizumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with aNSCLC who received at least once cycle of nivolumab or pembrolizumab between January 2015 and January 2017 were identified in our pharmacy database. Patient demographics, longitudinal BMIs, treatment start date, date of progression, and last follow-up were recorded. OS and PFS were assessed by log-rank tests and Cox proportional hazard analysis. Time-dependent Cox model based analyses were used to assess the association between time dependent BMIs.

      4c3880bb027f159e801041b1021e88e8 Result

      The study included 162 aNSCLC patients. Median age 68 yrs, male/female 40.1%/59.9%. BMI values were obtained longitudinally at baseline, 6 wks, and 12 wks. Median BMI: baseline 24.69, at 6 wks 24.75, and at 12 wks 24.89. Median change in BMI: baseline to 6 wks = -0.50 (range: -5.79 to +2.92), baseline to 12 wks = -0.33 (range: -6.52 to +3.41), and 6 wks to 12 wks = -0.21 (range: -4.56 to +2.73). Hazard ratios for change in BMI with OS: baseline to 6 wks HR 0.7198 (p=0.0010), baseline to 12 wks HR 0.8703 (p=0.0553), and 6 wks to 12 wks HR 0.8284 (p=0.0668).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Change in BMI over time is associated with OS in aNSCLC patients treated with nivolumab or pembrolizumab. Although decrease in BMI may simply be a prognostic marker for treatment with immune checkpoint inhibitors, it is possible that understanding potential relationships between cachexia and the immune system may be useful in developing strategies to improve response to immunotherapy.

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      P2.01-62 - Extracellular Vesicle-Based Egfr Genotyping in Bronchoalveolar Lavage Fluid from Non-Small Cell Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Jong Sik Lee  |  Author(s): Jae Young Hur, In Ae Kim, Hee Joung Kim, Wan Seop Kim, Kye Young Lee

      • Abstract

      Background

      Liquid biopsies for EGFR genotyping using plasma cell-free DNA (cfDNA) have limited value due to low sensitivity. Extracellular vesicles (EV) have been proven to contain mutant EGFR DNA in bronchoalveolar lavage fluid (BALF) from non-small cell lung cancer (NSCLC) patients. As an alternative to plasma liquid biopsies using cfDNA, we investigated the feasibility of EV-based liquid biopsy for EGFR genotyping using BALF from NSCLC patients, prospectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EV DNA was extracted from the BALF of NSCLC patients with confirmed tissue/cytology-based EGFR genotyping at initial diagnostic work-up stage. (N=137) The number of patients with stage I, II, III, and IV are 37 (27%), 6 (4.4%), 23 (16.8%), 71 (51.8%), respectively. The patients were selected by favorable demographic data for EGFR mutation. EGFR mutation testing was done by peptide nucleic acid (PNA) clamping-assisted fluorescence melting curve analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      The overall sensitivity and specificity of EGFR genotyping using BALF EV DNA were 69.5% and 83.3% and the concordance rate was 77.4%. (Kappa=0.534, P=0.000) The sensitivity was significantly increased along with the stage (42.1% in stage I, II, 60.0% in stage III, and 100% in stage IV). Especially, in stage IV disease, BALF EV-based EGFR typing did not miss all of tissue-proven 30 EGFR mutant cases and detected 9 additional mutant cases. Detection of EGFR mutation becomes significantly more sensitive as T stage increases. (T1 = 43.8%, T2 = 75%, T3 and T4 = 100%) Turn-around time (TAT) for EGFR genotyping using BALF EV DNA was 1-2 days, while it takes usually 2 weeks for tissue typing.

      8eea62084ca7e541d918e823422bd82e Conclusion

      BALF EV-based EGFR genotyping is a novel and highly promising method with rapid TAT and incredible accuracy in stage IV NSCLC patients. Further research in early stage disease is necessary and the matter of over-detection should be clinically validated by evaluating EGFR-TKI drug response.

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      P2.01-63 - Are Heart Doses Associated with Survival in NSCLC Treated with Post-Operative Radiotherapy? A National Population-Based Study

      16:45 - 18:00  |  Presenting Author(s): Chia Ching Lee  |  Author(s): Gail Wan Ying Chua, Huili Zheng, Yu Yang Soon, Ling Li Foo, Anuradha Thiagarajan, Swee Peng Yap, Tian Rui Siow, Wee Loon Ng, Kevin Lee Min Chua, Connie Yip, Brendan Seng Hup Chia, Yan Yee Ng, Zubin Master, Poh Wee Tan, Yun Inn Tan, Yuh Fun Leong, Joan Faith Evacula Loria, Balamurugan Vellayappan, Wee Yao Koh, Cheng Nang Leong, Jeremy Chee Seong Tey, Ivan Weng Keong Tham, Kam Weng Fong

      • Abstract

      Background

      Some early studies suggested that post-operative thoracic radiotherapy (PORT) using non-modern radiation techniques in non-small cell lung cancer (NSCLC) might cause significant treatment-related toxicities. Higher radiation doses to the heart have been recently linked to more cardiac events and worse overall survival (OS) in patients with locally-advanced NSCLC treated with thoracic irradiation. We embarked on a national population-based study to assess the association between radiation heart doses, acute myocardial infarct (AMI) rates and OS in NSCLC patients treated with PORT using contemporary radiation techniques.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Study eligibility criteria included stage I to III NSCLC treated with PORT from 2007 to 2014 in our public hospitals which comprised about 80% of national caseload. The clinical and dosimetric data were collected from the institutional electronic medical records and linked to the national death and AMI registries. Univariate Cox regression was performed using STATA version 13.

      4c3880bb027f159e801041b1021e88e8 Result

      43 eligible patients were identified. Median follow-up duration was 36.6 months. Characteristics of study population are summarized in Table 1. There were no AMI events. The 1- and 2-year OS were 74% and 65%. Univariate Cox regression analysis showed that age (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.10; P= 0.008) was the only significant factor associated with OS. Radiation heart doses, including mean heart dose, volume of heart receiving at least 5, 25, 30, 40, 50 Gy and dose to 30% of heart volume, were not associated with OS.

      Table 1: Characteristics of Study Population
      Characteristics N= 43
      Sociodemographic and Clinical Characteristics
      Age at lung cancer diagnosis, year, median (IQR) 63.6 (54.2-67.0)
      Gender
      Male
      Female

      18 (41.9%)
      25 (58.1%)
      Eastern Cooperative Oncology Group performance status
      0 and 1
      2

      41 (95.4%)
      2 (4.6%)
      Smoking status
      Current and former smoker
      Never smoker

      14 (32.6%)
      29 (67.4%)
      Diabetes mellitus
      Yes
      No

      7 (16.3%)
      36 (83.7%)
      Pre-existing ischaemic heart disease
      Yes
      No

      6 (14.0%)
      37 (86.0%)
      Chronic obstructive pulmonary disease
      Yes
      No

      1 (2.3%)
      41 (97.7%)
      Use of positron emission tomography-computed tomography for staging
      Yes
      No

      19 (44.2%)
      24 (55.8%)
      Use of brain magnetic resonance or contrast computed tomography for staging
      Yes
      No

      35 (81.4%)
      8 (18.6%)
      Tumour Characteristics
      Histology
      Adenocarcinoma
      Squamous cell carcinoma
      Non-small-cell lung cancer, not otherwise specified

      31 (72.1%)
      5 (11.6%)
      7 (16.3%)
      Tumour laterality
      Left
      Right

      16 (37.2%)
      27 (62.8%)
      Lobar location of tumour
      Upper
      Middle
      Lower

      25 (58.1%)
      5 (11.6%)
      13 (30.2%)
      Pathological T stage
      T1
      T2
      T3
      T4

      15 (34.9%)
      19 (44.2%)
      6 (13.9%)
      3 (7.0%)
      Pathological N stage
      N0
      N1
      N2

      10 (23.3%)
      4 (9.3%)
      29 (67.4%)
      Overall pathological stage
      Stage I
      Stage II
      Stage III

      3 (7.0%)
      9 (20.9%)
      31 (72.1%)
      Resection margin status
      R0
      R1
      R2

      28 (65.1%)
      13 (30.2%)
      2 (4.7%)
      Treatment Characteristics
      Type of surgery
      Lobectomy
      Pneumonectomy

      36 (83.7%)
      7 (16.3%)
      Use of concurrent or sequential chemotherapy
      Yes
      No
      Unknown

      31 (72.1%)
      11 (25.6%)
      1 (2.3%)
      Type of chemotherapy used
      Cisplatin + vinorelbine
      Cisplatin + gemcitabine
      Cisplatin + pemetrexed
      Carboplatin + vinorelbine
      Carboplatin + gemcitabine
      Carboplatin + pemetrexed
      Carboplatin + paclitaxel

      13 (30.2%)
      6 (14.0%)
      4 (9.3%)
      2 (4.7%)
      2 (4.7%)
      2 (4.7%)
      2 (4.7%)
      Thoracic radiation technique
      3D-conformal
      Intensity-modulated radiation therapy or Arc therapy

      30 (69.8%)
      13 (30.2%)
      Prescribed thoracic radiation dose, Gy, median (IQR)* 60.0 (50.0-60.0)
      Dosimetric Characteristics
      Mean heart dose, Gy, median (IQR) 9.4 (2.3-14.6)
      Heart volume received at least 5 Gy (heart V5), percentage, median (IQR) 34.0 (9.7-46.0)
      Heart volume received at least 25 Gy (heart V5), percentage, median (IQR) 15.0 (2.0-24.0)
      Heart volume received at least 30 Gy (heart V5), percentage, median (IQR) 12.3 (1.0-20.0)
      Heart volume received at least 40 Gy (heart V5), percentage, median (IQR) 4.6 (0.0-14.5)
      Heart volume received at least 50 Gy (heart V5), percentage, median (IQR) 2.0 (0.0-6.0)
      Dose to 30% of heart volume (heart D30), Gy, median (IQR) 7.4 (1.5-17.5)
      Mean lung dose, Gy, median (IQR) 11.2 (10.1-13.6)
      Lung volume received at least 5 Gy (lung V5), percentage, median (IQR) 48.0 (40.0-56.0)
      Lung volume received at least 20 Gy (lung V20), percentage, median (IQR) 20.4 (16.0-26.0)
      Planning target volume in 10 cc, median (IQR) 20.8 (15.1-38.8)
      Abbreviation:
      1. IQR, interquartile range
      *All doses are in equivalent dose in 2-Gy fraction

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study found that various radiation heart doses were not significantly associated with OS in patients with NSCLC treated with PORT. Studies with larger sample size and longer term follow-up are needed to assess cardiac outcome, given the possibility of late occurrence of AMI events.

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      P2.01-64 - Prognostic Value of PET-CT after Induction Chemoradiotherapy and Curative Surgery in IIIA-N2 NSCLC: A Multi-Institutional Analysis

      16:45 - 18:00  |  Presenting Author(s): Jong Hoon Lee

      • Abstract

      Background

      We evaluate the correlation of clinical staging on positron emission tomography-computed tomography (PET-CT) and pathologic staging and the prognostic value of PET-CT after induction chemotherapy in patients with locally advanced Non-Small Cell Lung Cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed 42 cases of clinical stage IIIA-N2 NSCLC who receive 2 to 4 cycles of pre-operative chemotherapy with or without radiation followed by curative resection. The maximum standard uptake value (SUVmax) of the suspected lesion on PET-CT was recorded. PET-CT findings after induction chemotherapy were compared with those of initial PET-CT and pathology after surgery.

      4c3880bb027f159e801041b1021e88e8 Result

      The accuracy of PET-CT in restaging of the primary tumor after induction chemotherapy was 50.0%. 18 (42.8%) of 42 patients were underestimated ycT stage, and 3 (7.1%) of 42 patients was overestimated ycT stage by PET-CT scan. The accuracy of PET-CT in restaging of the nodal disease was 71.4%. 6 (14.3%) of 42 patients were underestimated ycN stage, and 6 (14.3%) of 42 patients were overestimated ycN stage as compared with pathologic staging. The 2-year overall survival (OS) and relapse-free survival (RFS) rate were 68.5% and 40.9%, respectively. Complete responders (ycT0N0M0) on PET-CT after induction chemotherapy had a significantly longer RFS time than did incomplete responders (28.3 months versus 9.1 months, P = 0.021).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Complete response on PET-CT after induction chemotherapy with or without radiation was a good prognosticator for RFS in stage IIIA-N2 NSCLC patients who received surgery. However, response evaluation on PET-CT after induction chemotherapy should be interpreted with caution due to its unacceptable accuracy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-65 - Assessment of Individual and Combined of Five Serum Tumor Markers for Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Yuping Li  |  Author(s): Hanyan Xu, Junru Ye, Chengshui Chen

      • Abstract

      Background

      Tumor markers were often used to help in diagnosis lung cancer, The best known tumor markers in lung cancer were SCC, CEA,CYFRA21-1,NSE,and ProGRP. The roles of these tumor markers in diagnosis remain to be determined.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This retrospective study conducted between January 2015 and April 2017 at the First Affiliated Hospital of Wenzhou Medical University in China. A total of 2569 patients sought medical attention for a pulmonary mass presence to either confirm or exclude the disease.SCC,CEA,Cyfra21-1,NSE and ProGRP were examied with suspicious lung cancer. SPSS 20.0 used for all statistical analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      Finally,1135 patients were excluded,1434 patients were selected.Lung cancer was established in 1095 patients(737 males and 358 females), average age of(65.3±10.8)years and excluded in 339 patients (229 males, 117 females),average age of (55.7±13.4).Abnormal CEA were represented in 65.6% of adenocarcinoma. SCC-Ag and CYFRA21-1 significantly higher in 59.8% and 79.0% of squamous cell carcinoma respectively. Abnormal values of NSE and ProGRP were associated with 93.3% and 80.2% of SCLC.CEA and CYFRA 21-1 recorded sensitivity of 65.6% and 65.3% respectively in adenocarcinoma. In squamous cell carcinoma, SCC-Ag and CYFRA21-1 displayed sensitivity of 59.8% and 79% respectively. In SCLC, NSE and ProGRP showed sensitivities of 93.5% and 80.8%.The combination of different tumor markers yielded sensitivity values (>90%) and specificity values (>57%). The combination of five tumor markers recorded the highest sensitivity of 95.6%. The CYFRA 21-1 combine with CEA recorded the highest specificity 79.9%. ROC curves were plotted to explore the diagnostic role of these tumor markers individually and in combination. CYFRA 21-1 with AUC of 0.84〔95%CI 0.820-0.863〕performed better than CEA and the other remaining individual tumor markers. The combination of five tumor markers, with an AUC of 0.904〔95%CI 0.888-0.920〕 is the highest. showed as figure 1.

      截图00.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combined TMs can potentially improve the specificity and sensitivity values in LC diagnosis

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-66 - Comparison of EGFR Mutation Status in Tissue and Plasma Cell-Free DNA Detected by ARMS in Advanced Lung Adenocarcinoma Patients

      16:45 - 18:00  |  Presenting Author(s): Yuping Li  |  Author(s): Hanyan Xu, Sansan Su, Junru Ye, Chengshui Chen

      • Abstract

      Background

      EGFR mutation is a reliable and sensitive biomarker for the treatment of advanced lung adenocarcinoma patients using EGFR-TKIs. Tumor tissue has been used as the standard sample for EGFR mutation detection in the clinical practice currently, but it has some limitations. Therefore, EGFR mutation detection in plasma cell-free DNA has been applied to the clinical practice, however, its diagnostic accuracy remains not consistent.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The present prospective study enrolled adult patients presenting with advanced lung adenocarcinoma. EGFR mutations detection in plasma cfDNA and tumor tissues by ADx-ARMS were tested. NGS in plasma was performed in patients with inconsistent gene regions mutation in the paired plasma and tissue samples by ADx-ARMS. We calculated the clinical sensitivity, specificity, positive prediction value (PPV), and negative prediction value (NPV) of ADx-ARMS for EGFR mutation status in plasma cfDNA, considering the mutations in tumor tissues as gold standard for measurements. The objective response rate (ORR) and progression-free survival (PFS) were also calculated in patients with EGFR mutation and receiving first-generation EGFR-TKIs therapy.The study protocol was approved by the Institutional Review Board of the first affiliated hospital of Wenzhou Medical University(2016-017).

      4c3880bb027f159e801041b1021e88e8 Result

      203 patients were enrolled, mutations were discovered in 58.6% (119/203) of tumor tissues and same mutations in 31.0% (63/203) of the matched plasma using ADx-ARMS. The overall rate of consistency of the EGFR mutation statuses for the paired plasma and tissue samples was 71.9%. The sensitivity and the specificity of detecting EGFR mutations in the plasma by ADx-ARMS were 52.9% and 98.8%, respectively.There were 3 cases inconsistent tissue with plasma in gene regions: 1 carried both 19-Del +T790M in tumor tissue but carried single 19-Del in plasma, and 2 carried both L858R +T790M but single L858R in plasma. We validated by NGS. An objective response rate (ORR) of 58.3% was observed among the 72 patients who were mutation-positive in tumor tissues and received Gefitinib or Icotinib as first-line treatment. And the ORR was 61.9% among the 42 patients with EGFR mutations in plasma. The median PFS of patients with EGFR mutations detected by ADx-ARMS in tumor tissue and plasma were 9.50 months versus 10.25 months. The median PFS of patients with EGFThe median PFS of patients with EGFR wild-type in plasma was 8.50 months There were no significant differences among them (P=0.277).

      8eea62084ca7e541d918e823422bd82e Conclusion

      ADx-ARMS is an approach with high specificity but moderate sensitivity to detect the EGFR mutations in plasma cfDNA for patients with advanced lung adenocarcinoma.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-67 - The Prognostic Analysis of Lung Cancer Patients with Occult Malignant Pleural Disease at Thoracotomy

      16:45 - 18:00  |  Presenting Author(s): Shaolei Li  |  Author(s): Panpan Zhang, Shanyuan Zhang, Miao Huang, Yuanyuan Ma, Yue Yang

      • Abstract

      Background

      This study aims to determine the clinicopathological prognostic factors for occult malignant pleural disease (MPD) first detected at thoracotomy in patients with non-small cell lung cancer (NSCLC) and assess the outcome of surgical intervention.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 120 patients with MPD at thoracotomy from January 2006 to October 2016 were evaluated. Survival curves were estimated by the Kaplan–Meier method, and Cox regression analysis was performed to validate the selected risk factors. Clinical and pathologic parameters were balanced by propensity score matching when assessing surgical intervention.

      4c3880bb027f159e801041b1021e88e8 Result

      With a median follow-up of 34 months, the 5-year overall survival of 120 patients was 28.0%. Multivariate analyses showed male (p=0.044), advanced T stages (p<0.001), advanced N stages (p=0.02), pleural invasion in image (p=0.005), pleural effusion (p=0.027), surgical intervention (p=0.008) and EGFR status (p=0.003) were independent predictors of survival. The 5-year survival rate and median survival time (MST) for 21 patients with lobectomy were 71.6% and undefined, compared with 25.6% and 40.0 months in 46 patients with sublobectomy. When 53 patients only subjected to open-close surgery, their 5-year survival rate and MST were 23.4% and 30.2 months. After propensity score matching, both 21 patients were included in lobectomy group and sublobectomy /open-close group. The overall survival of lobectomy group was better than the control group (p=0.046).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The prognosis of MPD patients first detected at thoracotomy was affected by gender, stage, pleural invasion, pleural effusion, surgical intervention and EGFR status. Lobectomy maybe confers better survival compared with sublobectomy and exploratory thoracotomy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-68 - Capture-Based Sequencing Depicts Evolution Characteristics of Pulmonary Sarcomatoid Carcinoma

      16:45 - 18:00  |  Presenting Author(s): Xuewen Liu  |  Author(s): Xinru Chen, Fang Wang, Zhi Xie, Chunwei Xu, Hui Wang, Lianpeng Chang, Xuefeng Xia, Yanfang Guan, Xin Yi, Likun Chen

      • Abstract

      Background

      Pulmonary sarcomatoid carcinoma (PSC) is a very rare subset of highly aggressive and poorly differentiated non-small cell lung cancer. Mutation profiling of PSC was reported previously. However, the intratumor heterogeneity and evolution characteristics of PSC remains unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This study enrolled 39 patients (pts) with PSC. A median follow-up time was 7 months (ranged from 3 to 33 months). Each tumor sample was divided to cancer tissue and sarcoma tissue by microdissection. Matched distant normal tissues were also collected for removing germline background. Capture-based sequencing was performed using a panel covering 1021 genes related to solid tumors. Somatic mutations were used to analyze intratumor heterogeneity and evolution characteristics. Tumor mutation burden (TMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3 %. TMB-high pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).

      4c3880bb027f159e801041b1021e88e8 Result

      Capture-based sequencing had been done on 90 tissues, including cancer tissues, sarcoma tissues and matched distant normal tissues from 30 pts. Nine patients were excluded due to insufficient DNA samples. A median effective depth of coverage of 1299 × was obtained in tissue samples. A total number of 608 mutations were detected, including driver mutations in TP53 (73%, 44/60), MET (22%, 12/60), EGFR (20%, 12/60), KRAS (20%, 12/60), and NF1 (17%, 10/60). Interestingly, mutations in MET and KRAS were demonstrated to be mutually exclusive in cancer and sarcoma tissues. Shared mutations between cancer and sarcoma tissues were 43%. The median of TMB of sarcoma and cancer samples were both 8.6 mutations/Mb. High TMB were identified in 40% (12/30 pts) of sarcoma samples and 43% (13/30 pts) of cancer samples, respectively. TMB of sarcoma tissues was significantly correlated to that of cancer tissues (Pearson r= 0.92, p-value<0.01), with a consistence of 90 % Furthermore, the fraction of brunch mutations in cancer tissues was related to the worse OS of PSC (Log-rank, HR=3.2, 95% CI=1.1-9.4, p=0.04).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Sarcoma tissues shared mutations with cancer tissues. Mutations and TMB analysis could help to guide treatment decisions of PSC in both tyrosine kinase and immune checkpoint inhibitors. Evolution characteristics could serve as potential prognostic factors in PSC.

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      P2.01-69 - EZH2-Mediated Epigenetic Suppression Of GDF15 Predicts a Poor Prognosis and Regulates Cell Proliferation in Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Xiyi Lu  |  Author(s): Xinyin Liu, Renhua Guo

      • Abstract

      Background

      Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily of cytokines, has been reported to exert very heterogeneous functions in various tumors. However, the role of GDF15 and its underlying mechanism in mediating non-small cell lung cancer (NSCLC) progression remain unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      GDF15 expression level was analyzed in 66 NSCLC tissues by quantitative reverse transcription PCR (qRT-PCR). The effect of GDF15 on proliferation was evaluated by MTT and colony formation assays, flow cytometric analysis. NSCLC cells transfected with pcDNA-GDF15 or empty vector were injected into nude mice to study the effect of GDF15 on tumorigenesis in vivo. Chromatin immunoprecipitation (ChIP) assay was used to investigate the mechanism of action of GDF15 in the NSCLC cells.

      4c3880bb027f159e801041b1021e88e8 Result

      In this study, we found that GDF15 is down-regulated in paired NSCLC tissues and is correlated with poor clinical outcomes in NSCLC. Further experiments demonstrated that overexpression of GDF15 significantly repressed NSCLC proliferation both in vitro and in vivo. Mechanistic studies reveal that inhibition of EZH2 expression prevented its binding to the GDF15 promoter region and reduced the trimethylation modification pattern of H3K27.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Together, our data uncover that GDF15 is a direct target of EZH2, and as a regulator of proliferation, might serve as a candidate prognostic biomarker and target for new therapies in human NSCLC.

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      P2.01-70 - Tumor Treating Fields and Radiosurgery for Supra- and/or Infratentorial Brain Metastases (1-10) from NSCLC in the Phase 3 METIS Study

      16:45 - 18:00  |  Presenting Author(s): Uri Weinberg  |  Author(s): Minesh P Mehta, Vinai Gondi, Manmeet Ahluwalia,, Paul D. Brown

      • Abstract

      Background

      Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising low intensity alternating electric fields. TTFields has demonstrated efficacy in non-small cell lung cancer (NSCLC) in in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. This prospective, multicenter study [NCT02831959] investigated the efficacy, safety and neurocognitive outcomes of TTFields in NSCLC patients with brain metastases (BMs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NSCLC patients (N=270) with 1-10 BMs are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays and allows normal daily activities. Patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Patients in the control arm could cross over to TTFields at the time of second intracranial progression.

      Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial BMs from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent BMs were exclusionary.

      Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 BMs; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression.

      The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-71 - Clinical Outcome of Induction Chemoradiotherapy Followed by Surgery for the Patients with cN2 Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Akihiro Miura  |  Author(s): Junichi Soh, Kota Araki, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kazuhiko Shien, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

      • Abstract

      Background

      The treatment strategy for clinical N2 (cN2) non-small cell lung cancer (NSCLC) is still controversial, because its clinical outcome is unsatisfactory and cN2 NSCLC harbors various conditions. In this study, we investigated the clinical outcome of induction chemoradiotherapy (iCRT) followed by surgery in the patients with cN2 NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      During 1999 to 2016, 92 patients with cN2 NSCLC were surgically treated after iCRT in our hospital. Overall survival (OS) and relapse-free survival (RFS) were evaluated by the Kaplan-Meier method with log-rank test (univariate analyses) and by the cox proportional hazard model (multivariate analyses).

      4c3880bb027f159e801041b1021e88e8 Result

      Median follow-up was 49.3 months (range 3.0 - 216). Median age was 62 (21 - 79). Sixty-nine patients (75%) were male. Fifty-four and 38 patients were cStageIIIA and IIIB, respectively. Forty-six (50%) patients were adenocarcinoma. As for iCRT, the CDDP plus DTX regimen was applied for most of patients (96.7%), and the median radiation dose was 46Gy (36 - 60). Complete/major/minor pathological responses were exhibited in 29/36/27 patients, respectively. pCR was observed in 22 patients. The 5-year rates of OS and RFS were 64.1% and 48.1%, respectively. The patients with lower-lobe origin, cStage IIIA (UICC8th), poor radiological response (progressive or stable disease), minor pathological response, re-operation within 30days after surgery, or recurrence showed significantly worse OS than the others. In addition, the patients with lower lobe origin, cStageIIIA, multi-station N2, poor radiological response, or minor pathological response showed significantly worse RFS. The multivariate analysis revealed that the patients with lower-lobe origin tumors and multi-station N2 showed significantly worse OS [Hazard Ratio (HR) 2.55, 95% confidence interval (CI) 1.11 - 5.71, P= 0.028] and RFS (HR 2.45, 95%CI 1.34 - 4.69, P= 0.003), respectively. Adenocarcinoma, lower-lobe origin, multi-station N2, cStageIIIA, poor radiological response, and minor pathological response significantly correlated to recurrence. Among them, adenocarcinoma (odds ratio (OR) 3.27, 95%CI 1.21 – 8.89, P= 0.02), lower-lobe origin (OR 5.22, 95%CI 1.48 – 18.40, P= 0.01), and multi-station N2 (OR 3.63, 95%CI 1.32 – 9.88, P= 0.012) independently correlated to recurrence.

      8eea62084ca7e541d918e823422bd82e Conclusion

      iCRT followed by surgery may be one of the feasible treatment options for the patients with cN2-NSCLCs, especially for those which harbor non-lower lobe origin and multi-station N2 .

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      P2.01-72 - Bronchial Sleeve vs Pneumonectomy: Complications, Recurrences and Survival

      16:45 - 18:00  |  Presenting Author(s): Marc Boada  |  Author(s): Mario Montesinos Encalada, David Sanchez, Alejandra Libreros, Angela Guirao, Rudith Guzman, Josep Maria Gimferrer, Laureano Molins

      • Abstract

      Background

      The present study describes and compares the rate of complications in hospital length of stay (LOS), recurrences and long-term survival between pneumonectomies and bronchial sleeves in our center's experience.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a descriptive, retrospective study. All patients who underwent bronchial SL or PN for NSCLC in our center between 2011 and 2017 were included. Individual clinical report was done, other indications for surgery were excluded. General demographics, preoperative lung function, histology and postoperative complications were included. Oncologic follow-up was done to detect recurrence and death. The statistical program used was SPSS.

      4c3880bb027f159e801041b1021e88e8 Result

      From of 87 patients registered, 47 had bronchial sleeve resection (54,02%) and 40 pneumonectomy (45.97%). The average age: SL 63.7, PN 61,7 years. Males were predominate in both groups (SL 83%, PN 75%). The average size tumoral were: SL 4,8 cm, PN 7,5 cm, p=0.46). Histological type predominant was C. squamous: SL 57,44%, PN 60%, p=0,46). The average LOS was higher SL than PN (2,37 and 6,37 respectively). Upper SL were most frequent: LSD 23 cases, LSI 17 cases, left pneumonectomies were the most accomplished.

      25 patients had postoperative complications: SL 17 (68%), PN 8 (32%). The most frequent complications were persistent air leak (SL 6 cases, PN 0 cases, p=0.09) and cardiac arrhythmias. (SL 3 cases, PN 4 cases p=0.09)

      No case of local recurrence was found after both techniques and 8 cases of regional recurrences (SL 6, PN 2, p=0,81).

      No differences in terms of overall survival were detected when both techniques were compared (median survival in months, p=0.35).

      8eea62084ca7e541d918e823422bd82e Conclusion

      More postoperative complications were found in SL group with equal postoperative mortality, this is mostly because persistent air leak and bronchial stenosis, this could explain increase of LOS.

      There are no local recurrences in any groups, this could mean that both techniques are oncologically equivalent. Our definition of regional recurrences as tumor involving the ipsilateral lung might again explain the higher incidence in SL.

      There are no statistically differences in terms of OS in both techniques. However, long-term survival tendency appears to be in favor of SL specially after 5 years. This might be related to non oncologic late complications related to pneumonectomy.

      In conclusion, we consider SL as a feasible and secure technique with a reasonable incidence of inherent complications and equal oncological results.

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      P2.01-73 - Automated Image Analysis Tool for Tumor Volume Growth Rate to Guide Precision Cancer Therapy: EGFR-Mutant NSCLC as a Paradigm

      16:45 - 18:00  |  Presenting Author(s): Mizuki Nishino  |  Author(s): Satoshi Wakai, Tomoyuki Hida, Suzanne Dahlberg, Masahiro Ozaki, Hiroto Hatabu, Hisashi Tachizaki, Bruce E Johnson

      • Abstract

      Background

      Imaging remains a crucial component in the evaluation of the therapeutic benefit of precision cancer therapy, because it objectively characterizes tumor burden changes during therapy and provides guides for treatment decisions. The purpose of the present study is to develop an automated analytic module for calculation of tumor growth rate from serial CT scans and evaluate the module functionality and reproducibility in a pilot cohort of advanced NSCLC patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The module utilized a commercially available image-processing workstation equipped with a validated tumor volume measurement tool. A novel analytic software module was programmed with the capability to record and display serial tumor volume changes and to calculate tumor volume growth rate over time and added to the workstation. The functionality and reproducibility of the module was evaluated using a pilot cohort of 24 EGFR-mutant patients treated with EGFR inhibitors by two independent thoracic radiologists.

      4c3880bb027f159e801041b1021e88e8 Result

      The module analyzed chest CT scans from 24 patients (5 males, 19 females; median age: 61) with a median of 8 scans per patient, totaling 227 scans and provided a graphical display with an automated calculation of tumor growth rate after the nadir volume for each patient. High inter and intraobserver agreements were noted for tumor growth rates, with concordance correlation coefficients of 0.9323 and 0.9668, respectively. Interpretation of slow versus fast tumor growth using previously identified threshold of ≤0.15/month had a perfect interobserver agreement (κ=1.00), and an excellent intraobserver agreement (κ=0.895).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The present study describes the development of an image analytic module for assessing tumor growth rate and the data demonstrates the functionality and reproducibility of the module in a pilot cohort of EGFR-mutant NSCLC patients treated with EGFR-TKI. The image analytic module is an initial step for clinical translation of the tumor growth rate approach to guide cancer treatment in precision oncology.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-74 - Docetaxel-Related Febrile Neutropenia (FN) And Patient Reported Symptoms/ QOL (PROs) in East Asian (EA) and Non-EA Patients

      16:45 - 18:00  |  Presenting Author(s): Sotaro Enatsu  |  Author(s): Yukie Omori, Alan J. M. Brnabic, Narayan Rajan, Jin-Yuan Shih, Joo-Hang Kim, Keunchil Park

      • Abstract

      Background

      A post hoc analysis of JVCG, a Japanese phase 2 trial suggested that the QOL (quality of life) deteriorated more rapidly in patients with docetaxel-related FN than in patients without FN. A post hoc analysis of REVEL, a global phase 3 trial, was performed to explore the association between FN and PROs in East Asian (EA) (Korea, Taiwan) and Non-EA patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lung Cancer Symptom Scale (LCSS) and EQ-5D-3L were assessed at baseline, every cycle, at discontinuation and 30-day follow up. The summary statistics of LCSS total score and EQ-5D Visual Analog Scale (VAS) score were calculated. Time to deterioration (TtD) was defined as the time from randomization to the first 15-mm increase from baseline for the LCSS and first 15% decrease for the EQ-5D VAS and analysed with the Kaplan-Meier method and Cox proportional hazard model by treatment-emergent FN status regardless of assigned treatment. Also the changes in LCSS total score and EQ-5D VAS score from baseline to the treatment completion were summarized.

      4c3880bb027f159e801041b1021e88e8 Result

      1253 patients randomized to receive RAM+DOC (EA: n=43 and Non-EA: 585) or PLA+DOC (n=46 and 579). FN occurred in 21.3% of EA and 12.3% of Non-EA patients. Patient compliance with the LCSS and EQ-5D were 84.2% and 84.4%, respectively in EA and 82.7% and 83.2% in Non-EA patients. For EA patients, HRs (95% CI) for TtD were 0.572 (0.250, 1.313) in LCSS total and 0.792 (0.350, 1.790) in EQ-5D VAS, indicating longer TtD in PROs for patients without FN. For Non-EA patients, HRs (95% CI) for TtD were 0.994 (0.728, 1.357) in LCSS total and 1.023 (0.787, 1.330) in EQ-5D VAS and there seemed to be no difference in TtD between patients with and without FN. At treatment completion, the unadjusted mean change from baseline of LCSS total was numerically lower in EA patients without FN: 12.97 (with FN) vs 5.94 (without FN) (p=0.1748) and significantly lower in Non-EA patients without FN: 10.50 (with FN) vs 5.55 (without FN) (p=0.0147), demonstrating a greater PROs deterioration in patients with FN.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PROs of EA patients with FN deteriorated more rapidly than in those without FN in contrast with non-EA patients. This finding was consistent with a result in the Japanese phase 2 JVCG trial. Also Non-EA patients without FN maintained their PROs significantly better than patients with FN upon treatment completion. This trend was also shown in EA patients. Prevention of docetaxel-related FN may contribute to maintaining QOL.

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      P2.01-75 - Study of Molecular Alterations in Cytological Smears By FISH In Patients with Advanced Non Small Cell Lung Carcinoma (NSCLC).

      16:45 - 18:00  |  Presenting Author(s): Julieta Belén Pandolfi  |  Author(s): Julia Urbistondo, Maria Jose Labanca, Jose Nicolas Minatta, Mercedes Liliana Dalurzo, Paola Ximena De La Iglesia Niveyro.

      • Abstract

      Background

      Lung cancer represents one of the leading causes of cancer mortality worldwide. In most cases, its diagnosis is made at an advanced stage of the disease when patients are no longer candidates for surgical resection of the primary tumor. In these cases, small biopsies and cytological samples obtained through minimally invasive procedures, often represent the only chance of obtaining diagnostic material. This includes molecular study which increasingly incorporates more genes of interest into the diagnostic routine to define therapeutic approach. At the Pathology Department of the Hospital Italiano de Buenos Aires, the study of ALK, ROS1 and more recently, the study of MET, is performed on paraffin samples by immunohistochemistry (IHC) or by fluorescence in situ hybridization (FISH).

      Aims: To incorporate the use of FISH on cytological material within the practices of our department.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We collected cytological smears of 1) lung nodule or lung cancer metastases needle biopsies from patients with non-surgical stage disease (n=10); 2) imprinted cytological samples from positive mediastinoscopies during the intraoperative staging of patients with lung cancer (n=11); 3) positive pleural fluid in patients with pulmonary nodule (n=2). Then we performed FISH technique, evaluated the quality of the signal obtained, and compared the results with those obtained on paraffin sections. FISH technique on paraffin blocks was performed using 2XSSC/ proteinase K pretreatment as standardized by our lab. Cytology smears were destained and fixed in 10% methanol and incubated with FISH probe (ALK, ROS1 and MET).

      4c3880bb027f159e801041b1021e88e8 Result

      All cytology cases had scorable signals and were easy to interpret. Also, as no pretreatment was required, assay time was shorter. Depending on cellularity, one same slide was useful for analysis of the three probes.

      When comparing with IHC and FISH studies, we obtained a 100% correlation with ALK (n=23; positive=2, negative=21), ROS1 (n=5, all negative) and MET (n=5, all negative).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This work allowed us to optimize the use of different cytology samples frequently available in advance stage NSCLC for FISH studies. The use of cytological material might improve turnaround time for results and can become a useful tool in pathology labs, in particular when paraffin included material is limited.

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      P2.01-76 - The Impact of Concordance with a Lung Cancer Diagnosis Pathway Guideline on Treatment Access in Patients with Stage IV Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Luke Jeagal  |  Author(s): Andrew Pattison, Jonathon Yeung, Andrew Pierre, Laura Donahoe, Marcelo Cypel, Marc De Perrot, Kazuhiro Yasufuku, Gail Elizabeth Darling, Thomas Waddell, Shaf Keshavjee, Kasia Czarnecka-Kujawa

      • Abstract

      Background

      Lung cancer is the leading cause of cancer mortality with the majority of cases diagnosed at an advanced stage. Timely access to treatment is dependent on efficient and appropriate patient assessment and early referral for diagnostic workup. This study aims to assess the impact of referral concordance with a new Lung Cancer Diagnostic Pathway Guideline (LCDPG) on access to treatment in patients with stage IV lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a retrospective cohort study of patients with clinical stage IV lung cancer referred to the Diagnostic Assessment Program (DAP) at a Canadian tertiary cancer centre between November 1, 2015 and May 31, 2017. Patient referrals were defined as concordant or discordant based on Cancer Care Ontario LCDPG. The primary outcome; time to treatment from initial healthcare presentation; was compared between the concordant and discordant referrals.

      4c3880bb027f159e801041b1021e88e8 Result

      Two hundred patients were referred for clinical stage IV lung cancer during the study period. Of these referrals, 151 (75.5%) were assessed and referred in concordance with LCDP guidelines. Guideline concordant referrals were associated with reduced time to treatment from first healthcare presentation compared with guideline discordant referrals (55.3 vs 108.8 days, p<0.001). Time to diagnostic procedure (32.2 vs 86.7 days, p<0.001) and decision to treat (38.5 vs 93.8 days, p<0.001) was also reduced with guideline concordance. The most common reason for discordant assessment and referral was delayed or inadequate investigation of symptoms in a high risk patient (32.7% of discordant referrals).

      The mean time from referral to diagnostic procedure (19.4 [SD 16.0] days), decision to treat (23.3 [SD 17.1] days), and treatment initiation (39.7 [SD 26.3] days) did not significantly differ between concordant and discordant groups. Time from referral to decision to treat was within 28 days in 71.5% of patients. The mean number of hospital visits from referral to treatment was 4.9 (SD 3.5). Diagnosis was achieved with a single diagnostic test in the majority of patients (91%). The most common method of diagnosis was EBUS-TBNA (33.5%). The most common treatment modalities initiated were radiation (60.5%) followed by chemotherapy (43%) and targeted therapy (21.5%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Guideline concordant assessment and referral of patients with stage IV lung cancer results in reduced time to diagnosis and treatment. The utilization of a LCDPG for lung cancer provides a streamlined and efficient framework to facilitate early diagnosis and treatment. Future research and education should focus on improving factors leading to a delay in DAP referral.

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      P2.01-77 - Interconversion of Two Commonly Used Performance Tools: An Analysis of 5844 Paired Assessments in 1501 Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Kuruswamy Thurai Prasad  |  Author(s): Harpreet Kaur, Valliappan Muthu, Ashutosh Nath Aggarwal, Digambar Behera, Navneet Singh

      • Abstract

      Background

      Karnofsky Performance Status (KPS) scale and Eastern Cooperative Oncology Group (ECOG) scale are the most commonly used performance status (PS) tools worldwide. The current study aimed to assess correlation between KPS and ECOG PS in a large cohort from a lung cancer (LC) clinic database and to determine KPS categories which were most equivalent to ECOG PS scores.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients attending LC clinic at a tertiary care centre over a 5-year period were assessed with both KPS and ECOG PS scales at each visit. Correlation between KPS and ECOG PS was assessed using Spearman’s correlation coefficient. Different KPS categories equivalent to ECOG PS were compared using hit rate and weighted kappa (κw).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 1501 patients were assessed over study period providing 5844 paired KPS and ECOG PS assessments. The cohort had a mean (standard deviation SD) age of 58.4 (10.8) years with majority being current/ex-smokers (76.9%) and males (82.3%). NSCLC was commonest histological type (n=1196, 79.7%) with majority having advanced (stages IIIB/IV) disease (83.4%). Mean baseline KPS and ECOG PS scores were 77.6 (SD=14.4) and 1.5 (SD=1) respectively. Overall correlation between KPS and ECOG PS was good [Spearman r = (-)0.84, P<0.0001] but ranged from -0.727 to -0.972 between visits. KPS categories derived from our cohort (10-40 [ECOG 4], 50-60 [ECOG 3], 70 [ECOG 2], 80-90 [ECOG 1], 100 [ECOG 0]) performed better (hit rate 78.1%, κw = 0.749 [0.736-0.762] P<0.0001) than those suggested in the past literature.

      Table: Comparison of various suggested KPS categories for KPS-ECOG PS interconversion in the current cohort
      Author, Year N (Patients [assessments]) Suggested KPS Categories Hit rate κw (95% confidence interval)
      AJCC, 1977 - 10-20, 30-40, 50-60, 70-80, 90-100 43.6% 0.376 (0.363-0.389) P<0.0001
      Minna, 1985 - 20-30, 40-50, 60-70, 80-90, 100 75.2% 0.701 (0.687-0.714) P<0.0001
      Buccheri, 1996 536 [1656] 10-50, 60-70, 80-100

      83.2%

      0.695 (0.679-0.711) P<0.0001
      Ma, 2010 1385 (1385) 10-30, 40-50, 60-70, 80-90, 100 75.2% 0.701 (0.687-0.714) P<0.0001
      de Kock, 2013 955 (674) 10-20, 30-40, 50, 60-100 43.2% 0.079 (0.068-0.090) P<0.0001
      Current study 1501 (5844) 10-40, 50-60, 70, 80-90, 100 78.1% 0.749 (0.736-0.762) P<0.0001
      8eea62084ca7e541d918e823422bd82e Conclusion

      The current study provides largest set of paired KPS-ECOG assessments till date. Although both PS tools had good correlation, the performance of the KPS categories previously suggested as being equivalent to ECOG PS categories was found to be highly variable. Cancer clinics should develop and validate their own population-specific KPS categories for interconversion of KPS to ECOG PS.

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      P2.01-78 - Validation of InVisionFirst ctDNA NGS Profiling via ddPCR Testing in Patients with Non-Small Cell Lung Cancer (NSCLC)

      16:45 - 18:00  |  Presenting Author(s): Michael A. Pritchett  |  Author(s): Katherine Baker-Neblett, Katherine Finch Mileham, Vincent Plagnol, Karen Howarth, Tim Forshew, Gregory R. Jones, Clive Morris

      • Abstract

      Background

      Tumor tissue based molecular profiling is widely utilized to guide therapy in advanced NSCLC and recently, ctDNA assays have been developed to detect actionable alterations in a non-invasive manner. However, there are frequent reports of discordance between analysis platforms and here we compare the Inivata NGS ctDNA assay with ddPCR based ctDNA analysis and tissue NGS sequencing in patients with advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      InVisionFirst (Inivata) is a ctDNA NGS assay for detection of genomic alterations in 36 genes commonly mutated in NSCLC and other cancer types. A cohort of 52 patients underwent ctDNA analysis by InVisionFirst and were tested in a blinded manner for 4 actionable gene alterations (EGFR L858R & Ex19del, KRAS G12C & G12D) and 30 of the cohort also had testing for 5 additional alterations (EGFR T790, EML4-ALK fusions, ROS1 fusions, KRAS G12V and BRAF V600E) at one of two independent ddPCR laboratories. Finally, tissue analysis by NGS was available in 21 patients to arbitrate any discordance between the results of the 2 liquid biopsy techniques.

      4c3880bb027f159e801041b1021e88e8 Result

      Across the 9 specific genetic alterations investigated by both ctDNA platforms, 26 alterations were detected by the InvisionFirst platform and 23 were detected by the ddPCR platforms. The overall concordance of gene alterations was 98.5% (320/342) with positive agreement of 95.5% and negative agreement of 98.8%. Discordance was observed in 6 detected gene alterations, with 1 EML4-ALK fusion, 1 EGFR exon19 deletion and 2 KRAS G12Cs being detected by InVisionFirst but not by ddPCR, and 1 EGFR L858R and 1 KRAS G12D detected by ddPCR but not InVisionFirst. One G12C, the EML4-ALK, and the L858R alteration were confirmed by tissue NGS. The KRAS G12D was not confirmed by tissue NGS. No tissue was available to examine for the detection of the EGFR exon 19 deletion or the other KRAS G12C mutation. All other results were concordant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study in NSCLC patients demonstrates excellent concordance of the InVisionFirst ctDNA NGS assay with ddPCR based ctDNA analysis via blinded independent laboratories. The excellent sensitivity and specificity support the use of the InVisionFirst assay as a non-invasive “liquid biopsy” for molecular profiling.

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      P2.01-79 - Neurological Death is Common in Patients With EGFR Mutant Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Matthew Ramotar  |  Author(s): Sierra Barnes, Mark K. Doherty, David Shultz

      • Abstract

      Background

      Patients with EGFR mutant non-small cell lung cancer (EGFRmNSCLC) have a high incidence of brain metastases (BM). We sought to determine the rate of neurologic death in EGFRmNSCLC patients diagnosed with brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A single-institution prospectively managed database identified 204 patients with EGFRmNSCLC treated for brain metastases between 2000 and 2016. We estimated actuarial survival rates using the Kaplan-Meier method. The incidence of neurologic death (ND) was determined using a competing risks analysis. ND was correlated to clinical and treatment variables using Fisher’s exact test. Survival was calculated from the date of BM diagnosis. We defined neurologic death as death due to brain metastases or leptomeningeal disease.

      4c3880bb027f159e801041b1021e88e8 Result

      Fifty-six percent of patients had BM at the time of initial diagnosis. The initial BM treatment was up front stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or tyrosine-kinase inhibitor (TKI) alone in 22, 60, and 18 percent of patients, respectively. Two-year rates of OS in these subgroups were 64%, 38%, and 50%, respectively (p=0.016). The 5-year rate of neurologic death was 38%. Thirty-four percent died of non-neurologic causes, 8% died of unknown causes, and the remaining patients were alive at last follow-up. Median survival (MS) was 19 months; MS in patients who died of non-neurologic causes and neurologic causes was 23, and 15 months, respectively. Of age, staging, BM at diagnosis, history of TKI therapy, initial treatment of BM, staging at diagnosis, and leptomeningeal disease at diagnosis (LMD), only LMD was significantly associated with ND (p=0.047).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Neurologic death due to EGFRmNSCLC BM was more common in our cohort than has been previously reported, highlighting the need for dedicated studies focused on the best management of BM in this population.

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      P2.01-80 - Performance Status and Resource Utilization in Patients Receiving Palliaitve Care with Stage IV Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Candice Leigh Wilshire  |  Author(s): Joshua Robert Rayburn, Christopher R Gilbert, Roshanthi K Weerasinghe, Brian E Louie, Ralph W Aye, Alexander S Farivar, Eric Vallieres, Jed A Gorden

      • Abstract

      Background

      Palliative care (PC) services assist with the end-of-life needs of patients with advanced cancer; and clinical trials have associated early implementation of outpatient PC with increased survival, improved quality of life and reduction in healthcare utilization in stage IV non-small cell lung cancer (NSCLC). However, these studies only included patients with Eastern Cooperative Oncology Group (ECOG) performance status scores of 2 or less, which does not fully represent the spectrum of patients with stage IV NSCLC. The National Quality Forum (NQF) endorses metrics to measure quality and aggressiveness of end-of-life care. We aimed to determine the overall utilization of PC and the performance status of patients receiving outpatient versus inpatient PC and their resource utilization based on the NQF elements.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed patients diagnosed with cIV NSCLC between 6/1/2013-6/1/2017, managed at 7 sites with access to dedicated PC services. Patients were initially categorized by whether or not they received PC consultation, and then further stratified into outpatient and inpatient PC.

      4c3880bb027f159e801041b1021e88e8 Result

      We analyzed 445 patients, of which 19% (86/445) received a PC consultation. Of the 86 patients receiving PC, 47% (40/86) were outpatient and 53% (46/86) were inpatient. Median (25th-75th interquartile range) ECOG scores at PC consultation were 1 (1-3) and 4 (3-4) for outpatient and inpatient PC, respectfully (p<0.001). The NQF’s endorsed data elements for each group are shown in the figure.

      iaslc 2018 nqf.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients receiving inpatient PC had a significantly worse performance status with higher emergency department and intensive care unit usage than outpatient PC, suggesting inpatient PC accesses a different, sicker population with greater clinical needs. Comprehensive multidisciplinary initiatives focused on increased outpatient PC utilization and targeting the NQF metrics of quality and resource utilization are needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-81 - Treatment of Superior Sulcus Tumor: A Twelve-Year Single-Center Experience

      16:45 - 18:00  |  Presenting Author(s): Witold Rzyman  |  Author(s): Malgorzata Lazar-Poniatowska, Mariusz Lapinski, Marcin Ostrowski, Anna Wrona, Krzysztof Konopa, Jacek Jassem, Rafal Dziadziuszko

      • Abstract

      Background

      Superior sulcus tumor (SST), also known as Pancoast tumor, occurs in up to 5% of all non-small cell lung cancer patients. Owing to its proximity to vital thoracic structures, SST remains one of the biggest challenges of thoracic surgery. The results of the Southwest Oncology Group Trial 9416, in which SST patients were subjected to induction chemoradiation followed by surgical resection, established a widely accepted standard-of-care. Data on the efficacy of this approach outside of clinical trial setting are scarce. We present long-term outcomes in a large group of patients with SST who underwent surgery with or without preoperative treatment (PT) in a single tertiary referral center.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Study group included 76 consecutive patients treated between February 2006 and June 2017. All patients had histologically-proven and radiologically-defined T3-T4 N0-N1 M0 superior sulcus non-small cell lung cancer. Study group included 50 men (66%) and 26 women (34%) with a mean age of 56 years (range, 41-81 years). Squamous cell lung cancer constituted 55% of the population.

      4c3880bb027f159e801041b1021e88e8 Result

      Fifty-four patients (71%) underwent PT, 44 of whom received radiochemotherapy (58%), 4 radiotherapy (5%) and 6 chemotherapy (8%), and 22 (29%) were managed with surgery alone. All patients selected to PT underwent subsequent pulmonary surgery including lung and chest wall en bloc resection, and complete lymphadenectomy. In the entire group 71 lobectomies (93%), 3 segmentectomies (4%) and 2 pneumonectomies (3%) were performed. Surgery in patients managed with PT included 52 lobar resections (96%) and 2 pneumonectomies (4%). Complete or near complete pathologic response following PT was achieved in 67% of operated patients. In the entire group resection was complete (R0) in 62 patients (82%). Overall 30-day and 90-day mortality in the entire treatment group was 2.6% and 6.6%, respectively. Overall 3-year and 5-year survival probabilities were 44% (95% CI: 32%–56%) and 38% (95% CI: 26%–50%) respectively. A non-significantly higher 3-year survival probability was recorded in patients, who underwent PT compared to those managed with surgery alone (50% vs. 36%, respectively; log-rank p=0.27).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Real-world treatment outcomes in SST patients amenable to surgery are similar to those obtained in the general population of lung cancer patients. PT may increase long-term survival rate and is associated with low perioperative mortality, which justifies its routine application.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-82 - Neutrophil-to-Lymphocyte Ratio Complements the Prognostic Ability of PD-L1 in Non-Small Cell Lung Cancer Treated with PD-1/PD-L1 Inhibitors

      16:45 - 18:00  |  Presenting Author(s): Diana Saravia  |  Author(s): Sarita Agte, Naoyuki Okabe, Wungki Park, Deukoo Kwon, Raja Mudad, Hiroyuki Suzuki, Young Kwang Chae, Michael Oh, Ashkon Alexander Rahbari, Gilberto de Lima Lopes

      • Abstract

      Background

      PD-L1 expression is an imperfect predictor of outcomes for patients (pts) with advanced non-small cell lung cancer (aNSCLC) treated with PD-1/PD-L1 inhibitors (PD-1/L1i). This was demonstrated in the recent ARCTIC trial in which PD-L1 expression did not significantly correlate with outcomes. In the quest for additional markers, a high neutrophil-to-lymphocyte ratio (NLR) has been associated with poor outcomes and may reflect a higher myeloid-to-lymphoid balance. Here we show improved prognostic ability for response to PD-1/L1i when baseline NLR is added to PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We used a retrospective cohort of 146 aNSCLC pts from the authors’ institutions in the United States and Japan who received single-agent PD-1/L1i. We categorized patients into three groups; favorable: PD-L1 ≥ 1% and NLR < 5, intermediate: PD-L1 ≥ 1% or NLR < 5, and poor: PD-L1 < 1% and NLR ≥ 5. We correlated the outcome of each group with overall survival (OS) and progression free survival (PFS).

      4c3880bb027f159e801041b1021e88e8 Result

      Median follow-up was 11.1 months (M) (95% Confidence Interval [CI]: 9.1-13.1). 47 pts had PD-L1 <1% and 99 pts ≥1%, 81 pts had NLR <5 and 65 pts ≥5. There were 52, 76, and 18 pts in the favorable, intermediate, and poor groups, respectively. Median OS for the favorable group was not reached and it was 14.7 M (CI: 10.5-19.0) and 3.5 M (CI: 0-13.1), respectively for the intermediate and poor groups. Median PFS was 9.9 M (CI: 3.7-16), 3.2 M (CI: 2.1-4.3), and 1.1 M (CI: 0.8-1.4), respectively. The poor group (PD-L1 < 1% and NLR ≥ 5) was significantly associated with progressive disease (Odds ratio [OR]: 5.0, p=0.01) in comparison to the PD-L1 < 1% group (OR: 2.6, p=0.013).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Prognostic ability of PD-L1 expression is enhanced when combined with baseline NLR for aNSCLC pts treated with single-agent PD-1/L1i. This study raises the hypothesis that high NLR and low PD-L1 expression could serve to identify those pts less likely to benefit from these therapies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-83 - Evaluation of Dynamic Thiol/Disulphide Homeostasis in Advance Non-Small Cell Lung Cancer and Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Mehmet Ali Nahit Sendur  |  Author(s): Mutlu Hizal, Burak Bilgin, Muhammed Bulent Akinci, Salim Neselioglu, Ozcan Erel, Bulent Yalcin

      • Abstract

      Background

      The complicated pathogenesis of lung cancer is the mainstay of all its different histological subtypes. Oxidative stress has detrimental effects on chronical diseases as well as cancer. Thiol groups which have high antioxidant capacity, turn to disulpide (DS) groups with biochemical reactions that neutralize different oxidant compounds. Thiol/Disulpide homeostasis (TDH) has significant effects on cell mechanisms, transcription and apoptosis. Here, we present the role of dynamic TDH in both advanced non-small cell (NSCLC) and small cell lung cancer (SCLC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The patients who diagnosed with NSCLC and SCLC between 2015 and 2017 prospectively analysed. Serum samples of the patients obtained at the time of diagnosis and after first-line treatment. TDH tests were measured by the automated spectrophotometric method.

      4c3880bb027f159e801041b1021e88e8 Result

      57 patients (43 NSCLC and 14 SCLC) and 50 healthy controls enrolled to study. There was no statistical difference in age (median 61 and 60.5) and sex status between groups.Native thiol (NT) and total thiol (TT) levels were significantly lower in the patients’ group (Table 1).DS/NT ratio which is the best indicator of antioxidant capacity reached statistical significance between NSCLS patients and controls (p=0.04). After median 27.2 months follow-up,median overall survival (OS) was 9.5 months in NSCLC and 12.3 months in SCLC groups.Thiol or DS variables had no effect on survival.13 of the 30 patients had progressive disease after first-line chemotherapy. DS levels and DS/NT ratio were lower in patients after progression compared with levels at the time of diagnosis (p=0.013 and 0.033).

      Variable

      Patients

      Median (min-max)

      Controls

      Median (min-max)
      p
      Native Thiol 358 (215-3261) 429 (313-607) <0.001
      Disulpide 20.8 (0.05-55) 20 (8.4-37) 0.98
      Total Thiol 398 (253-573) 464 (354-632) <0.001
      Disulpide/ Native Thiol 0.05 (0.01-0.19) 0.05 (0.02-0.14) 0.08
      8eea62084ca7e541d918e823422bd82e Conclusion

      Lower levels of thiol groups may contribute to lung cancer pathogenesis as a result of enhanced oxidative stress.The deficiency of this antioxidant compounds may relate to structural damage of signal, transcription, apoptosis mechanisms in lung cancer cell lines. The lower levels of DS and DS/NT ratio after progression may be an indicator of the high tumor volume and enhanced cell turnover.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-84 - Patterns of Central Nervous System Metastases in EGFR Mutated or ALK Rearranged Non Small Cell Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Mansi Sharma  |  Author(s): Ullas Batra, Parveen Jain, Vivek Mahawar, Ankush Jajodia

      • Abstract

      Background

      Development of brain and leptomeningeal metastases has prognostic and therapeutic implications in oncogene driven non small cell lung cancer (NSCLC). A rising trend is being observed in the incidence of central nervous system (CNS) metastases in such populations, probably due to better imaging techniques as well as improved survival of patients. The presence of EGFR and ALK mutations could have a significant impact on the pattern of metastatic disease spread. Data from the Indian subcontinent on this subject is scarce. The information gained from this study may have clinical relevance in today’s era of first line use of second and third generation tyrosine kinase inhibitors (TKIs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      286 EGFR mutated (220) or ALK rearranged (66) NSCLC patients were selected for this retrospective analysis. All patients with clinically suspected CNS metastases underwent contrast enhanced MR imaging of brain. Two groups of patients were identified as per their driver mutation status. The CNS lesions were analysed with regards to number, size, site (parenchymal or meningeal) and nature (morphological heterogeneity and central necrosis)

      4c3880bb027f159e801041b1021e88e8 Result

      Incidence of brain metastases was found to be higher in the ALK group (24/66, 36.3 %) as compared to the EGFR group (68/220, 30.9%). Leptomeningeal spread in the ALK group was found to be less compared to the EGFR group (2/24, 8.3% as opposed to 18/68, 26.4%). Morphological heterogeneity and central necrosis in parenchymal lesions was more common in the ALK group (8/24, 33.3%) as opposed to EGFR group (2/68, 2.94%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The incidence, type and morphology of CNS lesions vary with the driver mutation status in NSCLC patients. This may have prognostic and therapeutic implications, especially in identifying patients who may benefit from upfront second or third generation TKI’s.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-85 - The Efficacy of the Traditional Chinese Medicine as Maintenance Therapy for Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

      16:45 - 18:00  |  Presenting Author(s): Peng Shen  |  Author(s): Lingyun Wu, Mengye He, Jiabin Chen, Kequn Chai

      • Abstract

      Background

      Maintenance therapy is very important for patients with advanced non-small cell lung cancer (NSCLC). To evaluate traditional Chinese medicine (TCM) as maintenance therapy for advanced NSCLC patients, we performed a meta-analysis of prospective randomized controlled trials (RCTs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      12 databases were searched up to April 2016. All RCTs comparing TCM and control treatment as maintenance therapy for stage III to IV NSCLC patients in non-progression status after completing first-line chemotherapy were retrieved. Total 25 RCTs with 1654 patients were enrolled from March 2005 to June 2014.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that TCM as maintenance therapy significantly increased the overall response rate (ORR) (risk ratio (RR)=2.23 95% confidence interval (CI)=1.28-3.88 P=0.004) and the disease control rate (DCR) (RR=3.15 95% CI=2.12-4.69 P<0.00001, Fig 1), while no significant difference was observed in the overall survival (OS) (P=0.44). Significant improvement was found in progression free survival (PFS)(HR=1.67 95% CI=0.40-2.93 P=0.01) and karnofsky performance status (KPS) in the TCM group (RR=3.26 95% CI=2.42-4.38 P<0.00001, Fig 2). There was no complication reported in these studies.

      dcr.jpg

      kps.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      TCM appears to be efficacious and well tolerated to be used as maintenance therapy for advanced NSCLC patients in non-progression status after completing the first-line chemotherapy. TCM as maintenance therapy is worth further study in future investigations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-86 - Genetic Profiling of Circulating Cell-Free DNA from Cerebrospinal Fluid and Plasma in ALK-Positive Lung Cancer with Brain Metastases

      16:45 - 18:00  |  Presenting Author(s): Liang Shi  |  Author(s): Jungfang Tang, Mingzhi Li, Li Tong, Hong Tao, Weihua Wu, Hongbo Wu, Lili Guo, Wei Wu, Hongxia Li, Qiyi Meng, Liyan Xu, Yunzhong Zhu, Zhe Liu

      • Abstract

      Background

      Brain metastases (BMs) occur in approximately 30% of patients with ALK-positive non-small-cell lung cancer (NSCLC), and in patients treated with crizotinib, central nervous system progression occurs in up to 70% of patients. Resistance mechanisms of BMs with ALK rearrangement remained unclear due to limited access to BMs lesions.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ten NSCLC patients with BMs carrying ALK-positive in tumors determined by Ventana anti-ALK (D5F3) immunohistochemistry assay were enrolled. Cell-free DNA (cfDNA) of cerebrospinal fluid (CSF) and plasma were tested by next-generation sequencing (NGS) with 168 genes panel.

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 10 patients, three were females and seven males aged from 29 to 57 years old (median age of 34 years old). In all of cases, CSF cytology were negative. In NGS assays, In patients with ALK-positive, fusion gene positive genes were detected in 30.0% (3/10), 80.0% (8/10) and 100% (8/8) patients of CSF cfDNA, plasma and tumor, respectively; and in ALK-positive of CSF, all of them had much higher allele fractions in CSF cfDNA than the other two media.13_01.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      For ALK-positive lung cancer with BMs, CSF may serve as liquid biopsy by detecting cfDNA within CSF to characterize the driver and resistant genes, dynamic genetic profiling of CSF would be an appropriate choice.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-87 - Profiling the Symptom Burden of Patients with Metastatic NSCLC Receiving Either Chemotherapy or Targeted Therapy: Real-World Data

      16:45 - 18:00  |  Presenting Author(s): Qiuling Shi  |  Author(s): Loretta A Williams, Viralkumar Bharatbhai Vaghani, Meita Hirschmann, Lara Lacerda Landry, Emily Roarty, Jianjun Zhang, Waree Rinsurnogkawong, Jeff Lewis, Charles Cleeland, Jack Lee, Jack A Jack A. Roth, Stephen Swisher, John V Heymach, George R. Simon

      • Abstract

      Background

      An understanding of the patient experience is lacking for newly developed cancer treatments, such as targeted therapies. We profiled the patient-reported outcome (PRO)-measured symptom burden experienced by patients with metastatic non-small cell lung cancer (mNSCLC) during 6 months of conventional chemotherapy or targeted therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      During 2017, patients with mNSCLC at a single institution were recruited and completed the MD Anderson Symptom Inventory lung cancer module (MDASI-LC) at clinic visits. The MDASI-LC assesses the severity of 13 core and 3 lung-cancer-specific symptoms and 6 interference items on 0‒10 scales (0=no symptom or interference, 10=worst imaginable symptom or complete interference). Descriptive statistics for MDASI-LC scores over 6 months of treatment were summarized. Symptom trajectories for the chemotherapy patients versus the targeted-therapy patients were compared via linear mixed-effects models.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 65 patients receiving chemotherapy and 27 receiving targeted therapy, the targeted-therapy group had more women (74% vs. 49%, P=0.029) and younger patients (57.6±12.2 vs. 64.2±9.9 years, P=0.012). Before treatment, both groups reported similar symptom burden, although sadness was worse in the targeted-therapy group (2.4±1.6 vs. 0.8±1.5, P=0.021). During the first 60 days of treatment, patients receiving chemotherapy reported significant increase in pain (estimate (est)=0.03, P=0.037) and interference with walking (est=0.04, P=0.025). Compared with those receiving chemotherapy, patients receiving targeted therapy experienced significantly less severe pain (est=‒1.17, P=0.024), fatigue (est=‒1.16, P=0.019), and shortness of breath (est=‒1.23, P=0.028) and less interference with walking (est=‒1.23, P=0.042) (figure 1). More severe dry mouth was reported by patients undergoing targeted therapy (est=1.17, P=0.027).

      figure1_shi_quiling.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      This real-world data demonstrates that, compared with conventional chemotherapy, targeted therapy correlates with less impairment of physiological condition and functioning in patients with mNSCLC. Additional follow up will confirm and expand these findings about the patient experience relative to treatment response.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-88 - C-Reactive Protein (CRP) as a Predictive Marker for Survival in Patients with Advanced NSCLC Treated with First Line Pembrolizumab Monotherapy

      16:45 - 18:00  |  Presenting Author(s): Yuji Shibata  |  Author(s): Terufumi Kato, Tadasuke Shimokawaji, Kouzo Yamada

      • Abstract

      Background

      Pembrolizumab have shown longer activity in patients with advanced non-small cell lung cancer (NSCLC) especially when PD-L1 expression was high. But even with high PD-L1 expression, more than half of them failed to response. We focused on C-reactive protein (CRP), inflammatory protein measured routinely in clinical practice, to find out its role as predictive biomarker for pembrolizumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed advanced NSCLC patients with PD-L1 high expression (EGFR mutation (-), EML-4-ALK fusion (-)) who were treated with pembrolizumab as first-line therapy in our clinical practice. Patients received pembrolizumab (200mg/body, q3W) until progressive disease or unacceptable toxicity. During treatment period we measured serum biochemistry and blood cell count regularly.

      We evaluated the association the factors such as serum marker including inflammatory protein, age, performance status, histology, smoking status, prior radiation therapy and presence or absence ofimmune-related adverse events after treatment with the effect such as antitumor response, progression‑free survival (PFS) and overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 31 patients treated with pembrolizumab from March 2017 to February 2018 were analyzed for this research. Their characteristics were: median age 72 (range 37-84),male/female 24/7, adenocarcinoma/squamous cell carcinoma/pleomorphic carcinoma/neuroendocrine carcinoma/NOS 17/5/3/1/5, clinical stage IIIB/IV/recurrence 3/21/7, median CRP level at pretreatment 1.15mg/dL (0.07-15.27). Among the candidate biomarker, there were no association except for CRP. Serum CRP level at pretreatment was not predictive, but change of serum CRP level at 6 weeks after anti-PD-1 therapy initiation was most predictive in the analysis. Depressed CRP group showed longer PFS and OS than elevated group (PFS: p=0.08, HR 0.29, OS: p=0.08, HR 0.28, log-rank test).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our analysis suggests that serum CRP elevation at 6 weeks of treatment predict for longer survival when pembrolizumab was given as first-line treatment.This finding might be related to inflammation status of patients and efficacy of anti-PD-1 inhibitor.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-89 - Synergistic Cytotoxicity Through MAPK/ERK Pathway and ALK Inhibition in Crizotinib Resistant EML4-ALK-Positive Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Nensi Shrestha  |  Author(s): Mhairi Nimick, Rhonda Rosengren, John Ashton

      • Abstract

      Background

      Anaplastic lymphoma kinase (ALK)-positive lung cancer is an aggressive cancer that most commonly arises through EML4-ALK chromosomal fusion. Crizotinib is the first-line treatment for ALK-positive lung cancer, providing a greater progression free survival and overall response rate than chemotherapy. However, patients invariably develop acquired resistance, usually within a year. Mechanisms of resistance include copy number gain, secondary mutations in ALK, or activation of bypass signalling pathways. The aim of this study was to investigate the combination effect of ALK inhibitor, crizotinib, and MEK inhibitor, selumetinib, in crizotinib resistance ALK-positive lung cancer cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Cytotoxicity of single and combined treatment of crizotinib and selumetinib in ALK-positive (H3122), ALK-negative (A549) and crizotinib resistance ALK-positive (CR-H3122) cells was determined by Sulforhodamine B assay. Chou-Talay analysis was performed to determine the nature of interaction between the two drugs used in combination treatment. Endogenous expression of p-ALK and p-ERK was determined by western blotting. The effect of combination treatment on cell cycle arrest and apoptosis induction was determined by flow cytometer.

      4c3880bb027f159e801041b1021e88e8 Result

      Combined treatment with crizotinib and selumetinib had significantly greater cytotoxicity and showed a synergistic effect compared to the single drug treatments in H3122 cells. The combination treatment had no synergistic effect in A549 cells, indicating that the cytotoxic effect was specific to ALK. The most prominent cytotoxic effect of the combination treatment was observed with CR-H3122 cells, with synergistic suppression of cell viability even at low drug concentrations. Endogenous protein expression of p-ALK and p-ERK was decreased by combination of crizotinib and selumetinib. Moreover, combination treatment lead to increased G1 arrest and apoptosis compared to single treatment in H3122 cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results showed that combination of crizotinib and selumetinib have potent cytotoxic effects in crizotinib resistant ALK-positive lung cancer. The proposed combination treatment could be a promising therapy for acquired crizotinib resistant ALK-positive lung cancers.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-90 - PD-L1 Expression as a Predictive Biomarker in Advanced Non-Small Cell Lung Cancer Patients with or without EGFR Mutation

      16:45 - 18:00  |  Presenting Author(s): Teerada Siripoon  |  Author(s): Pimpin Incharoen, Narumol Trachu, Dittapol Munthum, Kaettipong Kamprerasart, Thanyanan Reungwetwattana

      • Abstract

      Background

      The prognostic value of PD-L1 expression and its clinical relevance of NSCLC is controversy. The impact of PD-L1 expression as the predictive biomarker for EGFR-TKIs treatment is needed to explore.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Medical records of metastatic NSCLC during September 2015-2016 had been reviewed. PD-L1 immunohistochemistry (IHC) staining with Antibody clone 22C3 was used. The PD-L1 positive was defined by tumor proportion score (TPS) > 1%.

      4c3880bb027f159e801041b1021e88e8 Result

      204 patients were included. Patients with positive PD-L1 expression had significantly increased numbers of metastatic sites (P=0.009) and lung metastasis (P=0.045) compared to PD-L1 negative patients. Overall survival (OS) was longer in PD-L1 negative patients (22.7 months) compared to PD-L1 positive groups (13.6 months) (HR=1.48; P=0.03). Median OS were significantly different with the number of 7.2, 11.1, 25.7, 42.6 months in EGFR-/PD-L1+, EGFR-/PD-L1-, EGFR+/PD-L1+ and EGFR+/PD-L1- , respectively (P<0.001). Among EGFR positive patients, mOS of T790M-/PD-L1+, T790M-/PD-L1-, T790M+/PD-L1-, and T790M+/PD-L1+ were 22.1, 28, 42.6 and 48.4 months, respectively (P=0.03).

      Patient characteristics categorized by PD-L1 expression (N = 204)
      Characteristics

      PD-L1 Negative

      N=134 (65.69%)

      PD-L1 Positive

      N=70 (34.31%)

      P value

      Age

      - Median age (range)

      - < 65 years

      - > 65 years

      65 (36-85)

      64 (47.76)

      70 (52.24)

      65 (35-86)

      33 (47.14

      37 (52.86)

      0.933

      Sex

      - Male

      - Female

      62 (46.27)

      72 )53.73)

      37 (52.86)

      33 (47.14)

      0.371

      ECOG PS

      - 0-1

      - > 2

      116 (86.57)

      18 (13.43)

      57 (82.61

      12 (17.39)

      0.452

      Smoking status

      - Never

      - Ex-smoker

      - Current smoker

      82 (61.65)

      36 (27.07)

      15 (11.28)

      36 (52.17)

      18 (26.09)

      15 (21.74)

      0.131
      Mean smoking pack-year (range) 29.72 (2-100) 25.68 (2-40) 0.873

      Initial staging

      - Recurrent

      - Denovo metastasis

      32 (23.88)

      102 (76.12)

      14 (20)

      56 (80)

      0.529

      Histology

      - Adenocarcinoma

      - Squamous cell carcinoma

      - Adenosquamous carcinoma

      - Others

      117 (87.31)

      1 (0.75)

      2 (1.49)

      14 (10.45)

      58 (84.06)

      3 (4.35)

      2 (2.9)

      6 (8.7)

      0.288

      EGFR mutation

      - Negative

      - Positive

      47 (35.07)

      87 (64.93)

      32 (45.71)

      38 (54.29)

      0.092

      Exon 19 deletion

      - No

      - Yes

      87 (64.93)

      47 (35.07)

      50 (71.43)

      20 (28.57)

      0.348

      L858R

      - No

      - Yes

      100 (74.63)

      34 (25.37)

      53 (75.71)

      17 (24.29)

      0.865

      ALK results

      - Negative

      - Positive

      79 (92.94)

      6 (7.06)

      47 (97.92)

      1 (2.08)

      0.421

      Number of site of metastasis

      - 0-1

      - > 2

      88 (65.67)

      46 (34.33)

      37 (52.86)

      33 (47.14)

      0.009

      Lung metastasis

      - No

      - Yes

      92 (69.17)

      41 (30.83)

      38 (54.29)

      32 (45.71)

      0.045

      Bone metastasis

      - No

      - Yes

      101 (75.37)

      33 (24.63)

      53 (75.71)

      17 (24.29)

      0.957

      Liver metastasis

      - No

      - Yes

      122 (91.04)

      12 (8.96)

      62 (88.57)

      8 (11.43)

      0.573

      Pleural metastasis

      - No

      - Yes

      91 (67.91)

      43 (32.09)

      62 (88.57)

      20 (28.57)

      0.606

      Brain metastasis

      - No

      - Yes

      117 (87.31)

      17 (12.69)

      58 (82.86)

      12 (17.14)

      0.387

      Adrenal metastasis

      - No

      - Yes

      122 (91.04)

      12 (8.96)

      62 (88.57)

      8 (11.43)

      0.573

      figure pd-l1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      PD-L1 expression was associated with poorer survival outcomes among advanced NSCLC patients regardless of EGFR mutation status. PD-L1 expression is also the potential of predictive biomarker for EGFR TKIs treatment. The larger studies are needed to identify the prognostic and predictive values in T790M mutation population.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-91 - Treatment Patterns in Patients with Stage IIIB-IV NSCLC in Clinical Practice: Retrospective Analysis of a UK Trust Database

      16:45 - 18:00  |  Presenting Author(s): Michael Snee  |  Author(s): Sue Cheeseman, Matthew Thompson, Laure Lacoin, Will Sopwith, Carlos Chaib, Melinda Daumont, John R. Penrod, John O'Donnell, Geoff Hall

      • Abstract

      Background

      I-O Optimise is a new pan-European data platform developed to enable real-world insights into the management of thoracic malignancies. As part of this initiative, the current analysis reports the characteristics and treatment patterns for adult patients diagnosed with stage IIIB or IV NSCLC at Leeds Teaching Hospitals Trust (LTHT), hosting one of the largest integrated cancer centres in the UK.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective cohort study using longitudinal data already collected from electronic medical records at LTHT, including all adult patients diagnosed with stage IIIB-IV NSCLC between January 2007 and August 2017. Minimum follow-up was 6 months. Distinct lines of therapy (LoT) were identified using a clinically-verified algorithm based on the name and date of systemic anti-cancer therapy (SACT) administered and the gap between two treatments.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, 2119 patients were included. Mean age at diagnosis was 71.4 ± 11.2 years. Nearly one-third (32.7%) were clinically diagnosed without pathological confirmation (TABLE) and very few of these patients have SACT administration recorded. Following diagnosis, 648 patients (30.6%) received ≥1 LoT, 223 (10.5%) ≥2 LoT and 60 (2.8%) ≥3 LoT. Proportions of patients treated decreased with age (73.5% [25/34] aged 18-44 years; 52.7% [267/507] aged 45-64 years; 29.8% [310/1040] aged 65-79 years; 8.6% [46/538] aged 80+ years) and performance score (58.5% [387/662] PS0-1; 38.2% [158/414] PS2; 6.1% [52/848] PS3-4). Between the periods 2007-2011 and 2012-2017, increased proportions were treated (28.2% [263/933] and 32.5% [385/1186] respectively). Patient characteristics of the treated cohort and regimens administered for 1st and 2nd LoT are shown (TABLE).

      real onc_wclc 2018_submission_040518_table_hr.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Around 70% of this real-world cohort did not receive any SACT, and the administration of treatment was strongly associated with age and performance status. The changing availability of treatment options over time (including the emergence of immunotherapy) and survival outcomes by LoT will be presented in more detail for the cohort described.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-92 - “All-In-One” Window: A New Way of Looking at Chest CT Studies in Thoracic Oncology

      16:45 - 18:00  |  Presenting Author(s): Annemie Snoeckx  |  Author(s): Pieter Vuylsteke, Bart Broeckx, Ken Carpentier, Robert Corthouts, Elisa Luyckx, Simon Nicolay, Astrid Van Hoyweghen, Maarten J Spinhoven, Annelies Janssens, Jeroen Cant, Jan P Van Meerbeeck, Paul M Parizel

      • Abstract

      Background

      Historically, CT studies are always viewed in several window settings, optimized to evaluate specific anatomic structures and regions (mediastinal, lung, bone and vascular window). A newly developed image processing technique fuses these conventional windows into a single “all-in-one” window. This new window is specifically designed for comparison and follow-up of CT studies in oncology. The purpose of this study is to compare lesion detection on this “all-in-one” window versus conventional window settings.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this retrospective study, 50 consecutive thoracic oncology chest CT examinations, containing 417 documented lesions and features, were reviewed by 6 radiologists, subdivided into 2 groups of 3 radiologists each, with similar levels of expertise in each group (experienced, junior and radiology resident). All scans were reviewed in conventional window settings (as in routine daily practice), by one group and in the “all-in-one” window by the other group. Lesions were listed as ‘missed’ when they were not seen by at least two out of three observers and as ‘well diagnosed’ when seen by at least two out of three observers.

      4c3880bb027f159e801041b1021e88e8 Result

      Out of the 417 lesions, 68 lesions were missed: 21 on the “all-in-one” window, 30 on conventional views and 17 on both views. Statistical analysis with linear mixed model showed that use of the “all-in-one” window did not result in an increase of missed lesions (p=1). Conversely, we found a tendency towards better lesion detection on the “all-in-one” window, though not strongly significant (p=0.07). Inter-observer agreement in both groups was similar (p=0.462).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our proposed new way of looking at chest CT images seems promising. In this study, we showed that lesion detection on a single "all-in-one" window is at least as good as on multiple conventional window settings. In further research, we will investigate the effect on lesion measurement and characterization.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-93 - The Analysis of the Soluble Programmed Death-1 of Lung Cancer Patients with Different Characteristics

      16:45 - 18:00  |  Presenting Author(s): Xia Song  |  Author(s): Haibo Zhu, Ruifen Tian, wei Guo, Yi Guo, Junjun Xu

      • Abstract

      Background

      Programmed death 1 ligand-1(PD-L1) is important regulators in cancer immunity. The aim of this study was to evaluate the values of the expression of the soluble programmed death-1(sPD-L1) in the plasma of patients with lung cancer, and to investigate the associations between the expression level of sPD-L1 and clinicopathological features as well as effective and survival outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 200 patients with non-small cell lung cancer(NSCLC)(n=188) and small cell lung cancer(SCLC)(n=12) treatment naive were explored, 96 samples of healthy subjects and 13 samples of benign tumours were studied as control. The sPD-L1 expression was scored by the way of anenzyme-linked immunosorbent assay (ELISA). We followed up 67 patients with NSCLC before and after standard treatment, and blood samples were taken every two months. We compared sPD-L1 expression with clinicopathological features and patients outcomes.

      4c3880bb027f159e801041b1021e88e8 Result

      The Expression of sPD-L1 in patients of lung cancer was significantly higher than benign tumour group and healthy group (3.01±3.00ng/ml, 1.76±1.74ng/ml, 1.82±1.20ng/ml, P=0.002). The level of sPD-L1 in lung cancer was not associated with gender, age, smoking history, and histologic subtypes(P>0.05). The level of sPD-L1 was significantly higher in patients of worse PS(performance status)(PS≥2) than better PS(PS<2) (6.40±6.53 vs. 2.68±2.06 P=0.005). The level of sPD-L1 with later stages were remarkable higher than earlier stages(P<0.001) in NSCLC patients. The expression of sPD-L1 of the patients with epidermal growth factor(EGFR) mutated adenocarcinoma was higher than EGFR-wild group(4.30±1.82ng/ml vs. 3.76±1.57ng/ml, P=0.271). The decline of the level of sPD-L1 was correlated with the effects of good response and progressive disease(PD)(0.49±1.48ng/ml vs. 0.11±0.52ng/ml, P=0.307). As for survival, there was no difference between the decline of level of sPD-L1 and the progress free survival(PFS).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results indicated that the elevated expression of sPD-L1 of patients with NSCLC was associated with later stages and worse life conditions, and which may correlated with bad clinical response and poor prognosis. EGFR mutation status may affect the expression of sPD-L1. Further studies are needed to determine the role of sPD-L1 as a molecular prognosis marker for the treatment and prognosis of patients with lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-94 - Diagnostic Patterns of Non-Small Cell Lung Cancer at Princess Margaret Cancer Centre

      16:45 - 18:00  |  Presenting Author(s): Mike Sung  |  Author(s): Maral Nadjafi, Gilda Santos, Lisa Le, David Hwang, Ming Sound Tsao, Natasha B Leighl

      • Abstract

      Background

      Accurate classification of lung cancer subtypes has become critical in tailoring lung cancer treatment. Our study aimed to evaluate changes in diagnostic testing and pathologic subtyping of advanced non-small cell lung cancer (NSCLC) over time at a major cancer centre.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A review of patients diagnosed with advanced NSCLC at the Princess Margaret Cancer Centre between 2007-2009 and 2013-2015 was performed. Diagnostic method, sample type and site, pathologic subtype, and use of immunohistochemical (IHC) staining and molecular testing were abstracted.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 238 patients were reviewed in 2007-2009 and 283 patients in 2013-2015 (Table 1). Over time, the proportion of patients diagnosed with adenocarcinoma increased from 60.9% to 73.1% while NSCLC-not otherwise specified (NOS) diagnosis decreased from 18.9% to 6.4%, p<0.0001. There was a decrease in use of diagnostic bronchoscopy (26.9% vs 18.4%) and an increase with mediastinal sampling procedures including endobronchial ultrasound (9.2% vs 20.5%), p=0.0001. A substantial reduction in cases reported as NSCLC-NOS was observed among bronchoscopy, image-guided, and mediastinal sampling procedures. The reduction in NSCLC-NOS was also predominantly seen in cytology samples, from 22.0% to 4.0% (p<0.0001).

      IHC use increased over time from 41.6% to 76.3% (p<0.0001). Patients with larger samples and IHC analysis were more likely to have biomarker testing performed (both p<0.01). Within the group diagnosed with NSCLC-NOS, the use of IHC increased non-significantly from 64% (29/45) to 94% (16/18). With the exception of bronchoscopy samples, use of IHC increased significantly with each method of diagnosis and sample type.

      table 1. patient demographics and diagnostic sampling characteristics.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Customizing treatment based on pathologic subtype and molecular genotype has become key in treating advanced lung cancer patients. Greater accuracy of pathologic diagnosis is being achieved including through use of routine IHC.

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      P2.01-95 - Assesment the Fitness for Chemotherapy of NSCLC Patients using 6MWT

      16:45 - 18:00  |  Presenting Author(s): Zsuzsanna Szalai  |  Author(s): Annamária Szipőcs, Katalin Borbála Potyó, Zoltán Szász, Tamás F. Molnár

      • Abstract

      Background

      Decision making in chemotherapy in multimorbid advanced NSCLC patients is a complex and challenging task. Physcian reported ECOG performance status (PS), being reproducible, is the gold standard of functional status quantification, when planning an oncology treatment. Inaccurate assesment of PS score is associated with an increased risk of treatment complications and therapy related deaths.

      The aim of study was to measure the correlation between 6-minute walking test (6MWT), PS and chemotherapy endurance and to study the role of 6MWT in predicting treatment complications and deaths.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      138 advanced stage (IIIA, IIIB, IV) NSCLC consented patients were enrolled in a prospective study. They were grouped according to their 6MWT results, and correlation with PS, BMI, FEV1, laboratory values, chemotherapy regimes and cycles were analyzed, with respect to the treatment complications and deaths as endpoints. Statistical analysis was performed with SPSS, Inc., Chicago, IL (level of significance < 0,05).

      4c3880bb027f159e801041b1021e88e8 Result

      Statistical correlation was found between the 6MWT and chemotherapy endurance. Low 6MWT results (with a cut-off of 360 and 300 m respectively) were significantly associated with a very high risk of hematologic complications (36% and 42%), hospitalization (42% and 56%) and 3-month mortality (45% and 69%). No statistical correlation was found between 6MWT to PS, age, FEV1, BMI and initial lab values.

      8eea62084ca7e541d918e823422bd82e Conclusion

      6MWT seems to be a simple, reliable and objective tool in assessing a patient’s fitness to palliative chemotherapy for advanced NSCLC. Optimisation of treatment protocols, using 6MWT as a supportive tool to facilitate PS assesment, might prevent overtreatment of the patient and abuse of health service/insurance budgets.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-96 - Dysgeusia Associated with Nutritional and Quality of Life Parameters in Non-Small Cell Lung Cancer Patients Naïve to Chemotherapy

      16:45 - 18:00  |  Presenting Author(s): Jenny G. Turcott  |  Author(s): Eva Juarez, Karla Paola Sánchez-Lara, Oscar Arrieta

      • Abstract

      Background

      Dysgeusia (taste alteration) has been reported in more than 50% of patient undergoing chemotherapy, however, it can be present before treatment, and it can be associated with nutritional and quality of life parameters.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We evaluated 65 patients naïve to chemotherapy, the alteration of taste by self-reporting questionnaire and through rinse stimuli to identify detection and recognition thresholds of umami, sweet and bitter taste; as well as, their association with nutritional and quality of life parameters.

      4c3880bb027f159e801041b1021e88e8 Result

      Dysgeusia, perceived as a different taste from food was reported in 35% of patients. Those with dysgeusia presents less mean of weight (p=0.059), less lean body mass (p=0.027), higher Fat Mass (p= 0.027), less consumption of protein (0.059), iron (0.022) and sodium (0.034). Patients with dysgeusia reported unfavorable score in functional scales of Health Related Quality of Life (HRQL), than those without dysgeusia; including, Role Functioning (p=0.182*), emotional functioning (p=0.038), cognitive functioning (p=0.017) and social functioning (0.325*). And, the same for symptomatic scales: fatigue (p=0.016), nausea and vomiting (p=0.021), pain (p=0.133*), appetite loss (p<0.001) and constipation (p=0.005).

      diapositiva1.jpgdiapositiva2.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusion: Patients with non-small cell lung cancer present dysgeusia before treatment and affect clinical parameters, food consumption habits and quality of life. Nutritional- care must be provided opportunely.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-97 - Prognostic Factors in Resected Lung Mucinous Adenocarcinoma: Clinical and Pathological Features

      16:45 - 18:00  |  Presenting Author(s): Daisuke Ueda  |  Author(s): Yasuhiro Tsutani, Masaoki Ito, Yoshihiro Miyata, Morihito Okada

      • Abstract

      Background

      Mucinous adenocarcinoma is rare subtype of lung adenocarcinoma. This study aimed to discover which factors influenced prognosis of resected lung mucinous adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From April 1997 to March 2017, we retrospectively reviewed the clinical and pathological features in resected lung mucinous adenocarcinoma patients. We specially focused on KRAS mutation and NRG1 fusion, which were reported that MA often harbored them. We also examined CT findings (solitary type or pneumonic type) and spread through air space(STAS). The Kaplan-Meier method and log -rank test were used for the survival analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      57 patients were enrolled to the study. We detected KRAS mutation in 32 patients (56.1%) and NRG1 fusion in one patient (1.8%). G12D was the most common in terms of amino acid change of KRAS mutation (78%). There were no significant differences in overall survival (OS) and disease-free survival (DFS) between patients with KRAS wild type and those with KRAS mutation (p=0.70 and p=0.85[Office1] , respectively). In point of CT finding, there were 42 solitary type of tumors and 15 pneumonic type of tumors. OS and DFS were significantly worse in pneumonic type patients (p<0.01 and p<0.01[Office2] , respectively). STAS was observed in 32 patients. DFS was significantly shorter in patient with STAS(p=0.03) although OS was not(p=0.07).[Office3] Multivariate analysis revealed that CT finding (pneumonic type) was an independent prognostic factor of DFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pneumonic type on CT finding was an independent prognostic factor in patients with completely resected lung mucinous adenocarcinoma. KRAS status was not significantly related to the prognosis in our cohort.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-98 - Single-Isocenter Volumetric-Modulated Arc Radiosurgery for Non-Small-Cell Lung Cancer Patients with Multiple Brain Metastases

      16:45 - 18:00  |  Presenting Author(s): Megumi Uto  |  Author(s): Tomohiro Katagiri, Keiichi Takehana, Kengo Ogura, Takashi Mizowaki

      • Abstract

      Background

      Radiosurgery for multiple brain metastases (BMs) in patients with non-small-cell-lung cancer (NSCLC) is a well-established treatment option. However, only 1–4 BMs can be treated by conventional linear-accelerator-based radiosurgery because the treatment time becomes longer as the number of BMs increases. Advanced volumetric modulated arc therapy combined with image-guided radiotherapy enables the realization of single-isocenter volumetric-modulated arc radiosurgery (VMAR), a novel irradiation technique. VMAR irradiates multiple BMs simultaneously using only one isocenter and within a short treatment time. Here we report our initial experience with VMAR.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The clinical records of 19 patients with 115 BMs from NSCLC were retrospectively analyzed. All patients were treated by VMAR for multiple BMs from October 2015 to September 2017 at our institution and received follow-up magnetic resonance imaging at least once after VMAR. The median patient age was 69 years. The median Karnofsky Performance Scale score was 90; five patients had been previously treated with whole-brain radiotherapy. The histology of the primary tumor was squamous-cell carcinoma in one patient and adenocarcinoma in 18 patients; 12 patients had either an EGFR or ALK alteration. A planning target volume (PTV) was created by expanding the contrast-enhanced lesion with a 1- or 2-mm margin. The median peripheral prescribed dose was 28 Gy, delivered in five fractions. All lesions were set to be covered by ≥99.5 % of the prescribed dose.

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up period was 8.5 (range, 1.7–29.9) months. The median number of PTVs was four (range, 2–18). The median PTV was 0.49 (range, 0.13–13.49) cm3, and the median total PTV 8.3 (range, 1.52–18.87) cm3. The median PTV was significantly smaller in patients with than without genetic alterations to their tumor. The probabilities of local control, overall survival, and developing new BMs at 12 months were 100%, 68.4%, and 51.1%, respectively. Acute adverse events included grade 2 alopecia in four patients and seizure in one patient. The number of PTVs in patients with grade 2 alopecia was more than six. Two patients developed grade 2 central nervous system necrosis as a late adverse event. No grade 3 or higher toxicities were noted.

      8eea62084ca7e541d918e823422bd82e Conclusion

      While VMAR achieves good local control, the development of temporary alopecia remains to be addressed. More cases and a longer- follow-up period are required to verify the efficacy of VMAR.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-99 - Can NGS NSCLC Testing Be Implemented Without in House Expertise? Clinical Utility of the First FDA-Approved Lung Cancer NGS End-To-End Solution

      16:45 - 18:00  |  Presenting Author(s): Anagh Vora  |  Author(s): Sherrol McDonough, Aparna Aiyer, Anne Marie Velasco Roth, Juscilene Menezes, Jody Schulz, Justine Degrandpre, Erene Mina, Jay H. Shaw

      • Abstract

      Background

      Clinical utility and advantages of in-house NSCLC NGS testing compared with send-out testing are: shorter turn-around times for faster treatment, better tissue stewardship, and maintenance of specimen control within institutions, fostering direct communication between pathologists and oncologists on the most effective testing and treatment paradigms. Despite obvious benefits, in-house NGS testing widespread use has not occurred due to the need for specialized personnel, extensive hands-on time, and complexity in developing/validating home-brew panels, and bioinformatics result interpretation. To overcome these difficulties, Thermo Fisher Scientific developed the Oncomine™ Dx Target Test (ODxTT) to identify NSCLC guideline-recommended EGFR, ROS1, or BRAF mutations for their associated treatment with gefitinib, crizotinib, or dabrafenib/trametinib, respectively. This is the first FDA-approved NGS companion diagnostic test commercially available that can be implemented in local laboratories.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinical utility measured by objective response rate (ORR), and duration of response (DOR) in NSCLC patients was evaluated initially utilizing local laboratory tests (LLTs) and compared with the ODxTT across mutations and associated therapies.

      4c3880bb027f159e801041b1021e88e8 Result

      Comparison of ODxTT with the NSCLC BRAF V600E PCR assay in patient samples showed 100% (181/181; 95%CI 97.9-100%) overall percent agreement (OPA, excluding no calls). Clinical efficacy of the ODxTT in 2 cohorts with stage IV NSCLC treated with dabrafenib/trametinib (BRF113928 clinical trial) measured as ORR was 68.2% (15/22) for Cohort B and 60.9% (14/23) for Cohort C, which was similar to the results achieved with the LTT 63.2% ORR (36/57) for Cohort B and 61.1% ORR (22/36) for Cohort C. ORR of 83.3% (5/6; 95%CI: 35.88-99.58%) was achieved with crizotinib with an accompanying DOR of 17.5 months (N=5, 95%CI: 10.9-24.1) which tested positive with the ODxTT in patient samples (Phase-1, Pfizer-Study A8081001). OPA of 99.0% (188/190; 95%CI 96.25-99.87%) was achieved for EGFR Exon 19 deletion and 100% (197/197; 95%CI: 98.14-100%) for EGFR L858R with the ODxTT versus the Qiagen TheraScreen EGFR RGQ PCR Kit.Estimate repeatability of the ODxTT at each variant location was ≥98.8% (DNA) and 94.4% (RNA).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The FDA approved ODxTT demonstrated clinical utility by accurately detecting guideline-recommended mutations for the selection of associated targeted therapies eliminating additional expertise required to validate, implement, and run NGS LLTs.

      "For In vitro diagnostic use"

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-100 - Different Genetic Mutations Enriched in Circulating Tumor DNA Predict Different Metastatic Sites in Lung Adenocarcinoma Patients

      16:45 - 18:00  |  Presenting Author(s): Liyun Miao  |  Author(s): Jinjin Wang, Jun Zhao, Xinghao Ai, Gen Lin, Rongrong Chen, Xuefeng Xia

      • Abstract

      Background

      The mutation map of the lung adenocarcinoma is clear. However, differences of genetic mutations related to metastatic sites have not been addressed before and remain to be explored. Identification of mutation signature may help to predict metastasis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed 353 ctDNA samples from lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 59 genes.

      4c3880bb027f159e801041b1021e88e8 Result

      All the samples were divided into 2 groups based on the distance of the metastases: 165 samples was in the distal metastasis group including bone or liver metastases; 188 samples was in the proximal group, including lung, pleural or thoracic lymph node metastasis. The gene mutation number of the distal metastasis is higher than the proximal metastasis (4.92 vs 3.85, P=0.031). Gene mutations for each group are shown in the figure below. Similar to the genetic profiling of lung adenocarcinoma in COMIC database, the most frequently mutated genes were EGFR and TP53 in two groups. But the frequency mutation of NTRK1 in proximal metastasis group is three times more than that of the distal metastasis group (11/188, 5.9% vs 3/165,1.8%). And the frequency of ALK mutation in the distal metastasis group is two times more than that of the proximal metastasis group (10/165, 6.1% vs 6/188, 3.2%). Moreover, for the top 9 frequently mutant genes, there was 78% overlap in the two groups. However, the overlap with COSMIC database was 55% for distal metastasis group and 44% for the proximal metastasis.

      Distant metastasis group

      Proximal metastasis group

      COSMIC database

      gene

      Mutation frequency

      gene

      Mutation frequency

      gene

      Mutation frequency

      1

      EGFR

      70.30%

      EGFR

      73.94%

      EGFR

      31%

      2

      TP53

      60.61%

      TP53

      61.17%

      TP53

      31%

      3

      KRAS

      11.52%

      ERBB2

      9.04%

      KRAS

      18%

      4

      RB1

      10.30%

      KRAS

      9.04%

      STK11

      8%

      5

      NF1

      9.70%

      RB1

      7.45%

      CDKN2A

      7%

      6

      ERBB2

      7.88%

      NF1

      7.40%

      SMARCA4

      6%

      7

      APC

      6.67%

      APC

      6.91%

      NF1

      6%

      8

      ALK

      6.06%

      PIK3CA

      6.38%

      ATM

      5%

      9

      ATM

      6.06%

      RET

      5.85%

      KDR

      5%

      10

      PIK3CA

      6.06%

      NTRK1

      5.85%

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung adenocarcinoma patients with ALK mutation are more likely to have distant metastasis. While the patients with NTRK1 mutation are more likely to have proximal metastasis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-101 - Dynamic Monitoring of Gene Alterations with ctDNA by NGS for EGFR Mutated Lung Adenocarcinoma Treated with Gefitinib in BENEFIT Study (CTONG 1405)

      16:45 - 18:00  |  Presenting Author(s): Jie Wang  |  Author(s): Jian-Chun Duan, Shuhang Wang, Zhi-Jie Wang, Hua Bai, Jun Zhao, Hongjun Gao, Ying Cheng

      • Abstract

      Background

      Blood-based cell-free tumor DNA (ctDNA) could be dynamically monitored to provide gene alterations during EGFR-TKI treatment, which might offer critical clue for prognosis and clinical treatment decision. Here we reported the dynamic gene alterations monitoring using next generation sequencing (NGS) in BENEFIT study to explore the mechanisms of different responses and resistances to EGFR-TKI in EGFR-sensitizing-mutated lung-adenocarcinoma (LADC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with systemic treatment-naïve, stage IV LADC and EGFR-sensitizing-mutation in ctDNA were enrolled to receive gefitinib. Blood samples were dynamically obtained at baseline, every 8 weeks and at disease progression (PD). The dynamic analysis of quantity of ctDNA, multiple driver genes and tumor suppressors were investigated with NGS (Nextseq500 sequencer, consisting of critical exons/introns of 168 genes), and were correlated with efficacy and resistance.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally 181 LADC patients with EGFR-sensitizing-mutation (exon-19-deletion and exon-21-L858R-point-mutation) provided sufficient blood samples for NGS analysis at baseline, of which 143 patients obtained at least four timepoints of dynamic blood sample collection until PD (baseline, 8 weeks, 8 weeks before PD and PD). At baseline, 180 of patients (99.4%) were confirmed as EGFR-sensitizing-mutation with NGS (92 EGFR-19-deletion and 88 EGFR-L858R-point-mutation) including 44 (24.3%) EGFR-amplification, 116 (64%) TP53-mutation, or other known oncogenic drivers including MET (N=5, 2.8%), ERBB2 (N=7,3.9%), KRAS (N=6, 3.3%), BRAF (N=2, 1.2%), RET (N=1, 0.6%), ROS1 (N=1, 0.6%), or EGFR-T790M (N=4, 2.2%), which was correlated with poor efficacy compared with those with only EGFR-sensitizing-mutation (PFS 4.7 months [m] vs. 13.2m , p=0.002). Additionally, tumor suppressor genes exhibiting cumulative effect to poor prognosis: PFS for 164 patients with TP53&RB1&PTEN-mutation≤1 was 11.1m, while for 16 patients with TP53&RB1&PTEN-mutation>1,PFS was 4.7 m, p<0.0001. To cut-off date, 117 patients had PD, among them, 63 (54%) patients acquired EGFR-T790M-mutation presented as dominant resistance mechanism besides MET-amplification/ERBB2-amplification/ERBB2-S310F (N=16, 14%), RET fusion/splice (N=2, 1.7%), ROS1-C2336F-mutation (N=1, 0.9%), RB1-nonsense-mutation (N=2, 1.7%), TP53-Y205S-mutation (N=1, 0.9%) and TP53-Y205S-mutation accompanied with FGFR1-amplification (N=1, 0.9%). The remaining resistance mechanisms (31%) were unknown. Patients with only T790M-mutation had a significantly longer PFS (11.5m) compared with patients obtaining other acquired resistant mechanisms (3.0m). Interestingly, seventy-five (53.2%) patients had molecular progression before radiographic progression, and the median time difference was 8.7 weeks.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dynamic alterations of multi-drivers and suppressors together with EGFR-sensitizing-mutation and T790M-mutation could separate LADC into different subgroups with distinguished molecular features, which may play a vital role during EGFR-TKI treatment for resistance-predicting, and initial/subsequent treatment decision-making.

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      P2.01-102 - Comprehensive Next-Generation Sequencing Guided Targeted Therapies Improve Clinical Outcomes of Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Zhaoxia Wang  |  Author(s): Dongqin Zhu, Binbin Lu, Guojian Liu, Tianwei Xu

      • Abstract

      Background

      Next-generation sequencing (NGS) has been increasingly involved in the clinical decision-making of cancer care, the primary applications of which are the identification of sensitizing mutations for targeted therapies and drug-resistant mechanisms. Along with more clinical validations and approvals of several commercially available targeted NGS panels by FDA for mutation profiling, it has been debated that whether comprehensive NGS test should be used as a standard procedure in clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this study, we recruited 24 patients with stage IV lung cancer. 22 of them are adenocarcinoma and the other 2 are small cell lung cancer and squamous cell carcinoma, respectively. Genomic DNA from 13 tumor tissues, and circulating tumor DNA from 8 pleural effusions and 3 plasma samples in each corresponding patient were collected and subjected to targeted-NGS covering 416 cancer-related genes and 16 genes frequently rearranged in solid tumors. Targeted therapy or chemo/radiochemotherapy was applied in clinical practice with the consideration of patients’ requests and their affordability due to financial barriers. Patients’ clinical outcomes were further evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      Of all patients, 54% of them (n=13) were detected with sensitizing mutations that have targeted drugs available, including EGFR exon 19 deletion (n=2), L858R (n=2) and L861Q mutations (n=1), ALK fusion (n=1), ROS1 fusion (n=1), MET exon 14 skipping (n=1), as well as EGFR T790M (n=5) for 4 patients who had progressed on the first-generation tyrosine kinase inhibitors (1st-gen TKI) and 1 TKI-treatment naive patient. 69% of patients (n=9) with actionable mutations were subjected to targeted treatment, while the other 31% patients (n = 4) were treated with chemotherapy or radiochemotherapy. Consistent with clinical validations, the overall survival (OS) of targeted-treatment group is better than the systematic treatment group. On the other hand, for patients without detectable actionable mutations (n=11), 64% of patients (n=7) were underwent chemotherapy, while the rest were treated with 1st-gen EGFR TKI as requested by the patients. As expected, chemotherapy-treatment group had a similar OS as the TKI group. Collectively, patients with sensitizing mutations achieved significantly longer OS from the TKI treatments than those without actionable mutations (p=0.02).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data demonstrated that the existence of sensitizing mutation is the determining factor for the treatment efficacy of targeted therapies. In the real world, NGS test can not only be involved into the decision-making for the first line treatment, but also be instructive for treatment changes after drug-resistance developed

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      P2.01-103 - Neutrophil-to-Lymphocyte Ratio as a Predictor of Immunotherapy Treatment Outcomes in Advanced Non-Small Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Xiao Wang  |  Author(s): Wei Fu, Chen Hu, Jarushka Naidoo, Josephine Feliciano

      • Abstract

      Background

      Immune checkpoint inhibitors (ICIs) are a new class of therapy for patients with non-small cell lung cancer (NSCLC). Immunologic markers, such as serum neutrophil-to-lymphocyte ratio (NLR), are prognostic in patients with a variety of malignancies, with preliminary findings in patients on immunotherapy. In this study, we evaluate the association between NLR and ICI outcomes in NSCLC, including the development of immune-related adverse events (irAEs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a retrospective analysis of advanced or recurrent NSCLC patients receiving ICI from 2011 to 2017. Demographics, disease and treatment history, and pretreatment labs were recorded. An NLR³5 was defined as high and <5 as low, based on meta-analyses. Cox proportional hazards models and univariate and multivariate regressions were used to assess the association between NLR and overall survival (OS), progression-free survival (PFS), disease control rate at 10 weeks (DCR), and irAEs.

      4c3880bb027f159e801041b1021e88e8 Result

      183 patients were identified: 55.2% male, 76.5% Caucasian, mean age 65.3 years (range 38–90 years). Male sex, smoking history, prior radiotherapy, and pretreatment albumin were significantly associated with high versus low NLR (p < 0.05). In univariate analyses, pretreatment NLR was a significant predictor of OS (HR 1.47, p < 0.05, Fig. 1), PFS (HR 1.44,, p < 0.05), and DCR (OR 0.49, p < 0.05), but not irAEs (OR 1.37, p = 0.33). These findings persisted with multivariate analyses (OS HR 1.76, PFS HR 1.64, DCR OR 0.24, all p < 0.01; irAE OR 1.52, p = 0.33).nlr survival.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      High NLR was positively associated with OS, PFS, and DCR but not irAEs in NSCLC patients receiving ICI. Our results support the use of NLR as a biomarker for clinical outcomes. Prospective studies are needed to study this measure in patients undergoing ICI therapy, and further studies to identify predictive biomarkers of irAEs are warranted.

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      P2.01-104 - Plasma T-Cell-Derived Circulating DNA in Advanced NSCLC is Not Correlated with TIL but has a Potential of Prognostic Value

      16:45 - 18:00  |  Presenting Author(s): Chanida Vinayanuwattikun  |  Author(s): Bowon Weerasubpong, Poonchavist Chantranuwatana, Virote Sriuranpong

      • Abstract

      Background

      Non-tumor derived circulating DNA (nt-cirDNA) of advanced non-small cell lung cancer (NSCLC) patient, even not yet clear originated, was associated with prognosis. In this study, we investigated whether T-cell-derived circulating DNA (T-cirDNA) was the majority part of nt-cirDNA nor correlated with tumor-infiltrating T-lymphocyte (T-TIL).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Prognostic impact including demographic characteristics were integrated into the model. Using Quantitative real-time PCR with Taqman assay specific to VDJ segment of TCRβ (T-cell-receptor beta chain) was used to represented amount of T-cirDNA in plasma of 106 advanced stage NSCLC. Quantitative CD3-specific immunohistochemistry (IHC) staining from biopsy specimen, represented T-TIL, was done using Aperio ImageScope.

      4c3880bb027f159e801041b1021e88e8 Result

      T-cirDNA was detected in seventy-three advanced NSCLC patients with a median of 1.71 pg/ml [range 0-2260]. Forty-six patients were assessed for proportion of T-TIL per total cell with a median of 0.22 per mm2 [range 0.02-2.34]. No correlation was found between T-cirDNA and T-TIL. From multivariable analysis, active smoking status was the only factor correlated with low T-cirDNA level (P<0.001). Kaplan Meier survival analysis of T-cirDNA ratio (T-cirDNA/total cirDNA) shown a trend of favor prognostic outcome for high T-cirDNA ratio (more than 0.03 %), HR 0.67 [95% CI 0.43-1.04, P=0.07]media2.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      plasma T-cirDNA component, even not correlated with T-TIL, revealed a trend of prognostic impact in advanced stage non-small-cell cancer patients.

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      P2.01-105 - Tumor Treating Fields Plus Standard of Care for Non-Small Cell Lung Cancer Following Platinum Failure: Phase 3 LUNAR Study

      16:45 - 18:00  |  Presenting Author(s): Uri Weinberg  |  Author(s): Ori Farber, Moshe Giladi, Zeev Bomzon, Eilon D. Kirson

      • Abstract

      Background

      Tumor Treating Fields (TTFields) is a non-invasive, anti-mitotic treatment approved for glioblastoma based on significant survival outcomes in a Phase 3 trial. Efficacy of TTFields in NSCLC has been shown preclinically and the safety confirmed in a phase I/II pilot study combined with pemetrexed. In the LUNAR study [NCT02973789], we investigated if adding TTFields to immune checkpoint inhibitors or docetaxel following platinum doublet failure will increase overall survival.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: Patients (N=534), with squamous or non-squamous NSCLC, are stratified per selected standard therapy (immune checkpoint inhibitors or docetaxel), histology (squamous vs. non-squamous) and geographical region. Key inclusion criteria: disease progression while on/after platinum-based therapy, ECOG 0-2, no electronic medical devices in the upper torso, and absence of brain metastasis. Docetaxel or immune checkpoint inhibitors are given at standard doses. TTFields are applied to the upper torso for >18 hours/day, allowing patients to maintain daily activities. TTFields are continued until progression in the thorax and/or liver. Follow-up is performed once q6 weeks using CT scans of the chest and abdomen. On progression in the thorax and/or liver, patients have 3 post-progression follow-up visits and are then followed monthly for survival. The primary endpoint is superiority in OS with TTFields in combination with the standard of care treatments versus (vs) standard of care treatments alone. Key secondary endpoints compare the OS in patients treated with TTFields and docetaxel vs docetaxel alone, and patients treated with TTFields and immune checkpoint inhibitors vs those treated with immune checkpoint inhibitors alone. An exploratory analysis will test non-inferiority of TTFields with docetaxel compared to checkpoint inhibitors alone. Secondary endpoints include progression-free survival, radiological response rate, quality of life based on the EORTC QLQ C30 questionnaire and severity and frequency of adverse events. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

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      P2.01-106 - A Comparative Analysis of Genomic Alterations by Tumor Tissue and Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Go-un Woo  |  Author(s): Se Hyun Kim, Koung Jin Suh, Yu Jung Kim, Jin-Haeng Chung, Byung-Chul Lee, Nak-Jung Kwon, Jeong-Sun Seo, Jong Seok Lee

      • Abstract

      Background

      Genomic profiling of lung cancers using circulating tumor DNA (ctDNA) in the blood of patients is rapidly becoming established as a useful source of information to aid clinical decision-making. We evaluated the concordance of genomic alterations by ctDNA and tumor tissue DNA in Advanced Non-Small Cell Lung Cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tumor tissue DNA from formalin-fixed, paraffin-embedded (FFPE) samples and ctDNA from plasma samples were obtained at the time of diagnosis or at the time of progressive disease after receiving targeted therapy in 41 patients with stage IIIB or IV NSCLC in this prospective study (NCT03235765). Hybrid-capture based genomic profiling (Axen Cancer Panel, Macrogen) was performed to sequence 170 genes in both samples. Concordance is defined as the number of genomic alteration present in both samples divided by the number of genomic alteration in FFPE. Tumor mutation burden (TMB) was also measured.

      4c3880bb027f159e801041b1021e88e8 Result

      Most patients were adenocarcinoma (n=34, 82.9%). The total number of genomic alteration identified in FFPE and ctDNA were 751 and 561, respectively. Median concordance was 50% (8.0% – 100%). Among the clinical factors including smoking history, tumor size, PD-L1 status, EGFR mutation, TMB of tumor DNA, and concentration of ctDNA, concordance was negatively correlated with TMB of tumor DNA (Spearman's r= -0.504, P=0.001). When we divide low TMB (TMB-L) and high TMB (TMB-H) by the cut-off of 15/MB (median value), average concordance was 38.7% in TMB-H (N=20) and 59.7% in TMB-L (N=21) (Mann-Whitney, P=0.007). TMB by FFPE was significantly associated with the number of genomic alterations in FFPE (P<0.0001), but was not with the number of genomic alterations in ctDNA (P=0.128) or PD-L1 status (P=0.574).

      figure1 concordance in tmb-l and tmb-h.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study suggests that ctDNA genomic profiling may replace tissue-based genomic profiling in NSCLC patients with low TMB. However, both tissue and blood-based genomic profiling may be necessary for NSCLC patients with high TMB.

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      P2.01-107 - Analysis of Mutation Detection by ctDNA on the Basis of Metastatic Sites in Lung Adenocarcinoma Patients

      16:45 - 18:00  |  Presenting Author(s): Renhua Guo  |  Author(s): Huamin Xu, Jie Xia Zhang, Xinghao Ai, Li Liu, Jun Zhao, Xiaorong Dong, Liyun Miao, Rongrong Chen, Xuefeng Xia

      • Abstract

      Background

      Circulating tumor DNA (ctDNA) testing represents a powerful tool to detect gene alterations in patients. However, differences in mutation detected by ctDNA related to metastatic sites in lung cancer have not been addressed before and remain to be explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed 317 ctDNA samples from 310 lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 1021 genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were divided into two groups according to metastatic sites. Any case with metastasis to the bone, liver or adrenal gland falls into the major organ metastasis group, while any case with metastasis to the lung, pleura or lymph node belongs to the local metastasis group. No genetic alteration was detected in 14 (11.5%) of 122 samples in the major organ group and 35 (17.9%) of 195 in the local group. And distant metastasis is associated with more mutations on average detected by ctDNA (5.26 for the major organ group vs 3.72 for the local group; p=0.0039). As for genes involved, the most common mutated ones are EGFR and TP53 for both groups, with an overall mutation rate being 40.6% and 33.2% respectively. And just as average gene alterations mentioned above, the mutation rates of EGFR and TP53 are much higher in the major organ group (49.6% vs 35.2% for EGFR; 43.6% vs 26.9% for TP53). Besides, mutations of NF1, MLL3, KRAS and KEAP1 are more frequent in the major organ group while mutation rate of PIK3CA is slightly higher in the local group (Table).

      Table. Some mutated genes detected by ctDNA

      major organ metastasis (117)

      local metastasis (193)

      EGFR

      58 (49.6%)

      68 (35.2%)

      TP53

      51 (43.6%)

      52 (26.9%)

      KRAS

      9 (7.7%)

      7 (3.6%)

      MLL3

      9 (7.7%)

      6 (3.1%)

      NF1

      9 (7.7%)

      3 (1.6%)

      ERBB2

      5 (4.3%)

      6 (3.1%)

      PIK3CA

      3 (2.6%)

      7 (3.6%)

      KEAP1

      7 (6.0%)

      3 (1.6%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      More gene alterations were detected by sequencing of ctDNA in patients of lung adenocarcinoma with major organ metastasis compared to those with only local metastasis.

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      P2.01-108 - Temporal Heterogeneity of Resistant Mutations in Sequential ALK TKI Treated Lung Cancer Revealed by NGS-Based Liquid Biopsy

      16:45 - 18:00  |  Presenting Author(s): Yu Yang  |  Author(s): Yan Ding, Xue Wu, Yang W. Shao

      • Abstract

      Background

      Crizotinib and several next-generation ALK TKIs have been widely applied in the treatment of ALK-positive lung cancer patients. However, drug resistance is eventually developed to these ALK TKIs via heterogeneous resistance mechanisms, which is needed to be further explored. Due to the invasiveness and feasibility of repetitive tissue biopsies, liquid biopsy has become a promising alternative for dynamically monitoring tumor genomic evolution and guides decision-making for treatment adjustment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Primary tumor sample of a 71-year-old male patient diagnosed with stage IV lung adenocarcinoma was subjected for targeted next-generation sequencing (NGS) for identification of driver mutations. Mutation profiles of circulating tumor DNA (ctDNA) from seven sequential plasma samples during the treatment course of crizotinib, brigatinib, and lorlatinib were closely monitored.

      4c3880bb027f159e801041b1021e88e8 Result

      The dynamic mutation profiles during the disease course were represented in the Figure. As EML4-ALK v1 fusion was detected in the primary tumor, the patient was administrated with crizotinib and reached a progression-free survival (PFS) of 11 months when ALK G1269A was identified upon progression. As a result, brigatinib, a second generation ALK TKI overcoming G1269A-driven resistance, was applied. Dynamic monitoring of patient’s ctDNA during brigatinib treatment showed a dramatic drop of G1269A mutant allele frequency (MAF) to undetectable level, whereas a novel F1174L became the dominant clone. The disease progressed after 9-month of brigatinib treatment, and the patient was switched to lorlatinib. A third mutation E1210K quickly overtook F1174L as the dominant clone with the accumulation of more concomitant mutations towards the end of the treatment (8 different mutations) with a PFS of 9 months. Interestingly, brigatinib-sensitive G1269A came back after 6-month of lorlatinib treatment.

      fish plot.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      Temporal heterogeneity of ALK activating mutations was observed along the treatment course of different TIKs via NGS-based liquid biopsy, which could provide guidance for stepwise treatment strategy for better patient care.

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      P2.01-109 - Treatment Duration—­A More Reasonable Definition to Evaluate the Efficacy of Crizotinib in ALK Positive Advanced NSCLC

      16:45 - 18:00  |  Presenting Author(s): Guangjian Yang  |  Author(s): Di Ma, Junling Li, Puyuan Xing, Xuezhi Hao, Haiyan Xu, Yan Wang

      • Abstract

      Background

      Crizotinib has demonstrated its superior efficacy in ALK positive NSCLC patients when used as first-line regimen, with a median overall survival (OS) of more than 4 years, whereas a median progression-free survival (PFS) of only 10.9 months. Patients who continued crizotinib beyond progressive disease (CBPD) could still obtain additional survival benefits of 6-8 months after disease progression. In terms of that, PFS, the frequently used primary endpoint in clinical trials, may not be able to provide accurate information on impact of this intervention in multiple lines therapy. Here we proposed “treatment duration” as an intermediate clinical endpoint between PFS and OS that further define efficacy of crizotinib in multiple lines of treatment and reported the exploratory data in a real-world cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively enrolled 150 ALK positive NSCLC patients who had acquired crizotinib resistance from Aug 2011 to May 2017. The median PFS of crizotinib and median OS (from crizotinib initiation) were analyzed. Treatment duration of crizotinib, the time from crizotinib initiation to discontinuation, was also calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      The median PFS of crizotinib in the 150 ALK positive advanced NSCLC patients was 14.4 months (95% CI: 11.3-17.4). Overall, 58 patients (38%) continued CBPD and the median post-progression PFS was 10.4 months, resulting in a median treatment duration of crizotinib in the total cohort of 20.2 months (95% CI: 14.3-26.0). And median OS was 30.1months (95% CI: 21.3-38.8). 77 (51%) patients who received crizotinib as first-line therapy exhibited both longer median PFS (17.7 months, 95% CI: 12.5-22.9; vs. 12.2months, 95% CI: 7.6-16.8) and median OS (35.2 months, 95% CI: 23.2-47.1; vs. 25.4 months, 95% CI: 14.4-36.3) compared to those selected crizotinib as second- line and above therapy. The treatment duration among them were 23.1 months (95% CI: 14.7-31.4) and 18.9 months (95% CI: 11.4-26.3), respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Crizotinib showed superior efficacy in ALK positive NSCLC patients. Treatment duration may be more reasonable to define the efficacy of crizotinib in multiple lines therapy of ALK positive NSCLC.

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      P2.01-110 - Unique Genomic Profile Revealed by Malignant Pleural Effusion

      16:45 - 18:00  |  Presenting Author(s): Zhihua Guo  |  Author(s): Weiqiang Yin, Dongyong Yang, Zhanhong Xie, Huifang Shi, Wei Du, Lijun Peng, Jianxing He

      • Abstract

      Background

      The accumulation of malignant pleural effusion (MPE), often occurring in advanced lung cancer patients, is the result of pleural space invasion by malignant cells, which disrupt the drainage of pleural fluid. Numerous studies have confirmed the clinical utility of MPE for mutation detection from single gene perspective, often focusing on classic driver genes. Very few studies have interrogated MPE as a media for liquid biopsy using targeted sequencing. In this study we investigated the potential of using MPE as a media for liquid biopsy using targeted sequencing.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Matched plasma and MPE samples were obtained from 154 patients with advanced NSCLC. Among them, 17 patients had matched primary tissue sample and MPE precipitates. Ultra-deep targeted sequencing using a panel consisting of 168 lung cancer-related genes, spanning 160 kb of human genome was performed with an average sequencing depth of 10,000x for MPE and 1,000x for tissue samples.

      4c3880bb027f159e801041b1021e88e8 Result

      Using tissue sample as a reference, detection rates of driver mutations in MPE cfDNA (supernatant), MPE precipitates and plasma are 100%, 70.6% and 82.3%, respectively. The median maximum allelic fractions (MAF) for MPE cfDNA, precipitates and plasma are 12.9%, 14.8% and 3.6%, respectively. MPE and tissue have comparable median MAF, which is significantly higher than plasma (p=0.01), demonstrating the superiority of MPE cfDNA in mutation detection. Next, we compared and contrast genomic profiles derived from MPE cfDNA and plasma cfNDA. Collectively, in 154 patients, we identified 939 variants from MPE and 865 variant from plasma; among them, 770 variants were shared by the two media; 169 variants were MPE specific and 95 variants were plasma specific. EGFR and TP53 are the two most frequently occurring mutations in both MPE cfDNA and plasma cfDNA. MPE cfDNA of 56 patients had CNVs detected; in contrast, only 27 patients had CNVs detected from plasma sample, resulting in a significantly higher detection rate in MPE cfDNA (p<0.01). Collectively, we identified 201 CNVs; among them, 164 were shared by both media; 33 are MPE specific and the remaining 4 are plasma specific.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Collectively, our study demonstrates superiority of MPE cfDNA as an alternative media for liquid biopsy. In addition to higher detection rate and MAF, MPE cfDNA also revealed a unique genomic profile, especially in capturing CNV.

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      P2.01-111 - Clinical Features and Prognosis of Eighty-Five Patients with Primary Pulmonary Lymphoepithelioma-Like Carcinoma

      16:45 - 18:00  |  Presenting Author(s): Qin Yin Yin  |  Author(s): Guo Ying Gao, Cheng Zhi Zhou, Yi Qian Liu, Xiao Hong Xie, Xin Qing Lin, Zheng Zhu, Zhan Hong Xie, Jie Xia Zhang, Ou Yang Ming, Rong Chang Chen, Shi Yue Li

      • Abstract

      Background

      Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare subtype of lung cancer that is less reported and not well understood around the world.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective analysis of clinical features for 85 patients was conducted to determine the prognostic factors in terms of age, gender, radiographic features, serum tumor markers, TNM stages, pathological features, treatment and prognosis.

      4c3880bb027f159e801041b1021e88e8 Result

      PLELC preferentially affects the young (< 60 years old: 71.8%) nonsmokers (72.9%), without significant difference in gender. The median follow-up time was 15 months (1-37 months) for the whole group and most patients were in the early stage with opportunity of operation (50.6%). For the advanced stage group, patients mainly received chemotherapies and radiotherapies, the 0.5-year and 1.5-year PFS rates were 61% and 29%, respectively. The TNM stage (P=0.014) and performance status (PS) (P=0.040) were associated with PFS significantly in the univariate analysis, while TNM stage was an independent prognostic factor in multivariate analysis (P=0.026). In the subtype analysis, patients in the advanced stage receiving Gemcitabine plus platinum (GP group) or Paclitaxel plus platinum (TP group) had better PFS than Pemetrexed plus platinum (PP group) (P=0.005).

      8eea62084ca7e541d918e823422bd82e Conclusion

      PLELC had a better prognosis compared with other types of non-small cell lung cancer (NSCLC) and was sensitive to radiotherapy and chemotherapy. The current results recommended that the GP and TP should be used as first-line treatment of PLELC. The TNM stage and PS were predictive in prognosis of PLELC patients.

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      P2.01-112 - Prognostic Value of Changes in Neutrophil-To-Lymphocyte Ratio in Patients with Lung Cancer Treated with Nivolumab

      16:45 - 18:00  |  Presenting Author(s): Takashi Yokoi  |  Author(s): Eisuke Shibata, Ryo Takahashi, Koji Mikami, Shingo Kanemura, Yuichi Koda, Yoshiki Negi, Eriko Fujimoto, Yumiko Akano, Akio Tada, Toshiyuki Minami, Kozo Kuribayashi, Takashi Kijima

      • Abstract

      Background

      Nivolumab, an anti-programmed cell death 1(PD-1) antibody, is a standard regimen for the second-line treatment of non-small cell lung cancer (NSCLC). However, compared with molecular-targeted drugs, the response rate to nivolumab is low, and biomarkers of efficacy are currently lacking. It has been recently reported that the neutrophil-to-lymphocyte ratio (NLR) can be a biomarker of efficacy. Here, we examined the possibility for NLR to predict efficacy of nivolumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively examined all patients with NSCLC who were treated with nivolumab at our institution.

      4c3880bb027f159e801041b1021e88e8 Result

      We compared 35 patients with NLR of ≥3 and 44 with NLR of <3, all of whom were treated with nivolumab. There was no difference in response rates between the two groups. The median (m) PFS and mOS were 130 and 583 days in the NLR≥3 group, whereas those were 169 days and not reached (NR) in the NLR<3 group. Longer PFS and OS were observed in the NLR<3 group than in the NLR≥3 group. Next, we analyzed the relationship between treatment efficacy and relative change of NLR (NLR), the ratio of the value at 4 weeks after the administration of nivolumab to the value at baseline. In 42 patients with NLR of 1, mPFS and mOS were 122 and 564 days, respectively. In 31 patients with NLR of <1, mPFS and mOS were 280 days and NR, respectively. PFS and OS were significantly better in the group with NLR of <1. With respect to adverse events, grade 1-2 rashes were observed in 29% of patients in the group with NLR of <1 and in 9.5% of patients in the group with NLR of 1.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Relative ratio of NLR at 4 weeks/at baseline is a predictive biomarker in patients with NSCLC who are treated with nivolumab.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-113 - Prognostic Roles of Neoadjuvant and Adjuvant Chemotherapy for Treating Patients with Operable Stage III-N2  Non-Small Cell Lung Cancer (NSCLC)

      16:45 - 18:00  |  Presenting Author(s): Luo-Sheng Yong  |  Author(s): Shuenn-Wen Kuo, Pei-Wen Yang, Pei-Ming Huang, Mong-Wei Lin, Ke-Cheng Chen, Jang-Ming Lee

      • Abstract

      Background

      The therapeutic options for stage III-N2 positive NSCLC, including the diseases with ipsilateral mediastinal or subcarinal lymph node involvement, are with multidisciplinary approaches. The NCCN and ASCO guideline recommends the cisplatin-based adjuvant chemotherapy (Ad C/T). Meanwhile, some studies revealed the benefits of managing the N2 node disease with the neoadjuvant chemotherapy (Neo C/T) followed by surgery. We currently analyzed the clinical benefit of Neo C/T and Ad C/T for treating N2 positive NSCLC in a single-center cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study was done retrospectively. A total of 258 patients with N2+ who received surgical resection in dept. of surgery, National Taiwan University Hospital during 2004 to 2016 were enrolled. The mean follow-up duration was 44 months. Both the overall survival (OS) and progression-free survival (PFS) were compared between C/T (-) (patients without chemotherapy treatment) , neo C/T, and Ad C/T groups using multivariate analysis and Kaplan-Meier estimates .

      4c3880bb027f159e801041b1021e88e8 Result

      There were 77, 55 and 126 patients in C/T (-), Neo C/T, and Ad C/T groups respectively. Patient's characteristics revealed the distributions of age and operation methods among these 3 groups were significantly differences. Patients treated with chemotherapy (combining Neo C/T and Ad C/T groups) were with significant reduced hazard for death compared to C/T (-) group (HR [95 % CI]= 0.55 [0.37-0.83), P=0.004). No significantly difference in overall survival was found between neo C/T and Ad C/T groups (HR [95 % CI]= 0.84 [0.54-1.32), P=0.451). The median overall survival time after surgery for the patients in neo C/T, and Ad C/T, and C/T (-) groups were also significant different (46.2, 56.9, and 26.9 months in C/T (-), Neo C/T, and Ad C/T groups respectively, P<0.001). However, there was no significant difference in patients received C/T or not in progression-free survival.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Both Ad C/T and Neo C/T provide clinical benefit for the patients with operable stage III N2 NSCLC . These is no significantly difference between Ad C/T and Neo C/T groups in both overall and progression-free survival .

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-114 - The Correlation Among PD-L1 Expression, TMB and Lung Immune Prognostic Index in Chinese Patients with Advanced Lung Adenocarcinoma

      16:45 - 18:00  |  Presenting Author(s): Pei Yuan  |  Author(s): Yuan Li, Lili Jiang, Yueping Liu, Wei Liu, Jianming Ying

      • Abstract

      Background

      Anti-PD-1/PD-L1 immunotherapy was approved as first-line treatment on the part of NSCLC patients, but not all can benefit, some studies have shown that PD-L1 expression, Tumor Mutation Burden (TMB) and Lung Immune Prognostic Index (LIPI) can be respectively used as an effect predictor of NSCLC immunotherapy. We aim to explore the correlation of the three predictors in Chinese patients with advanced lung adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled 53 biopsy specimens of the advanced lung adenocarcinoma patients from four China centers, measured complete blood cell counts and lactate dehydrogenase (LDH) before biopsy, detected PD-L1 level by three IHC assays (22C3, 28-8, SP263) ,driver genes and TMB by NGS. LIPI was divided into three groups.

      4c3880bb027f159e801041b1021e88e8 Result

      In the cohort, 28 (52.8%) were male; median age was 59 (range, 34-81) years. There were 7 (13.2%, 7/53) with positive PD-L1(≥50%) based on 22C3. Three assays were highly concordant for tumor cells (ρ=0.740-0.826), lower for immune cells (ρ=0.462-0.543). Six (of 34,17.6%) were high TMB (at least 10/Mb). All were male (p=0.031), in which 5 were associated with TP53 mutation, 3 had DNA replication or damage repair–related gene mutations and 4 showed high PD-L1 on immune cells (p=0.031). LIPI didn't show significant correlation with PD-L1 or TMB (p>0.05). 3 of 20 with targetable driver gene alterations (ALK/EGFR/ROS1) were high PD-L1 or TMB. In the targetable driver gene wild cases, there were 8 (of 14) high PD-L1 or TMB.figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      28-8, 22C3 and SP263 assays were aligned on tumor cell staining.There was no significant correlation among PD-L1, TMB and LIPI, which may be independent and complemented. High TMB might occur in male, show high PD-L1 on immune cells and accompanied with TP53 mutations. High PD-L1 or TMB was frequently found in the targetable driver gene wild cases.The prognostic value of PD-L1 and TMB on advanced NSCLC will be further followed.

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      P2.01-115 - Evaluation of EGFR T790M of Cell Free Circulating DNA in Plasma by Droplet Digital PCR for Progressive Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Zhihong Zhang

      • Abstract

      Background

      In Non-Small Cell Lung Cancer (NSCLC) harboring EGFR mutations, a second-site point mutation at position 790 (T790M) is associated with acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. Osimertinib is selective for T790M resistance mutation in patients with NSCLC. However, the mutation rate of EGFR T790M is unclear in Chinese patients.The purpose of this study is to understand the status of EGFR T790M in the real world.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      422 Patients with recurrent NSCLC who had been receiving TKI treatment at The First Affiliated Hospital of Nanjing Medical University were enrolled consecutively. Patient blood samples were drawn after the first generation TKI failure. Patients who met the following criteria : patients harboring EGFR activating mutation who developed PD during TKI treatment. Patients had received TKI alone therapy or TKI plus chemotherapy . The droplet digital PCR assay was conducted by droplets generation using QX200 generator (Bio- Rad Laboratories, Inc., Hercules, CA, USA).

      4c3880bb027f159e801041b1021e88e8 Result

      374 (88.6%) of them were successfully analyzed for EGFR T790M genotyping analysis by droplet digital PCR. 48(11.4%) of them failed to follow-up analysis owing to insufficient cfDNA amount,177(47%) plasma samples had found EGFR T790M mutation (Fig1a). Analyzing the allele frequency of EGFR T790M, we found 19% (33/177) positive patients of EGFR T790M was Less than 0.1% (Fig1b). The allele frequency of EGFR T790M between 0.1% and 0.5% was account for 38%(68/177). The 32% (56/177) of patents were more than 1%. This result indicated that the detection of EGFR T790M required higher sensitive method, otherwise it might cause missed detection.fig1(a,b).jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Droplet digital PCR is a highly sensitive, absolute quantitative detection technique. The EGFR T790M is detected in up to 47% of these patients in the real world. Almost 68% of the allele frequency of EGFR T790M is less than 1%. It means that the detection of EGFR T790M requires a higher sensitive detection method.

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      P2.01-116 - The Potential of Assessing Blood Tumor Mutation Burden (bTMB) Using a Large Panel 

      16:45 - 18:00  |  Presenting Author(s): Kai Zhang  |  Author(s): Yong Tang, Xinhua Xu, Weiping Tao, Zhiguo Rao, Fanghong Wu, Shixing An, Jun Liu, Jinsong Yang, Ting Hou, Lu Zhang, Yu Zhang, Li Liu, Sheng Zhang

      • Abstract

      Background

      TMB, measuring the number of non-synonymous mutation per megabase of DNA, has shown to associate with response to checkpoint inhibitors in a number of cancers, including lung cancer. Whole exome sequencing (WES), the gold standard for evaluating TMB, is less cost-effective. Multiple studies have shown large panels can yield comparable results in tissue samples. However, the feasibility of assessing bTMB using a large panel has not been extensively evaluated. In this study, we evaluated TMB of 30 treatment-naïve advanced NSCLC patients by performing WES on tissue samples as well as targeted sequencing on matched tissue and plasma samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      WES was performed on tissue samples with an average sequencing depth of 300x. Targeted sequencing was performed on matched tissue and plasma using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. An average sequencing depth of 1,000X and 10,000x were achieved for tissue and plasma samples, respectively. TMB was calculated as the ratio of mutation count to the size of coding region of the panel (1.26Mb), excluding copy number variations, fusions, large genomic rearrangements and mutations occurring on the kinase domain of EGFR and ALK.

      4c3880bb027f159e801041b1021e88e8 Result

      In tissue samples, TMB derived from WES and our panel is comparable with a R2 value of 0.87, and a correlation value of 0.86. cfDNA from 8 patients had no mutation detected using the 520 panel potentially due to low fraction of ctDNA present in the circulation. TMB derived from cfDNA of the remaining 22 patients showed a good correlation with TMB derived from tissue using either our panel (R2=0.94, correlation =0.93) or WES (R2= 0.85, correlation=0.87), demonstrating the feasibility of assessing TMB from cfDNA using a large panel. Next, using TMB calculated from WES as gold standard, we attempted to derive a cutoff to stratify TMB high patients from TMB low patients. Our data revealed 15 mutations per mb as an optimal cutoff using the 520 panel, achieving an AUC of 97.6% for tissue samples and 97.2% for plasma samples.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study demonstrated the feasibility of evaluating TMB from cfDNA using a large panel, opening the avenue of TMB estimation using liquid biopsy. Further validations in prospective clinical trials are needed to solidify its predictive value in response to immunotherapy.

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      P2.01-117 - Concurrent Gene Alterations in Treatment-Naïve EGFR-Mutant Advanced Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Xuefeng Xia  |  Author(s): Jun Zhao, Min Zhang, Jiexia Zhang, Likun Chen, Renhua Guo, Gen Lin, Tiejun Yin, Hong Shi, Wenxian Wang, Chunwei Xu, Rongrong Chen

      • Abstract

      Background

      EGFR-TKIs is the standard first line treatment for EGFR-mutant advanced non-small-cell lung cancer (NSCLC). However, 20% to 30% of patients who receive EGFR-TKIs exhibit primary resistance. The gene alterations in treatment-naïve EGFR-mutant advanced NSCLC should be better explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed gene test results of 980 treatment-naïve advanced NSCLC samples in our institute. Tumor biopsy, ctDNA, pleural effusion or cerebrospinal fluid samples were analyzed using hybridization capture-based NGS ER-seq method, white blood cells as control, which enables simultaneously assess single-nucleotide variants (SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) variation at least 59 genes (range 59-1021 genes).

      4c3880bb027f159e801041b1021e88e8 Result

      Three hundreds and eighty one cases with EGFR sensitive mutation were identified, 358 adenocarcinoma, 7 squamous cell carcinoma, 1 adenosquamous carcinoma and 15 NSCLC. Among the patients, 88 patients (23.1%) harbored concurrent actionable mutations with EGFR, which 43 were exon 19 deletion, 37 were L858R and 8 were uncommon EGFR mutations. One patient had co-occurring L858R, T790M and CDKN2A frameshift mutation. The actionable mutations were from 23 genes, which involved in cellular signaling pathways, and some genes had been reported associated with EGFR-TKIs resistance (details in table). Except the actionable mutations, TP53 mutations were detected in 225 samples (59.1%, 225/381), which 35.1% (79/225) in exon8. Bcl-2–like 11(BIM) deletion were detected in 31 (8.1%, 31/381) white blood cells.

      Signaling Pathways

      Concurrent gene alterations

      Frequency(N=88)

      Cell cycle*

      CDKN2A

      3.9%

      CDK4

      2.1%

      CCNE1

      0.8%

      CCND1

      0.8%

      CCND3

      0.3%

      PI3K/AKT/mTOR*

      PIK3CA

      2.9%

      PTEN

      1.3%

      TSC1/2

      1.0%

      AKT2

      0.3%

      NF1

      0.3%

      RTKs*

      MET

      0.8%

      HER2

      0.8%

      FGFR2

      0.3%

      FGFR3-TACC3

      0.3%

      Ras/Raf/MAPK*

      KRAS

      0.8%

      Homologous Recombination Repair pathway

      BRCA2(sc+gm)

      0.8%

      BRCA1(sc)

      0.5%

      ATM

      0.5%

      PALB2

      0.3%

      Others

      CTNNB1

      2.9%

      MDM2

      2.4%

      SMARCA4

      0.8%

      JAK2

      0.5%

      sc, somatic mutation;

      gm, germline mutation;

      *, genes had been reported associated with EGFR-TKIs resistance

      8eea62084ca7e541d918e823422bd82e Conclusion

      Concurrent gene alterations in treatment-naïve EGFR-mutant advanced NSCLC is common, and mutiple genes are involved. This maybe contribute to the primary resistance to EGFR-TKIs in EGFR-mutant advanced NSCLC. Indicate the importance of multiplex molecular test and further researches of target therapies.

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      P2.01-118 - LINE-1 Retrotransposition Promotes the Occurrence and Progression of Lung Squamous Cell Carcinoma

      16:45 - 18:00  |  Presenting Author(s): Jinpu Yu  |  Author(s): Rui Zhang

      • Abstract

      Background

      Retrotransposition is a kind of chromatin rearrangement containing the non-coding region, which makes up about half of the human genome. Long interspersed element-1 (LINE-1) retrotransposition is the only currently known active autonomous transposon in humans and might cause genetic instability, which was reported to occur with high frequency in a variety of tumor tissues. However, the relationship between LINE-1 and lung squamous cell carcinoma (LUSC) is unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed 504 cases of LUSC samples based on the RNA-seq database in TCGA and screened out 13 LINE-1 retrotransposons with the high occurrence. The somatic LINE-1 retrotransposition were detected in 109 clinical LUSC samples in comparison with their matched adjacent normal tissue samples, as well as the correlation between expression of LINE-1 retrotransposon genes and patients' survival. Then we focused on L1-FGGY and explored its regulation on cell proliferation, apoptosis, migration and invasion in vitro, as well as its roles on promoting tumorigenesis in vivo. We also applied two nonnucleosidic reverse transcriptase inhibitors, nevirapine (NVR) and efavirenz (EFV) both in vitro and in vivo, to investigate whether pharmacological modulation of endogenous reverse transcriptase activity may represent a novel approach in the treatment of LUSC.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that 1/3 of tumor samples possessed LINE-1 inserted retrotransposons and the expression of retrotransposon genes in LUSC was significantly higher than that in the corresponding para-carcinoma tissues, indicating that the presence of LINE-1 retrotransposon was related to the occurrence of LUSC. Furthermore, we also found that the survival time of patients with low retrotransposon gene expression was long, while the survival time of patients with high retrotransposon gene expression was short. In this study, we focused on L1-FGGY and further investigated the mechanism of the LINE-1 retrotransposition in regulating the occurrence and progression of LUSC and discovered that the expression of L1-FGGY and FGGY was negatively correlated in LUSC patients. We then discovered that knockdown of FGGY could promote cell proliferation, inhibit cell apoptosis, as well as facilitate cell migration and invasion in vitro. Furthermore, inhibition of FGGY could promote tumorigenesis and tumor metastasis in vivo, which collectively indicated that FGGY might function as a tumor-suppressor gene.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We not only uncovered that the LINE-1 retrotransposition L1-FGGY promotes the development of LUSC by inhibiting the expression and function of the tumor-suppressor gene FGGY, but also revealed that LINE-1 retrotransposon might be a new biomarker for early diagnosis, prognosis evaluation, and targeted therapy in the future clinical translation.

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      P2.01-119 - Phase III Randomized Trial of Palonosetron and Dexamethasone with Aprepitant to Prevent Full Dose Single-Day Cisplatin-Based CINV in Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Yongchang Zhang  |  Author(s): Nong Yang, Fang Wu

      • Abstract

      Background

      This study aimed to determine the efficacy and safety of aprepitant, palonosetron and dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in patients with locally advanced or metastatic lung cancer receiving full dose single-day cisplatin-based combination chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients diagnosed with locally advanced or metastatic lung cancer received full dose single-day cisplatin-based chemotherapy were randomized (1:1) to aprepitant plus palonosetron and dexamethasone, or placebo plus palonosetron and dexamethasone. Primary endpoint was complete response (CR; no vomiting/retching and no use of rescue medication) of nausea and vomiting in the overall period (0-120 h) in first cycle. The secondary endpoints were the proportion of nausea and vomiting, who received rescue antiemetic medication with metoclopramide, the response of cross over patients and safety were also evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      244 patients were randomized. There was no difference between two groups with personal characteristics. The aprepitant significantly improved CR for vomiting in the overall period (92.6% vs. 79.93%, p<0.01), rather than nausea-free (75.4% vs.71.3%, p>0.05) in first cycle. The percentage of patients who received rescue antiemetic medication was decreased for aprepitant group (14.8% vs. 37.1%, p<0.001). Patients without using aprepitant suffered with nausea and vomiting in cycle 1 were crossed over to aprepitant group (N=32), the rate of nausea and vomiting in cycle 2 were decreased to 37.5% (p<0.05) and 25% (p<0.05) respectively. There was no drug related i ntolerance side effects.

      Primary and secondary endpoints
      aprepitant placebo
      CR for vomiting 92.60% 79.93%
      nausea-free 75.40% 71.30%
      received rescue antiemetic medication 14.80% 37.10%

      8eea62084ca7e541d918e823422bd82e Conclusion

      Aprepitant plus palonosetron and dexamethasone proved to be effective and well-tolerated in preventing CINV for full dose single-day cisplatin-based combination chemotherapy.

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      P2.01-120 - First Study to Evaluate the Efficacy of SB Oral Solution to Prevent Neutropenia and FN Induced by Platinum-Based Chemotherapy in Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Yongchang Zhang  |  Author(s): Fanxu Zeng, Ting Li, Li Liu, Nong Yang

      • Abstract

      Background

      The aim of this study is to investigate the efficiency of Shengbai Oral Solution to Neutropenia and Febrile Neutropenia induced by platinum-based chemotherapy in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 295 lung cancer patients from January 2014 through December 2016 were treated with platinum-based chemotherapy including etoposide or paclitaxel liposome combined with cisplatin (75mg/m2, one day finished) or carboplatin (AUC=6.25, one day finished), and 91 of them were treated with Shengbai Oral Solution. Using the ratio 1:2 with propensity score matching (PSM), the control group of 169 patients was matched to the experimental group of 91 patients, and the remaining 35 patients were excluded. The primary end point was to evaluate the effectiveness of Shengbai Oral Solution in preventing grade 2/3/4 drug-related toxicities of neutropenia. And the secondary outcome was to evaluate the rate of Febrile Neutropeniathe, cost and toxicity. All the patients were from this clinical trials with the NCT number of NCT01980212.

      4c3880bb027f159e801041b1021e88e8 Result

      There were no difference between two groups, with gender, age, smoking status, histologic grade, and histologic type included. The study revealed that compared with the control group, the ratio of neutropenia in the experimental group was significantly lower (34.07% vs 64.50%, HR 0.53, p<0.05), as expected, the grade 2/3/4, 3/4 neutropenia had similar results (30.77% vs 55.62%, HR 0.55, p<0.01), (14.29% vs 23.67%, HR 0.60, p<0.05), respectively. And the secondary endpoint showed that Shengbai Oral Solution can signifcantly reduce the rate of Febrile Neutropenia and did not significantly increase the additional medical expenses. There was no intolerance drug related toxicity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study suggested that Shengbai Oral Solution was effective on reducing neutropenia and Febrile Neutropenia caused by chemotherapy in patients with lung cancer and was worth promoting in clinical.

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      P2.01-121 - Genomic Profiling of Pulmonary Lymphoepithelioma-Like Carcinoma

      16:45 - 18:00  |  Presenting Author(s): Chengzhi Zhou  |  Author(s): Zhanhong Xie, Yinyin Qin, Xiaohong Xie, Xinqing Lin, Jiexia Zhang, Ming Ouyang, Bing Li, Jing Liu, Suiyi Mai, Lu Zhang

      • Abstract

      Background

      Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare and distinct type of primary lung cancer which is characterized by Epstein-Barr virus (EBV) infection. Only a few hundred cases have been reported since its discovery in 1987. Due to its extreme rareness, its genomic landscape remains elusive. In this study, we performed targeted ultra-deep sequencing to interrogate the genomic profile and tumor mutation burden of 10 patients with pulmonary LELC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ten patients with advanced pulmonary LELC patients were enrolled. Tissue biopsy samples were subjected to targeted sequencing with an average sequencing depth of 1,000x, using a panel consisting of 295 cancer-related genes, spanning 2.02Mb of human genome. TMB was calculated as the ratio of number of mutations to the size of coding region of the panel, excluding copy number variations, fusions and large genomic rearrangements.

      4c3880bb027f159e801041b1021e88e8 Result

      We enrolled 10 patients (4 males and 6 females) with advanced pulmonary LELC and a median age of 60. Eight of them are non-smokers and 2 are smokers. Collectively, we identified 65 somatic mutations spanning 52 genes, including 33 SNVs, 3 insertions or deletions (INDELs) and 29 copy-number amplifications (CNAs). No mutation in classic NSCLC driver gene was identified, in an agreement of published data. The most frequently mutated genes were TP53, FGFR3, FGFR4, FGFR19 and CCND1, occurring in 30% (3/10) patients followed by KIT and KMT2D, occurring in 20% (2/10) patients. Interestingly, 7 patients had mutations in epigenetic regulators, such as DNA methyltransferase and chromatin remodelers. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of pulmonary LELC with nasopharyngeal carcinoma and EBV positive gastric cancer mutation profiles obtained from TCGA, and revealed similarity with both of them. Patients in this cohort had a median TMB of 3.75/Mb (ranged from 1.25/Mb to 10/Mb), which is significantly lowered than lung adenocarcinomas. All patients had PD-L1 overexpression; 4 of them with PD-L1 expression in greater than 50% of tumor cells and the remaining 6 patients had PD-L1 expression between 5%-49% of tumor cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, we elucidated a distinct genomic landscape associated with pulmonary LELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for LELC.

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      P2.01-122 - Individual Precision Surgery for Locally Advanced Non-small Cell Lung Cancer Based on Molecular Staging and Typing : The Chinese Experience.

      16:45 - 18:00  |  Presenting Author(s): Qinghua Zhou

      • Abstract

      Background

      Lung cancer is the leading cause of cancer deaths in the world. For patients with advanced non-small cell lung cancer (NSCLC), survival prognosis is very poor with chemotherapy and radiotherapy. However, the possibility of occult metastases may lead to discrepancy between clinical and pathologic staging and under-estimation of the disease severity, and how to individualized choose the appropriate patients with locally advanced non-small cell lung cancer for surgery is controversies. In this study, we presented here the Chinese experience: individual precision surgery for locally advanced non-small cell lung cancer based on molecular staging and molecular typing.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We developed several molecular biomarkers and molecular models from Circulation Tumor Cell (CTC ) detection, mi-RNA chip, Gene Chip from 1990. We used these Molecular biomarkers and molecular models for molecular staging, molecular typing, choosing indication of operation and neoadjuvant chemotherapy, predicting postoperative recurrence and prognosis of locally advanced non-small cell lung cancer.

      4c3880bb027f159e801041b1021e88e8 Result

      We developed two molecular staging model for individualized surgical treatment for locally advanced non-small cell lung cancer involving heart, great vessels or both. 3728 patients with locally advanced non-small cell lung cancer were underwent completely resection of the cancer in the three medical center. The 1-, 3-, 5- and 10 year survival rate were 76.5%,63.7%,32.8% and 23.4%, respectively. We used our molecular staging and typing model for neoadjuvant chemotherapy for 665 patients with locally advanced lung cancer. The 1-, 3-, 5- and 10-year survival rate were 79.35%, 51.46%, 27.39% and 20.34% of the patients, respectively. We used our molecular typing model to divide N2 lung cancer into invasive N2 and Non-invasive N2 group. We used our molecular models adenocarcinoma and squamous carcinoma to divide T4 lung cancer into high recurrence and low recurrence groups, and help postoperative adjuvant therapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our molecular staging and typing models can help us carry out individual precision surgery, predicting prognosis and cancer recurrence of the cancer for locally advancer no-small cell lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-123 - Translational Medicine of Lung Cancer Metastasis: From Bench to Bedside

      16:45 - 18:00  |  Presenting Author(s): Qinghua Zhou

      • Abstract

      Background

      Cancer invasion and metastasis is not only the malignant marker and characteristics, but also the main cause of failure to cure and lose their life of the patients with lung cancer.30% of the lung cancer patients had distant metastasis diagnosed with lung cancer. 80% to 90% of the patient dead of distant metastasis. In this study, we presented the results of individual translational medicine of lung cancer metastasis: from bench to bedside.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A pair of lung cancer cell lines (L9981 and NL9980) with same inherit background, different metastatic potential were screened and identified by Single Cell Limited Dilution Cloning. Several differential mi-RNA and gene profiles were screened and identified by mi-RNA array and gene chips from the cells, and peri-cancerous and cancer tissues of patients. Molecular model for early diagnosis and prediction of lung cancer metastasis, molecular typing model of N2 lung cancer were developed by molecular biostatics. 5 small molecular compounds inhibiting lung cancer metastasis were screened and identified based on the molecular targets related to lung cancer metastasis.

      4c3880bb027f159e801041b1021e88e8 Result

      We successfully established a pair of lung cancer cell lines with same inherit background, different metastatic potential. High-metastatic cell line L9981 with LOH of gene, deletion of mRNA and protein expression of nm23-H1and high metastasis potential, and low-metastatic cell line NL9980 with normal NM23-H1 and low metastasis potential. After knockdown the nm23-H1 gene in NL9980 cell, the Nl9980 cell was endowed the same biological property as L9981 cell has. We got a differential panel of mi-RNAs and gene signature. We found that the patient with LOH of gene, deletion of mRNA and protein expression of nm23-H1 more likely to have distance metastasis and poor prognosis. Based on these findings, we proposed a hypothesis of “Lung Cancer Metastatic Suppressive Cascade” and translate the hypothesis into clinical use in the patients. We got several molecular model for early diagnosis and prediction of lung cancer metastasis of lung cancer after operation; a molecular typing model of dividing N2 lung cancer into invasive N2 and Non-invasive N2. Finally, we use the molecular targets related to lung cancer metastasis to screen and identify 5 small molecular compound inhibiting lung cancer metastasis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A pair of lung cancer cell lines with same inherit background, different metastatic potential was successfully established. We established several molecular staging and typing models related to lung cancer metastasis and translated them into clinical application in lung cancer patients.

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      P2.01-124 - SIB-IMRT in Symptomatic Brain Metastases for NSCLC: A Randomized Controlled Study of WBRT Comparing 25Gy and 30Gy

      16:45 - 18:00  |  Presenting Author(s): Jian Zhu  |  Author(s): Qinghui Dong, Wei Wang, Xingni Tang, Yinnan Meng, Feng-Ming Spring Kong, Haihua Yang

      • Abstract

      Background

      Intensity Modulated Radiation Therapy with Simultaneous Integrated Boost (SIB-IMRT) can better control intracranial local control rate and even prolong overall survival in non-small cell lung cancer (NSCLC) patients with brain metastases. However, some patients suffer severe neurocognitive dysfunction largely due to whole brain radiation. The purpose of this study is to explore the appropriate dose of whole brain RT when SIB-IMRT is applied.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 75 patients with symptomatic brain metastases in NSCLC were randomly divided into 25Gy and 30Gy groups with 10 fraction whole brain radiation therapy (WBRT). The tumor beds with 3 mm expansion (PGTV) were synchronously boosted to 50Gy in both groups. The primary endpoint of the study was intracranial progression-free survival (iPFS) and neurocognitive dysfunction. Secondary endpoints objective response ratio (ORR) of 1 month after treatment and overall survival (OS) were included.

      Trial registration number: ChiCTR-INR-17013204.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 38 and 37 patients in 25Gy and 30 Gy groups, respectively. There was not significant differences in age, gender, performance status and number of brain metastasis between these groups (all Ps>0.05). The median follow-up is 15 (range 2-39) months. The median iPFS was 11 months (95%CI:8.7-13.3) in the 25Gy Group and 8 months (95%CI:4.4-11.6) in the 30Gy Group (P=0.104). The median OS was 13 (95%CI:11.4-14.6) months in the 25Gy Group, which is significantly better than 8 (95%CI:4.4-11.6) months in the 30Gy Group (P=0.025). The mini-mental state examination(MMSE)of neurocognitive dysfunction found significant differences in the 25Gy Group vs. 30Gy Groups, 27.4±1.26 vs. 26.4±2.03 (P=0.027) at 12 months after radiotherapy (Table 1).

      Table 1. MMSE score statement

      Treatment arms

      P value

      25Gy group

      30Gy group

      Before radiotherapy

      28.03±1.57

      27.56±2.55

      0.322

      1-month After radiotherapy

      28.29±1.33

      27.92±2.13

      0.228

      3-monthAfter radiotherapy

      28.12±1.01

      27.98±1.24

      0.323

      6-month After radiotherapy

      27.47±1.55

      27.29±1.49

      0.061

      12-month After radiotherapy

      27.40±1.26

      26.37±2.03

      0.027

      Abbreviations: MMSE = mini mental state examination.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Based on this small randomized study, the 25Gy group with SIB did not reduce iPFS, but significantly improved OS and decreased toxicity of neurocognitive dysfunction at 12 months after radiotherapy, compared to the 30Gy group with 10 fractions SIB-IMRT in patients with NSCLC with symptomatic brain metastases.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-125 - EGFR Mutations by NGS in Advanced Squamous Cell Lung Cancer  

      16:45 - 18:00  |  Presenting Author(s): Govind Babu K  |  Author(s): Deepak Koppaka, Ramprasad Vl

      • Abstract

      Background

      Targets for Squamous cell lung cancer are none as against adenocarcinomas.Also there is limited data available from ct DNA in these patients

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This prospective observational study looked at patients with squamous cell carcinoma lung, either newly diagnosed or having a progressive disease on prior therapy were enrolled. cf-DNA was extracted from peripheral blood and analyzed for EGFR, KRAS, NRAS, BRAF mutations using NGS.20 ml of the blood sample was collected from the patient prior to the initiation of therapy or at progression.

      4c3880bb027f159e801041b1021e88e8 Result

      Sixteen patients of squamous cell carcinoma lung were enrolled into the study. The mean circulating cell-free tumour DNA extracted from the plasma was 96.6 ng (Range, 15-200 ng). Genomic analysis by NGS on the extracted DNA revealed mutations in the EGFR pathway among 8 (50%) patients. The commonest mutation was Exon 21 Leu858Arg (4 patients). One patient had Exon 20 Thr790Met mutation. One patient had complex mutations with coexisting Exon 21 Leu858Arg and Exon18 Gly719Arg in the same sample. Two patients had KRAS Exon2 Gly12Cys mutation.

      Among the patients with Exon 21 mutation, two patients were treatment naïve and two patients were having a progressive disease (one post Gemcitabine/Carboplatin-based chemotherapy and another post Gemcitabine/Carboplatin and Docetaxel chemotherapy). Patient with complex mutations had progressive disease post Gemcitabine/Carboplatin. Patient with Exon 20 T790M mutation had a hyper-progressive disease post-Nivolumab based regimen. While one patient with KRAS mutation one patient was treatment naive while another had progressive disease post Gemcitabine/Carboplatin-based regimen (Table 2).
      img_2941.jpeg

      Two patients with Exon 21 mutations who progressed on earlier lines of treatment received Gefitinib. One patient had progressive disease at 3 months while the other patient succumbed to the disease two months after starting Gefitinib. Treatment Naïve patients with EGFR Exon 21 mutations (N=2) upfront received Gemcitabine and Carboplatin-based chemotherapy. Of this 1 patient is currently progression-free and another patient progressed 6 months post chemotherapy and at progression was started on Gefitinib. Patient has a stable disease after 3 months of treatment and still on gefitinib. Patient with Exon 20 T790M mutation was stated on nab-paclitaxel and succumbed to the illness 6 months later. Patient with complex mutations received Docetaxel as second-line chemotherapy and had a progressive disease 4 months after the initiation of therapy and died.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Treatment options for squamous cell carcinoma lung detection of EGFR mutations helps increase the treatment armamentarium for management of these patients. cf-DNA is a good technique for detecting relevant mutations

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      P2.01-126 - MicroRNA-330-3p Modulates Tumor Vascular Normalization After Hypofractionated Radiotherapy by Targeting p-STAT3/ HIF-1 Alpha Pathway

      16:45 - 18:00  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Xiong Chun Jin, Chunhua Wei, Hui Lu, Fan Tong

      • Abstract

      Background

      Our study aimed to explore the effect of microRNA-330-3p (miR-330-3p) on radiosensitivity of NSCLC on HFRT both in vivo and in vitro.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The miR-330-3p over-expressed H460 (H460-OE) and HCC827 (HCC827-OE) cell lines were established using lentivirus vector expressed miR-330-3p. Tumor-bearing nude mice and the dorsal skinfold window chamber (DSWC) models (divided into H460-OE, HCC827-OE, H460 and HCC827 groups) were established and received 0-Gy (control group) or 12-Gy (HFRT group) radiation respectively. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; co-immunofluorescence of α-SMA/CD34 staining was employed to detect the coverage rate of pericyte cells on tumor vessels; pimonidazole hydrochloride (PIM) was used to detect the hypoxia; Western blotting and RT-PCR were used to detect the expression levels of p-STAT3/HIF-1α/VEGFA signal pathway and downstream factors CXCL12/CXCR4. In vitro, after radiation, the colony formation assay was used to detect the radiosensitivity. The rate of apoptosis cells were detected by flow cytometry. Moreover, STAT3 inhibitor, S3I-201, was used to further verify the mechanism of miR-330-3p regulating HIF-1α and its downstream factor by Western blotting.

      4c3880bb027f159e801041b1021e88e8 Result

      The curve of relative volume-time displayed that the radiosensitivity of miR-330-3p over-expressed xenografts decreased as compared to H460 and HCC827 xenografts. HFRT-induced decrease of MVD and hypoxia, increase of pericyte coverage on tumor vasculars in H460 and HCC827 xenografs were inhibited in H460-OE and HCC827-OE xenografts (P <0.05). Colony formation assay showed that the radiosensitivities in miR-330-3p over-expressed groups decreased and the flow cytometry assay showed that after HFRT, apoptosis rate was higher in H460-OE than H460 cell lines. Western blotting and RT-PCR displayed that, both on the 7th and 14th day after HFRT, the levels of p-STAT3, HIF-1α, VEGFA and CXCL12/CXCR4 in miR-330-3p over-expressed xenografts were higher than that in HCC827 and H460 xenografts (P <0.05). The in vitro studies showed that 2-28 hours after HFRT, the expression levels of p-STAT3, HIF-1α and VEGFA in H460-OE cells was up-regulated as compared to H460 cells (P<0.05). After adding S3I-201, the levels of p-STAT3/HIF-1α could not be inhibited in H460-OE, but could be inhibited in the H460 group (P<0.05). Also compared to the HCC827 cells after HFRT, the levels of p-STAT3 in HCC827-OE group could not inhibited by S3I-201 (P<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      miR-330-3p may decrease the HFRT-radiosensitivity of NSCLC via upregulating the p-STAT3/HIF-1α pathway and its downstream factors, VEGFA and CXCL12/CXCR4, therefore inhibiting vascular normalization effect of HFRT.

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      P2.01-127 - Efficacy of Endostar Combined with Whole Brain Radiotherapy in Patients with NSCLC Brain Metastases

      16:45 - 18:00  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Lingjuan Chen, Chunhua Wei, Ruiguang Zhang, Hui Lu, Pengcheng Li, Gang Wu

      • Abstract

      Background

      Brain metastasis (BM) is the leading cause of poor prognosis, recurrence, and death in non-small-cell lung cancer (NSCLC) patients. The effectiveness of whole-brain radiotherapy is unsatisfactory. Endostar was reported as an anti-angiogenic agent, which could promote vascular normalization in tumor. This study is to investigate the influence of endostar combined with cranial radiation to cerebral blood flow, immune status and survival of the patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      28 NSCLC patients with multiple brain metastasis(more than four)were randomly divided into two groups. The experimental group (n = 14) received WBRT (30Gy/10F) combined with Endostar (15mg/m2, 7days), and the control group (n=14) received WBRT (30Gy/10F) alone. Magnetic resonance perfusion imaging was carried out pre- and one month post-radiation to detect regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF) and mean transit time (MTT) of the contrast medium. The changes of blood T lymphocyte subpopulation, the cognitive function and overall healthy level were evaluated pre- and post- radiation every two months against the MMSE, MoCA and EORTC QLQ-C30 scales. Moreover, Tumor progression was established by certified oncologists based on whole brain MRI scan.

      4c3880bb027f159e801041b1021e88e8 Result

      In the endostar group, rCBV, rCBF and MTT had a 122%, 210% and 11% higher in the target lesion region one month post radiation, compared with baseline data, while in the control group, rCBV, rCBF and MTT had a 18%, 20% and 26% lower change. These results showed a significant improvement of the cerebral perfusion in the endostar group. The T lymphocyte subpopulation increased in the Endostar group, especially the CD8+ T lymphocyte with a significant difference compared with the control group(p=0.0233). At the same time, the intracranial PFS (iPFS) was 349 days vs. 287 days and the PFS was 229 days vs. undefined between the Endostar group vs. the control group, but neither with significant difference, may for the limit of sample size. After cranial radiation, the cognitive function, physical, role, social and emotional functions improved in the endostar group, while a small fluctuation in the control group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study showed that endostar could promote vessel normalization and improve cerebral perfusion, and ameliorate the immune status, cognitive function and quality of life of the patients, which may also improve the survival of the patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-128 - Low Positivity Rate in T790M Detection with ctDNA in NSCLC and Post EGFR-TKI Progression – Timing or Sensitivity?

      16:45 - 18:00  |  Presenting Author(s): Carlos Gil Ferreira  |  Author(s): Mariano Zalis, Mauro Zukin, Clarissa Mathias, Carolina Kawamura Haddad, Eldsamira Mascarenhas, Luiz H. Araujo, Tatiane Caldas Montella, Marcelo Graziano Custodio, Bruna Silva, Carolina Bustamante, Giuliana Montenegro, Angelita Muras, Marcelo Reis

      • Abstract

      Background

      The approval of Osimertinib in Brazil in 2016 for post EGFR-TKI progression T790M+ NSCLC treatment allowed offering to the patient the best available therapy, when, it is mandatory to identify the occurrence of T790M mutation before initiating the treatment. The prevalence of T790M mutation as resistance mechanism post EGFR-TKI treatment is estimated to be around 60%. Considering the limitations for tumor tissue biopsy in progressive disease setting, identifying molecular changes by using alternative tumor DNA sources, such as blood samples, serum, and plasma can become an interesting strategy in cases where a tissue specimen or acceptable quality biopsy is not available. However, the sensitivity of ctDNA analysis for T790M may be disappointingly low.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective analysis of ctDNA samples database collected between June 2016 and December 2017 in Brazil. Blood samples of patients with post EGFR-TKI progression were submitted, at discretion of attending physicians, for EGFR mutation testing by cobas®.

      4c3880bb027f159e801041b1021e88e8 Result

      761 tests were included. The positivity rate was 43.9% for EGFRm and 10.4% for T790M. Considering EGFRm positive tests, the positivity rate for T790M among EGFRm positive was 23.7%. Data are shown in Table-1. This positive rate is lower than expected and may be explained by three factors: T790M ctDNA cobas® low sensitivity; test request before progression; or T790M prevalence lower in Brazilian population. Still, more detailed testing using tissue and/or more sensitive methods are needed before definitive conclusion. Tissue test should continue being recommended as gold standard in T790M detection on this patient setting.

      Table 1- Frequency and mutations detected by ctDNA cobas® test in Brazil.

      Exon

      18

      19

      20

      21

      19 + 20

      21 + 20

      Mutation

      G719X

      19Del

      19Ins

      T790M

      L858R

      L861Q

      19Del + T790M

      L858R

      +

      T790M

      Number

      9

      183

      1

      9

      60

      2

      53

      17

      Positivity rate (%)

      1.2

      24.1

      0.1

      1.2

      7.9

      0.3

      7.0

      2.2

      % of EGFRm

      2.7

      54.8

      0.3

      2.7

      18.0

      0.6

      15.9

      5.1

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings suggest that ctDNA approach in post EGFR-TKI progression may not be the best diagnostic strategy to identify resistance T790M mutation as first option. When patient cannot be submitted to tissue biopsy at progression, ctDNA test is an acceptable alternative.

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      P2.01-129 - Potential Impact of KRAS Molecular Profiling of Non-Squamous Non-Small Cell Lung Cancer (NSCLC).

      16:45 - 18:00  |  Presenting Author(s): Nagla Abdel Karim  |  Author(s): Joshua Pathrose, Hassana Fathallah, Ihab El Desouki, Ashley Perry, Sandra Starnes, John Morris

      • Abstract

      Background

      Several studies suggest that patients with KRAS-mutant (KRASmut) NSCLC fail to benefit from platinum-based systemic chemotherapy and are not likely to have targetable mutations. Molecular profiling has the potential to identify other potential targets that might provide novel therapy for KRASmut NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this study, we purified RNA from archived tumors of patients with stage I and II NSCLC wild-type (wt) and mutant (Mut) KRAS and from paired normal tissue from 20 and 17 patients, respectively, and assessed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) the expression of four genes involved in DNA synthesis and repair including thymidylate synthase (TS), BRCA1, ECCR1, RAP80, and the proto-oncogene, SRC. Additionally, we assessed expression of PD-L1 IHC 22C3 by immunohistochemistry using an antibody against PD-L1 IHC 22C3.

      4c3880bb027f159e801041b1021e88e8 Result

      Our results show that in KRASmut tumors, ERCC1, TS, and SRC expression were increased in comparison to paired normal lung tissue (p ≤ 0.04). Expression of BRCA1 and RAP80 were similar in both KRASmut tumor and the paired-normal tissue. Furthermore, expression of BRCA1, TS and SRC were significantly increased in KRASwt tumor relative to their expression in normal lung (p ≤ 0.044). Expression of ERCC1 and RAP80 were similar in KRASwt tumors and paired normal tissue. Interestingly, SRC expression in KRASmut tumor was decreased in comparison to KRASwt tumor. There was a notable expression of PD-L1 (cut off level of 50%) in the tumor and surrounding stromal cells in 2 out of 20 KRASmut tumors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, within the limitation of our retrospective study, KRASmut NSCLC would likely be platinum, taxane and pemetrexed resistant, having a low level of PD-L1 expression. KRAS wt BRCA1 positive tumors tend to be sensitive to taxane therapy and possibly platinum-based drugs. Our result suggests the need to develop targeted therapies for KRASmut NSCLC and other therapies specific to the molecular profile of the tumor.

      ERCC1 BRCA1 TS SRC PD-L1 (50%)
      mt.Kras + - + - 10%
      Wt.Kras - + + +
      Normal Lung Tissue - - - -

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-130 - Detection of Actionable Mutation Status in Advanced Non-Small Cell Lung Cancer by Next-Generation Sequencing of Circulating Tumor DNA

      16:45 - 18:00  |  Presenting Author(s): Xia Song  |  Author(s): YanLi Yang, wei Guo

      • Abstract

      Background

      Genotype directed therapy has become increasingly important for personalized therapy of patients with advanced non-small cell lung cancer(NSCLC),but obtaining tumor tissue for genetyping remains a challenge.Plasma circulating tumor DNA(ctDNA) analysis by next-generation sequencing (NGS)may allow for noninvasive evaluation.We demonstrate the feasibility and clinical utility of ctDNA NGS in the management of advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 114 plasma samples were detected by NGS to identify actionable oncogenic driver mutations or mechanisms of resistance in 108 patients with advanced NSCLC.Among those 108 patients,there were 79 paired tissue DNA (tDNA) detected using ARMS PCR,We also evaluated the concordance in detecting of EGFR between ctDNA and paired tDNA.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 114 plasma ctDNA , 47(47/114,41%) actionable somatic mutations and 1 EGFR T790M germline mutation were dectected.EGFR variants were most common(39/114,34%).Among the 79 patients with matched tDNA and ctDNA, 32(32/79,41%)therapeutically targetable EGFR mutations were detected in tDNA and 30(30/79,38%) in ctDNA samples, yielding an overall concordance of 70%,the sensitivity and specificity of NGS were 59% and 77%.Of the 47patients with tDNA negative,11(11/47,23%)patients harbored EGFR mutation detected in ctDNA during the course of their disease.Of the 31 patients with brain metastases,22(71%)harbored an EGFR sensitive mutation(15,48%EGFR 19del and 7,23%EGFR L858R).Of the 40 patients who resistant to 1st and 2nd EGFR-TKI therapy,14(14/40,35%) showed the T790M acquired resistance mutation.the mean time of EGFR-TKI resistance was 11.5months.Patients with T790M mutations had significantly better PFS than those without T790M.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CtDNA NGS can be adopted as a tool for providing precision genomic analysis and dynamic monitoring, thus improving patient management, and even,undertaking hereditary counseling.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-131 - Apatinib as an Alternative for Advanced Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Jiexia Zhang  |  Author(s): Zhuolin Wu, Hui Pan, Meifeng Ye, lixuan Chen, Weiping Qian

      • Abstract

      Background

      Methylsulfonic apatinib showed promising efficacy for the treatment of non–small-cell lung cancer (NSCLC) as one of the TKIs which specifically inhibits VEGFR-2. We aimed to assess the efficacy of apatinib in each lines of treatment to patients with advanced/metastatic NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed variables and outcomes of patients with advanced NSCLC, who had received apatinib between January 1, 2016 and April 30, 2018, including: 5 patients of first line treatment, 16 second line treatment, 20 third line treatment and 6 fourth and fifth line treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      The most frequent treatment-related adverse events were hypertension, proteinuria, hand-foot skin reaction and hemoptysis. Among the 47 cases included in the final analysis, the median progression-free survival among patients was 5.66 months specialized in: 0-24.0 months in first line treatment, 0-10.0 in second line treatment, 2.0-10.0 in third line treatment and 0.6-5.4 months in fourth and fifth line treatment. The median overall survival time for apatinib were 25.97 months, 21.4-28.5 months in third line treatment and 0-64.9 months in fourth and fifth line treatment. No significance was found in either PFS and OS among lines of treatment, histology and EGFR mutation status.阿帕替尼 摘要.png

      Figure 1 PFS and OS of apatinib in different lines of treatment

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results indicate the administration of apatinib could be used as an alternative for advanced/metastatic NSCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-132 - Comparison Molecular Profiles in NSCLC by Using Different NGS Platforms and<br /> Different Variant Frequency Cutoff

      16:45 - 18:00  |  Presenting Author(s): Thanyanan Reungwetwattana  |  Author(s): Somthawin Lukrak, Pimpin Incharoen, Supoj Detarkom, Sarunporn Techasurungkul, Narumol Trachu, Nareenart Iemwimangsa, Pareena Janchompoo, Wasun Chantratita

      • Abstract

      Background

      There are several methods to detect molecular alterations in precision medicine era. This is a pilot study aimed to explore the concordance of molecular alterations testing using NGS different platforms and different cutoff allele frequency in NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ten NSCLC patients’ FFPE were retrieved for DNA extraction. All qualified samples were analyzed using NGS on 45 cancer genes panel on Ion Torrent system NGS Gene read Qiagen Lung Cancer Panel. Variants from NGS with coverage of are higher than 1000X. The cutoff 1% and 3% of variant allele frequency were considered positive. EGFR, BRAF, KRAS were validated by Real-time PCR technique using the Amoy DX and Actionable Insights Tumor Panel in GeneReader NGS system.

      4c3880bb027f159e801041b1021e88e8 Result

      We found 90%/30% EGFR-mutation, 40% BRAF V600E, 70%/30% KRAS-mutation by NGS using allele frequency cutoff at 1% and 3%, respectively. We validated by Real-Time PCR and Actionable GeneReader showed 70%/40% EGFR-mutation, 20%/10% BRAF V600E, and 0%/30% of KRAS-mutation (Table1). Regarding EGFR-mutation, 5 cases of discordance showed positive at 1% but negative at 3% cutoff allele frequency by NGS and validated by Real-Time showed positive all 5 cases. Two negative cases by Real-Time PCR show positive in NGS cutoff 1% (2/2) and 3% (1/2). In early stage (80%), there was 60% of EGFR 19 del detected by NGS cutoff 1%. The patients have continued follow-up at the clinic with the mDFS of 4.7 years. Two stage IV patients with exon19del were death and received EGFR-TKI as a second-line treatment with mOS at 1.1 and 1.2 years.

      Table 1

      Number of 10 cases positive

      NGS IonTorrent Cutt Off at 1%

      NGS Ion Torrent Cutt Off at 3%

      NGS GeneReader

      Real-time PCR

      EGFR Mutation

      9

      3

      4

      7

      Exon 19 Del

      6

      2

      2

      5

      L858R

      1

      0

      2

      2

      >1 EGFR Mutations

      2

      1

      0

      0

      No Mutation

      1

      7

      6

      3

      8eea62084ca7e541d918e823422bd82e Conclusion

      Different platform of NGS and different cutoff variant allele frequency gave the different result of gene frequency. We need to explore the standard of NGS testing including the proper cutoff for allele frequency in order to establish the most efficient method and correlate with the clinical treatment outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.03 - Biology (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
    • +

      P2.03-01 - Prevalence of EGFR Alterations in Chilean Lung Cancer Patients: A Retrospective Study

      16:45 - 18:00  |  Presenting Author(s): Hector Galindo  |  Author(s): Roger Gejman, Maria L. Bravo, Matias Muñoz, Ignacio N Retamal, Bruno Nervi, Cesar Sanchez, Carolina Ibañez, Jose Peña, Jorge Madrid, Juan Briones, Patricia Perez, Marcelo Garrido, Mauricio P Pinto

      • Abstract

      Background

      Recently, several countries in Latin America (LA) have entered into an epidemiological shift, switching the burden of disease from infectious to chronic non-transmittable disorders. In fact, many studies anticipate that Lung Cancer (LC) will soon emerge as the first cause of mortality in the region, possibly over the next decade. In Chile, LC is currently the second leading cause of cancer death and responsible for >2,500 deaths every year. Epidemiological data from Chilean LC patients is scarce and scattered. On the other hand, Tyrosine Kinase Inhibitor (TKI) drugs have been successfully used in a subset of LC patients that harbor alterations in the Epidermal Growth Factor Receptor (EGFR) gene. Here, we aimed to quantify the prevalence of EGFR alterations in the Chilean population

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective study that involved 1,405 biopsies from 1,385 Chilean LC patients. Then we selected patients with EGFR alterations and retrieve clinical data from these patients including age, gender, histological type, smoking habits and type of EGFR alteration. We also analyzed overall survival (OS) rates

      4c3880bb027f159e801041b1021e88e8 Result

      We found that 300 out of 1,385 (21.7%) had clinically relevant EGFR alterations. Within this group median age at diagnosis was 65 yr. As expected, most patients were female (64%), and classified as Non-Small Cell Lung Cancer adenocarcinomas (94.5%). Also in patients with EGFR alterations, the majority were either non-smokers or light smokers (93.1%). Regarding the type of EGFR alterations the most prevalent was the exon 19 deletions (50.6%) followed by Leucine-to Arginine 858 (L858R, 28.9%). Further analyses indicated that OS within this group was 15 months. Also, information clinical follow-up and TKI treatment was available for 87 patients. As expected the use of TKIs in these patients significantly improved OS

      8eea62084ca7e541d918e823422bd82e Conclusion

      The prevalence of EGFR alterations in the Chilean population is 21.7%, a value between the Caucasian and Asian population, 18.6% and 57.1% respectively. This value is also comparable to other reports from countries within LA such as Argentina (14.4%), Uruguay (18.3%), Colombia (24.7%) and Peru (37%). Similarly, OS was 15 months and the most frequent EGFR reported alteration was exon 19 deletions. Finally, the use of TKIs in these patients significantly improves OS.

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      P2.03-02 - Cell-Free DNA (cfDNA) Testing in Lung Adenocarcinoma (LUAC) Patients: Spanish Lung Liquid Versus Invasive Biopsy Program (SLLIP)

      16:45 - 18:00  |  Presenting Author(s): Ramon Palmero  |  Author(s): Alvaro Taus, Santiago Viteri, Margarita Majem, Enric Carcereny, Javier Garde-Noguera, Enriqueta Felip, Miguel Sampayo, Lourdes Gomez, Noemi Lopez, Steven R. Olsen, Matthew Jackson, Iris Faull, Daniel Dix, Niki Karachaliou, Rafael Rosell

      • Abstract

      Background

      Liquid biopsies are a revolution in cancer diagnostics as a minimally invasive alternative to tissue biopsy. cfDNA is used for the detection of biomarkers in LUAC patients if a tumor tissue sample is not available. We conducted the SLLIP study to prospectively validate Guardant360 for the detection of 7 targetable activating alterations (EGFR, ALK, ROS1, BRAF, MET, RET, and ERBB2) in LUAC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Blood samples from treatment-naïve stage IIIB-IV LUAC patients were analyzed using Guardant360, a next-generation sequencing panel covering 73 genes. The assay includes complete exon sequencing for 19 cancer genes, sequencing of critical exons in 54 genes, and detection of amplifications (18 genes), fusions (6 genes), and indels (23 genes) with high overall clinical sensitivity rates (85%) and ultra-high specificity (>99.9%). Indels and point mutations can be detected at a mutant allele fraction as low as 0.1%. Guardant360 was compared with tissue genotyping performed as standard of care, using a variety of “real life” techniques. The primary objective was to demonstrate the non-inferiority of Guardant360 versus tissue analysis for the detection of the 7 genetic alterations. The study is registered with ClinicalTrials.gov, number NCT03248089.

      4c3880bb027f159e801041b1021e88e8 Result

      186 LUAC patients were enrolled over a period of 11 months (August 2016-July 2017). Median age 64, 65% male, 72% smoker/ex-smokers, 85% ECOG performance status 0-1. Targetable activating alterations were detected by the Guardant360 assay and by tissue analysis in 25% (n=47) and 26% (n=49) of patients, respectively (non-inferiority P=0.268). Thirty patients (16%) had alterations identified by both modalities. None of the 186 patients was successfully tested in tissue for all 7 alterations. Of the 17 patients who were negative in tissue but for whom Guardant360 identified targetable alterations, 3 had BRAF V600E mutations. For none of these patients was BRAF tested in tissue. Clinical efficacy per biomarker and treatment modality are awaited.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Guardant360 cfDNA and tissue analysis detect relevant somatic tumor alterations at similar rates in LUAC patients. Under-genotyping in tissue is common but can be mitigated by the use of cfDNA next generation sequencing assays.

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      P2.03-03 - Upfront Next Generation Sequencing in NSCLC: A Publicly Funded Perspective

      16:45 - 18:00  |  Author(s): Tracy Stockley, Ming Sound Tsao, Joshua Morganstein, Suzanne Kamel-Reid, Laura Ranich, Frances A Shepherd, Penelope Bradbury, Geoffrey Liu, David Hwang, Prodipto Pal, Joerg Schwock, Scott Boerner, Adrian Sacher, Jennifer H Law, Natasha B Leighl

      • Abstract

      Background

      A growing number of targeted drug treatments in non-small cell lung cancer (NSCLC) have led to the need for molecular profiling beyond the standard of care (SOC) EGFR/ALK. Here we present actionable targets, impact on patient treatment, clinical trial opportunities and costs using the Illumina TruSight Tumor 15 panel (TST15) for NSCLC samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue-based next generation sequencing using the TST15 was reflexively performed on all newly diagnosed cases of non-squamous NSCLC at the University Health Network (Toronto, Canada) from February 2017-February 2018. The panel identifies hot spot mutations in KRAS, EGFR, TP53, PIK3CA, BRAF, ERBB2, FOXL2, GNA11, GNAQ, KIT, NRAS, PDGFRA, RET, AKT1 and MET, but not fusions, copy number variations (CNV) nor MET exon 14 skipping mutations. Patient age, stage, pathologic subtype, and genotyping results were collected prospectively. Treatment changes as a result of TST15 and clinical trial opportunities (clinicaltrials.gov) were identified. Incremental testing costs were based on direct laboratory costs, but not personnel and administration costs.

      4c3880bb027f159e801041b1021e88e8 Result

      Testing included 342 samples from 336 patients. The TST15 panel identified 409 mutations from 342 samples. Sample demographics include: male: 53, and stage 1/2/3/4: 34/8/15/43%. Incremental actionable targets beyond EGFR and ALK were identified in 3.5% of patients (ERBB2 2.3%, BRAF V600E 1.2%). Most mutations occurred in TP53 (43%), EGFR (24%) and KRAS (26%). Co-mutations occurred in 32% (TP53, KRAS, EGFR) of samples. To date, one patient has had a treatment change as a result of TST15 beyond targeting EGFR. Above SOC clinical trial options were identified for 88% of stage IV and 26% of stage III patients. 3.6 samples were needed to identify one actionable mutation, predominantly in EGFR, at an estimated cost of $1919 CAD per target.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Extended genotyping with TST15 in NSCLC identifies an additional 3.5% of patients with actionable mutations above SOC and improves clinical trial options for patients. Despite this, impact on patient treatment beyond targeting EGFR is minimal. To enhance the number of targets and minimize costs, affordable population-based comprehensive testing with a panel that includes fusions/CNV is needed.

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      P2.03-04 - Next Generation Sequencing in Lung Cancer Using the Oncomine Comprehensive Assay: The Canadian Publicly Funded Experience

      16:45 - 18:00  |  Author(s): Tracy Stockley, Jennifer H Law, Muqdas Shabir, Lisa Le, Ming Sound Tsao, Suzanne Kamel-Reid, Tong Zhang, Maggie Sawczak, David Hwang, Prodipto Pal, Geoffrey Liu, Penelope Bradbury, Frances A Shepherd, Adrian Sacher, Natasha B Leighl

      • Abstract

      Background

      Standard of care (SOC) diagnostics for patients with stage IV non-small cell lung cancer (NSCLC) in Canada includes EGFR and ALK testing. Other genomic alterations are not tested routinely; however, access to enhanced molecular testing may broaden treatment options, clinical trial access, and improve outcomes for patients. This study uses the Oncomine Comprehensive Assay (OCA) v3, a next generation sequencing (NGS) panel in NSCLC to evaluate actionable targets, clinical trial eligibility, treatment impact, costs, turnaround time, and patient preference.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Consecutive consenting stage IV NSCLC outpatients at the Princess Margaret Cancer Centre without EGFR/ALK/KRAS/BRAF derangement diagnosed at the University Health Network (UHN) in Toronto, Canada will be enrolled to undergo OCA testing on diagnostic samples. The selected platform (OCA v3, ThermoFisher) includes 161 genes including hotspots, fusions, and copy number variations. Patient age, pathologic subtype, genotyping results and treatment history will be collected. Primary endpoints include incremental actionable targets identified and clinical trial opportunities (clinicaltrials.gov) added through incremental testing beyond SOC. Secondary endpoints include treatment changes as a result of OCA testing, costs from the perspective of the Canadian public healthcare system, patient willingness-to pay, and test turnaround time.

      4c3880bb027f159e801041b1021e88e8 Result

      The study activated in February 2018 with 7 patients enrolled as of April 2018. Results of the value of incremental OCA testing beyond standard of care in the Canadian public healthcare system will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      While OCA testing in patients with advanced NSCLC may identify more actionable targets than selected genotyping, its cost effectiveness in the Canadian healthcare system is unknown and will be determined through this study.

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      P2.03-05 - Biologic Profiling of Brain Metastasis from Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Tomohito Saito  |  Author(s): Ryoichi Iwata, Masato Maruyama, Yosuke Nakano, Kohei Ofune, Satoshi Matsuda, Masaki Kaibori, Tomohiro Murakawa, Mikio Hayashi

      • Abstract

      Background

      Bain metastasis develops in approximately 50% of patients with non-small cell lung cancer (NSCLC), resulting in poor prognosis and low health-related quality of life. Immunological microenvironment and functions of ion channels have been indicated to play pertinent roles in epithelial‐to‐mesenchymal transition (EMT) and its reverse mesenchymal‐to‐epithelial transition (MET), crucial steps in distant metastasis, but their actual roles in brain metastasis of NSCLC remains unclear. The aim of this study is to investigate biologic profiles of brain metastasis of NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Formalin-fixed paraffin-embedded (FFPE) samples of brain metastasis and paired primary sites were collected from 3 patients with NSCLC undergoing surgical resection between Jan. 2012 and Dec. 2017. Total RNA was extracted from the archived FFPE, of which integrity was briefly checked by Nanodrop. Gene expression was detected by nCounter (NanoString Technologies, WA, USA) with PanCancer Immune Profilling Panel and custom-made KMU IonChannel Panel that covered selected 100 genes. Detected data was analyzed by nCounter Advanced Analysis (version 2.0.115). Factors with unadjusted P-value < 0.01 were regarded as candidates for further investigation.

      4c3880bb027f159e801041b1021e88e8 Result

      Brain metastasis showed upregulations of MCOLN3 and YTHDF2 (unadjusted P-value= 0.0093 and 0.0063, respectively) compared to the primary site. Conversely, primary site showed upregulations of IFNAR1, TNFRSF4, CXCL11, CT45A1, MAP3K5, TAL1, LAG3 and MARCO.

      In LATE-BREAKING ABSTRACT, we will report following data:

      1) Immunohistochemistry results of the candidate proteins in resected brain metastasis and primary sites of NSCLC from larger population. In situ hybridization is also planned.

      2) Additional data of expression profiles of the candidate genes in sphere cell line from brain metastasis and primary site of NSCLC.

      volcano plotnew.annotationbrainmeta.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Biologic profilings of brain metastasis from NSCLC may subsequently help to understand underlying mechanism and ultimately lead to novel targeted therapy.

      Futher details will be added in LATE-BREAKING ABSTRACT.

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      P2.03-06 - Serum Syndechan-1 Levels in Patients with Nonsmall Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Ibrahim Tek  |  Author(s): Ozkan Yetkin, Gulay Yetkin, Meryem Iraz

      • Abstract

      Background

      Cytokines as polypeptide or glycopeptide molecules are the essential mediators of immune response and the inflammatory reactions in addition to numerous biological reaction they are involved in. Syndecans have an important role in a variety of cellular functions including cell proliferation and migration, and cell- /cell and cell-/matrix interactions. Syndechan-1 is a transmembrane heparan sulphate proteoglycans that is present on most cell types. In this study we aimed to evaluate the levels of syndecan-1, levels in non-small cell lung cancer (NSCLC), and to evaluate their relationship with tumor progression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Sixtysix patients (F=3, M=63) with non-small cell lung cancer and 22 healthy (F=3, M=19) subject were enrolled this study. Patients with infections or other systemic disease were not included in the study. Serum levels of syndecan-1 was measured by ELISA system. Serum samples were obtained from each patient before the initiation of any type cancer treatment. They were centrifuged at 3000 rpm for 10min, and then stored at -70°C. Unpaired t-test was used to compare continuous variables between the patient group and control group and within the patient group according to TNM classification. Correlation analysis between cytokines and tumor stage was performed using the Pearson correlation coefficient. Sensitivity, specificity, positive predictive value and negative predictive values for syndecan-1 were determined using receiver operator characteristic analysis (ROC). These analyses were done to define clinically valid cutoff points to predict distant metastasis. A two-sided p values less than 0.05 was considered to be statistically significant.

      4c3880bb027f159e801041b1021e88e8 Result

      Serum levels of syndecan-1 in patients with NSCLC were significantly higher than those of controls (p<0.001). In addition, mean levels of synde- can-1 in stage IV disease were significantly higher than non-metastatic NSCLC (p<0.001). In the patients with only one distant metastasis, levels of syndecan- 1 were found to be lower than those of the patients with multiple distant metastases. Syndecan-1 has high sensitivity (78%), specificity (91%), positive (88%) and negative predictive (80%) values for prediction of metastasis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, we found that syndecan-1 changes significantly in serum of patients with NSCLC. In our study, these changes correlated well with the stage of lung cancer. Syndecan-1 with a high sensitivity, specificity and positive predictive value may be used in predicting the presence and nature (single or multiple) of metastasis. The authors believe that the current findings will provide clinicians with new insights, allowing them to implement more individualized treatment strategies in patients with lung cancer.

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      P2.03-07 - Radiomic Signatures Linked to Genetic Alterations as Detected by Next-Generation Sequencing: A Radiogenomics Analysis of Early-Stage NSCLC

      16:45 - 18:00  |  Presenting Author(s): Sibo Tian  |  Author(s): Eduard Schreibmann, Subir Goyal, Manali Rupji, Richard J Cassidy, Chase E Escott, Matthew J Ferris, Pretesh R Patel, Walter John Curran, Jr., Kristin A Higgins

      • Abstract

      Background

      Radiomics uses large-scale quantitative analysis of extracted image-based features to identify tumor phenotypes. Such frameworks based on computed tomography (CT) have identified informative features in lung cancer related to treatment response and prognosis. Molecular profiles have been increasingly recognized in non-small cell lung carcinoma (NSCLC) as predictors of clinical outcomes. The aim of this study is to isolate radiomic signatures which are associated with genomic alterations discoverable by extended panel testing.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with early-stage NSCLC who received definitive local treatment and underwent next-generation sequencing were included for this analysis. 35 genomic alterations representing 32 genes were evaluated using SNaPshot (Life Technologies), TruSight (Illumina Inc), Guardant360 (Guardant Health) or a FISH panel of ALK, MET, ROS1 and RET. Regions of interest including each primary tumor volume were delineated on diagnostic CTs datasets; they were defined as either tumor only (TO), or tumor with a 1cm anatomically-modified anisotropic margin (TM). Measures describing delineation and tumor appearance within each volume were extracted using in-house software, recording HU characteristics, inhomogeneity, and first and second-degree texture statistics. 91 structural, textural, and intensity features were extracted. Univariate logistic regression was performed to test the performance between each extracted feature and the presence of genomic alterations.

      4c3880bb027f159e801041b1021e88e8 Result

      40 patients with diagnostic CTs available for feature extraction were included for analysis. The rate of mutation prevalence in the most commonly altered genes were: TP53 (52.1%), cMET (34.5%), KRAS (27%), PTEN (13.8%), EGFR (13.2%), and MET (12.1%). 5 features were associated with TP53 mutations using TO-extracted features, and 4 using the TM-based approach. cMET was linked to Hounsfield minimum (odds ratio [OR] 1.01, p=0.027), and Sobel minimum (p=0.049) using the TO approach. Long run emphasis standard deviation (STD) [OR 0.36, p=0.04], and long run low grey level emphasis STD (OR 0.37, p=0.04) correlated with cMET mutations using the TM approach. Laplacian sharpening mean was associated with the presence of EGFR mutations using both extraction approaches; finding OR 1.10 (p=0.04, TO method) and OR 1.12 (p=0.02, TM method). No other features were linked to EGFR alterations. Gradient magnitude variance was associated with PTEN using tumor-with-margin volumes (OR 0.83, p=0.028). No features were significantly linked to KRAS mutations using either extraction approach.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Multiple radiomic features were associated with TP53, cMET, EGFR, and PTEN mutations. Integration of such signatures may help inform prognosis for a heterogenous cohort of patients with early-stage non-small cell lung carcinoma.

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      P2.03-08 - Molecular Spectrum of Patients with MSH2 Mutations in Chinese Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Quxia Zhang, Wu Zhuang, Youcai Zhu, Yanping Chen, Meiyu Fang, Gang Chen, Tang Feng Lv, Yong Song

      • Abstract

      Background

      Although inactivation of MutS Homolog 2 (MSH2) genes may predict sensitivity to immunotherapy in non-small cell lung cancer. little is known about their etiology and prognosis in non-small-cell lung cancer (NSCLC). The aim of this study is to investigate mutations and prognosis of NSCLC harboring MSH2 mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 326 patients with non-small-cell lung cancer were recruited between July 2012 and December 2015. The status of MSH2 mutation or other genes were detected by next generation sequencing.

      4c3880bb027f159e801041b1021e88e8 Result

      MSH2 gene mutation rate was 9.51% (31/326) in non-small cell lung cancer, including H839R (5 patients), L390F (4 patients), E809K (3 patients), I169V (3 patients), I544M (1 patient), R217C (1 patient), T8M (1 patient), T552S (1 patient), A189S (1 patient), Q493P (1 patient), I735V (1 patient), A45T (1 patient), A573T (1 patient), R534L (1 patient), V712Sfs*5 (1 patient), F58L (1 patient), S676L (1 patient), N583S (1 patient), I766V plus A2V (1 patient) and Q419K plus Q629R (1 patient), and median overall survival (OS) for these patients was 16.0 months. Among them, all patients were MSH2 gene with co-occurring mutation. Briefly, patients with (n=6) or without (n=25) co-occurring EGFR mutations had a median OS of 6.5 months and 17.0 months respectively (P=0.02); patients with (n=20) or without (n=11) co-occurring TP53 mutations had a median OS of 14.0 months and 17.0 months respectively (P=0.85).

      8eea62084ca7e541d918e823422bd82e Conclusion

      MSH2 is involved in MMR, controlling several aspects of genome stability. Immunotherapy may displayed moderated efficacy in patients with MSH2 mutation. EGFR accompanied mutations might play a good prognosis in MSH2 gene mutation NSCLC.

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      P2.03-09 - The Real World of NTRK Fusion Data in the Chinese Lung Cancer Populations: A Multicenter Study

      16:45 - 18:00  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Youcai Zhu, Yueping Liu, Yu Chen, Quxia Zhang, Hong Wang, Wu Zhuang, Xiaohui Chen, Jinhuo Lai, Meiyu Fang, Ye Tao, Shuguang Xu, Xue Qian, Hongyu Zhao, Shangli Cai, Gang Chen, Tang Feng Lv, Yong Song

      • Abstract

      Background

      NTRK fusions have been recently identified as a therapeutic target in a rare fraction of Caucasian patients with lung cancer (3.3%). The aim of this study was to evaluate the prevalence of NTRK fusions in Chinese lung cancer populations, which had not been reported earlier, and to describe targeting potential in Chinese lung cancer populations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A multicenter study in China was initiated from February 2014, and lung cancer patients have been enrolled as of December 2017. Capture-based comprehensive genomic profiling was performed on 2719 lung cancer FFPE samples (non-squamous/squamous/small=2061/349/309) sequenced to a mean coverage depth of > 650X for up to 381 cancer-related genes. Genomic alterations (GA) included short variant (SV) base subs and insertions/deletions, copy number alterations, and rearrangements/fusions. Tumor mutational burden (TMB; mut/Mb) was calculated on up to 1.2 Mb of sequenced DNA.

      4c3880bb027f159e801041b1021e88e8 Result

      Of this entire cohort, just one (0.04%) patient was identified with a TPM3-NTRK1 fusion. The patient was diagnosed with SCLC. TPM3-NTRK1 fusion was found by biopsy using NGS, the genes co-altered with NTRK fusion was no concurrent with KRAS, EGFR, ALK, ROS1, or other known drivers were identified in the study cohort cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NTRK fusions are a rare molecular subtype in Chinese lung cancer populations. Given clinical evidence for the activity of targeted therapy approaches, molecular eligibility for clinical trials of larotrectinib or entrectinib should include these fusion subtypes. The clinical evidence for responsiveness of NTRK fusions driven lung cancer provides an opportunity to personalize treatments and improve clinical outcomes for patients.

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      P2.03-10 - Gene Mutational Profiling Of Chinese TKI-Sensitizing EGFR Mutations NSCLC Patients Required Resistance to Icotinib Using NGS

      16:45 - 18:00  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Youcai Zhu, Wu Zhuang, Yanping Chen, Gang Chen, Meiyu Fang, Tang Feng Lv, Yong Song

      • Abstract

      Background

      Icotinib is an oral first-generation epidermal receptor 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor (TKI). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is EGFR-T790M mutation. Other mechanisms, such as MET amplifications, BRAF mutations and PIK3CA mutations, were also reported. In this study, we performed gene mutational profiling in a cohort of 162 TKI-sensitizing EGFR mutations NSCLC patients and acquired resistance to icotinib using targeted NGS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 162 patients with stage IIIb-IV TKI-sensitizing EGFR mutations NSCLC were undergoing tumor biopsies, blood or serous effusions withdrawing by the time of acquiring resistance to icotinib. We used targeted NGS to detect genes status of patients.

      4c3880bb027f159e801041b1021e88e8 Result

      In total, we identified 373 genetic alterations with a median of 2.3 mutations per patient. 64.20% (104/162) of patients still exhibit TKI-sensitizing EGFR mutations, and 46.30% (75/162) of patients acquired EGFR-T790M mutations. Besides other known resistance mechanisms, we identified MET amplification 6.17% (10/162) of patients, BRAF mutations in 3.09% (5/162) of patients, and PIK3CA mutations in 2.47% (4/162) of patients. Interestingly, we also observed RBM10, ASXL1 and BMX mutations in EGFR-T790M wild patients, which are restricted to icotinib treatment resistance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study uncovered mutational profiles of TKI-sensitizing EGFR mutations NSCLC patients with icotinib resistance with potential therapeutic implications. Our analysis strongly suggests that MET amplification, BRAF mutations and PIK3CA mutations may serve as bypass resistance mechanisms in patients who are EGFR T790M wild type.

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      P2.03-11 - PDGFRA Defines a Unique Molecular Subtypes of Chinese Non-Small Cell Lung Cancer Patients

      16:45 - 18:00  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Quxia Zhang, Wu Zhuang, Youcai Zhu, Yanping Chen, Meiyu Fang, Gang Chen, Tang Feng Lv, Yong Song

      • Abstract

      Background

      Activation of the platelet-derived growth factor (PDGF) signaling system has been implicated in the development and malignant progression of non-small-cell lung cancer. Recently, the platelet-derived growth factor receptor A (PDGFRA) gene mutations are identified in non-small-cell lung cancer (NSCLC). While the genetic locus of PDGFRA mutation NSCLC patients is unclear. The aim of this study is to investigate mutations and prognosis of NSCLC harboring PDGFRA mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 467 patients with non-small-cell lung cancer were recruited between July 2012 and December 2015. The status of PDGFRA mutation and other genes were detected by next generation sequencing.

      4c3880bb027f159e801041b1021e88e8 Result

      PDGFRA gene mutation rate was 2.14% (10/467) in non-small cell lung cancer, including S716R (1 patient), L615* (1 patient), A916T (1 patient), H104R (1 patient), V536M (1 patient), N505K (1 patient), V421I (1 patient), V538M (1 patient), M578K (1 patient) and V544A (1 patient), and median overall survival (OS) for these patients was 24.0 months. Among them, all patients were PDGFRA gene with co-occurring mutation. Briefly, patients with (n=2) or without (n=8) co-occurring EGFR mutations had a median OS of 19.0 months and 24.0 months respectively (P=0.96); patients with (n=6) or without (n=4) co-occurring TP53 mutations had a median OS of 24.0 months and 19.0 months respectively (P=0.99); patients with (n=2) or without (n=8) co-occurring BRCA2 mutations had a median OS of 25.0 months and 19.0 months respectively (P=0.17); patients with (n=2) or without (n=8) co-occurring IDH2 mutations had a median OS of 15.0 months and 24.0 months respectively (P=0.22).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Mutation type of PDGFRA has a potential for predicting the course of the disease and might contribute to management individualization of NSCLC patients. EGFR, TP53, BRCA2 and IDH2 gene accompanied may have less correlation with PDGFRA mutation in NSCLC patients. Imatinib may displayed moderated efficacy in patients with PDGFRA mutation.

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      P2.03-12 - EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer

      16:45 - 18:00  |  Presenting Author(s): Shun Lu  |  Author(s): Yongfeng Yu, Ziming Li, Yang W. Shao, Xue Wu, Yan Ding, Hairong Bao, Hong Jian

      • Abstract

      Background

      Inherited genetic determinants of lung cancer risk remains relatively elusive. Rare germline mutations in EGFR and ERBB2 have previously been reported in lung cancer patients, which may be associated with the genetic susceptibility to lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed the next-generation sequencing (NGS) results targeting 416 cancer-relevant genes, including the whole exons of EGFR and ERBB2, in a cohort of 9091 Chinese lung cancer patients.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 9091 Chinese lung cancer patients, nine germline mutations from 12 patients were identified within or adjacent to the kinase domain of EGFR: K757R (two patients), D1014N (two patients), I646S, G724S, V786M, T790M, L792F, R831H, and L844V, and one germline mutation was identified adjacent to the kinase domain of ERBB2: V1128I. The incidence of EGFR T790M germline mutation is much lower compared with the reported frequency in the Caucasian patients. Somatic mutations detected in the 12 patients carrying rare EGFR/ERBB2 germline mutations were most commonly EGFR exon19 deletion, L858R, and G719S mutations, and rare EGFR: S768I mutation and a novel D770delinsDNPH indel mutation. The superior response to afatinib of the patient carrying only EGFR L844V germline mutation suggests that this germline mutation might be sensitive to TKI treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Here we indentified eight novel EGFR germline mutations and the ERBB2: V1128I germline mutation were linked to the genetic susceptibility of lung cancer in Chinese population.

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      P2.03-13 - SWATH MS Analysis of Serine Hydrolase Activity in Human Lung Adenocarcinoma for Biomarker Discovery

      16:45 - 18:00  |  Presenting Author(s): Sven Hillinger  |  Author(s): Tatjana Sajic, Stephan Arni, Walter Weder, Rudi Aebersold

      • Abstract

      Background

      Serine hydrolases (SHs), one of the largest enzyme families, have previously been shown to be implicated in the development of lung cancers. Activity-based protein profiling (ABPP) is a proteomic method that uses active site-directed chemical probes to selectively target the active form of the subsets of the enzymes in question, and then by a combination of a streptavidin-biotin enrichment step and mass spectrometry quantifies the catalytically active amount of the enzyme molecule. In this project, we monitored both forms of serine hydrolase, the “catalytically active” and “inactive”, in a distinct patient cohort of lung adenocarcinoma biopsies. For this purpose, we combined the activity-based proteomics for serine hydrolase and SWATH mass spectrometry (MS), which ensures highly reproducible protein quantification in a large panel of clinical samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Twenty four lung biopsies of long- and short surviving patients with stage IIIA adenocarcinomas and their normal tissue counterparts were available as OCT-embedded tissue. The common OCT sample clean-up by organic solvents is not compatible with the ABPP protocol since organic solvents can inactivate the molecular structure of the enzymes. The additional challenge of the ABPP protocol includes a streptavidin-biotin enrichment step of the active enzymes, which also leads to sample contamination by streptavidin peptides, and negatively influences MS spectra analysis and, consequently, biomarker discovery.

      Therefore, we proceeded with optimizations of sample preparation in ABPP experiments and developed an OCT clean-up protocol compatible with “enzyme-substrate binding” of activity-based chemical probes and the targeted portion of the active enzyme. To prevent digestion on streptavidin beads and MS spectra contamination, we used the reproducible and accurate SWATH MS to indirectly measure the active enzyme form in the biopsy-extract solution.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified over 4000 lung tissue proteins from a few milligrams of OCT-embedded biopsies, and confirmed good data quality for further SH enzyme quantification. In addition to the analysis of total proteome, 278 distinct proteins were identified on the parallel streptavidin bead samples, with chemical probes being used to deplete the active enzyme from the biopsy-extract.

      Each SWATH experiment reported the percentage of “active” enzyme form through the indirectly measured ratio between the “inactive SHs” (sample depleted for active SHs) and the “total” SHs (non-depleted sample). We detected around 80 enzymes with the “active” form comparably measured in three independent experiments, which amount generally accounted for between 5–55% of the total enzyme concentration.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combination of ABPP and SWATH MS enables highly reproducible protein quantification in biomarker discovery.

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      P2.03-14 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant and Squamous Cell Non-Small Cell Lung Cancer (NSCLC)

      16:45 - 18:00  |  Presenting Author(s): Masaoki Ito  |  Author(s): Carles Codony-Servat, Jordi Codony-Servat, Ilaria Attili, Jordi Berenguer, Jillian Wilhelmina Paulina Bracht, Nuno Gil, Morihito Okada, Niki Karachaliou, Peng Cao, Rafael Rosell

      • Abstract

      Background

      To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR, KRAS and Squamous cell carcinoma (SCC) cell lines.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carry EGFR and KRAS mutations, respectively, and H520 PAK1 amplified squamous NSCLC cells. Cell viability assays and western blotting were applied to evaluate the effect of auranofin (PKCi inhibitor) plus IPA-3 (PAK1 inhibitor). Since IPA-3 is only for laboratory use, we also tested auranofin in combination with OTSSP167 (a MELK inhibitor in phase I trials), which, in our experience, inhibits pPAK1 (Thr423 and Thr212 in the HCC827 cell line).

      4c3880bb027f159e801041b1021e88e8 Result

      Auranofin plus IPA-3 was highly synergistic (CI less than 0.4) in EGFR mutant (HCC827), KRAS mutant (H23) and SCC with PAK1 amplification (H520 cells). Similar synergism was found with the combination of auranofin plus OTSSP167 in the 3 cell lines (Figure). the combination of auranofin with either IPA-3 or OTSSP167 ablated EGFR phosphorylation and downstream signaling pathways: ERK, AKT, STAT3, YAP1 and inhibited the expression of RTKs: AXL, MET and CDCP1. We created EGFR mutant gefitinib and osimertinib resistant cell lines (PC9-GR3, GR4, OR2, OR4). Auranofin plus IPA-3 was highly synergistic in all cell lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These observations suggest that the combination of auranofin with OTSSP167 can be used for treatment of different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification.

      image.jpg

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      P2.03-15 - Integrin-Linked Kinase (ILK), Protein Tyrosine Phosphatase SHP2 and B lymphoma Mo-MLV Insertion Region 1 Homolog  (Bmi-1) in EGFR-Mutant NSCLC

      16:45 - 18:00  |  Presenting Author(s): Niki Karachaliou  |  Author(s): Imane Chaib, Jillian Wilhelmina Paulina Bracht, Martyna Filipska, Ana Drozdowskyj, Andrés F. Cardona, Alain Vergnenegre, José Miguel Sánchez-Torres, Mariano Provencio, Filippo De Marinis, Enric Carcereny, Noemi Reguart, Rosario García Campelo, Mariacarmela Santarpia, Santiago Viteri, Trever G Bivona, Rafael Rosell

      • Abstract

      Background

      The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is jeopardized by the activation of multiple signaling pathways. ILK regulates the expression of Bmi-1, a well-known epithelial mesenchymal transition-inducing transcription factor. SHP2 function is required for MAPK pathway activation, and also plays a role in receptor tyrosine kinase signaling pathways.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinical data were assessed in accordance with the protocol approved by the institutional review board and de-identified for patient confidentiality. Pretreatment tumor specimens from advanced EGFR-mutant NSCLC patients (pts) were collected from eight sites in Spain, France, Italy and Colombia. mRNA gene expression analysis was performed by TaqMan (qRT-PCR). We examined the mRNA levels of ILK, SHP2 and Bmi-1.

      4c3880bb027f159e801041b1021e88e8 Result

      With a median follow-up of 26.7 months, median progression-free survival (PFS) was 9.3 (95% CI, 7.6-14.2) and 15.7 months (95%CI, 12.3-30.1) for pts with high and low ILK mRNA, respectively (P=0.0002), (HR for disease progression, 2.4; 95% CI, 1.3-4.5; P=0.002). Median PFS was 11.4 (95% CI, 8.2-14) and 24.1 months (95% CI, 8.2-30.9) for pts with high and low SHP2 mRNA, respectively (P=0.009), (HR, 2.4; 95% CI, 1.2-4.7; P=0.01). Median PFS was 8.2 (95% CI, 4.8-13.1) and 24.1 months (95% CI, 14.2-36.5) for pts with high and low SHP2 mRNA, respectively (P=0.001), (HR, 2.9; 95% CI, 1.4-5.9; P=0.002). Median overall survival (OS) was 17.9 (95% CI, 13.2-33) and 34.4 months (95% CI, 18.5-44.2) for pts with high and low ILK mRNA, respectively (P=0.200), (HR, 1.5; 95% CI, 0.79-3; P=0.200). Median OS was 18.5 (95% CI, 14-33) and 36.7 months (95% CI, 16.7-47.1) for pts with high and low SHP2 mRNA, respectively (P=0.018), (HR, 2.5; 95% CI, 1.1-5.8; P=0.020). Median OS was 17.6 (95% CI, 8.6-39.1) and 36.7 months (95% CI, 19.1-64.1) for pts with high and low Bmi-1 mRNA, respectively (P=0.004), (HR, 2.2; 95% CI, 1.0-5.1; P=0.040).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The disturbance of RTKs, including ILK-SHP2-Bmi-1 axis, occurs frequently in EGFR mutant NSCLC patients, significantly limiting the PFS and OS. The levels of ILK, SHP2 and Bmi-1 could be predictive for upfront combinatory therapy of EGFR TKI plus a MAPK pathway inhibitor (SHP2 or MEK inhibitors).

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      P2.03-16 - TGF-β Induced EMT and Stemness Characteristics are Associated with Epigenetic Regulation in Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Seung Joon Kim  |  Author(s): Nahyeon Kang, Bit Na Kim, Chan Kwon Park, Young Kyoon Kim

      • Abstract

      Background

      Transforming growth factor-β (TGF-β) promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT). EMT is often associated with acquisition of stem-like characteristics. In this study, we investigated whether EMT and stem-like characteristics induced by TGF-β could associated with epigenetic regulation in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Human normal epithelial (BEAS-2B) and cancer (A549, H292, H226 and H460) cell lines were incubated with 10 ng/ml of TGF-β for 3 days. Transcriptome analysis of BEAS-2B and A549 cells treated with TGF-β were performed by using next-generation sequencing (HiSeq 2500 system). Western blotting was performed to analyze the expression of epithelial marker (E-cadherin) and mesenchymal markers (N-cadherin, fibronectin, vimentin and α-SMA). Wound healing assay, Matrigel invasion assay, sphere formation assay and in vivo mice tumor model were used to assess functional characteristics of EMT and stemness acquisition. TGF-β induced DNA demethylation was identified by methylation-specific PCR and bisulfite sequencing.

      4c3880bb027f159e801041b1021e88e8 Result

      Next-generation sequencing revealed significant changes in the expression of stem cell markers, CD44, CD87 and CD90 in both BEAS-2B and A549 cells. Functional analysis revealed increased wound healing, Matrigel invasion, sphere formation and in vivo mice tumor formation after TGF-β treatment. TGF-β induced EMT was associated with acquisition of stem-like characteristics. CD44, CD87 and CD90 were activated by either TGF-β and treatment with AZA. MSP showed decreased CD44, CD87 and CD90 promoter methylation after TGF-β treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These results suggest that TGF-β induces stem cell characteristics which are related with CD44, CD87 and CD90 reactivation by promoter demethylation.

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      P2.03-17 - EGFR T790M Mutation may not be Generated through Selection by EGFR-TKI from Randomly Occurring Mutations in Vitro Using ENU

      16:45 - 18:00  |  Presenting Author(s): Yoshihisa Kobayashi  |  Author(s): Tetsuya Mitsudomi

      • Abstract

      Background

      It is postulated that T790M resistant mutation is a result of selection by EGFR-TKI from clones that have randomly generated mutations. If so, it would be possible to detect the process of convergence from random mutations to T790M, depending on exposure time for EGFR-TKI.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      After exposure of Ba/F3 cells expressing EGFR Del19 to ENU (N-ethyl-N-nitrosourea) for 24 hours, they were cultured with various concentrations of 3 EGFR-TKIs at trough concentrations (Fig.). At 1, 6, 12, 24, and 48 hours, cell viability was evaluated and single cell cloning was performed. EGFR exons 18 to 21 were analyzed by Sanger sequencing.

      4c3880bb027f159e801041b1021e88e8 Result

      Percentages of viable cells exposed to TKI were approximately 80%, 50%, < 20%, and < 3% at 1, 6, 12, 48 hours, respectively. These ratios were almost similar among 3 TKIs. Of 50 clones that had survived TKI treatment, T790M was detected in 12 (24%) (Fig.). Notably, two were detected in cells exposed to erlotinib or afatinib only for one hour (Fig.). In addition, we found 2 G873E (c.2876G>A) mutations, known to be oncogenic, with the same TKI treatment. In contrast, 36 clones (72%) with TKI or additional 19 clones without TKIs that had been exposed to only ENU did not harbor any secondary EGFR mutations. secondary mutations of established clones.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      It is unlikely that EGFR T790M mutation is generated through selection by EGFR-TKI from randomly occurring mutations. Rather, it appears that T790 is the preferred target of mutagenesis through yet an unknown mechanism which occurs after only one-hour treatment.

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      P2.03-18 - X-Inactivation Specific Transcript (XIST)-Mediated miRNA Sequestration In NSCLC

      16:45 - 18:00  |  Presenting Author(s): Erin A Marshall  |  Author(s): Greg L. Stewart, Adam P Sage, Wan Lam, Carolyn J Brown

      • Abstract

      Background

      Long non-coding RNA (lncRNA; >200nt) transcripts have been recently recognized as crucial regulators of gene expression. XIST is a prototypical lncRNA involved in cis-silencing of an X chromosome in females; however, there are conflicting reports of lncRNA-mediated regulation in cancer biology and therapeutics through “sponging” of single miRNAs that cause upregulation of canonical miRNA-target genes. XIST-associated sex-specific differences afford the opportunity to study lncRNA sponging systems within a cancer type. Existing studies considering one miRNA in singular cancer types do not account for important biological considerations, including sex and localization of miRNA and XIST transcripts. Here, we detail an in-depth and unbiased pipeline for the discovery of candidate miRNA and gene targets in lncRNA sponging, and validate the miRNA that may be mediating these interactions in XIST.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a comprehensive analysis of the role of XIST in the positive regulation of protein-coding genes using male and female lung adenocarcinoma (LUAD) samples as a model. To find genes regulated by XIST-mediated miRNA sponging, we correlated all Ensembl-annotated genes with XIST expression in female LUAD (n=307; rho>0.4, p<0.05). Using a specialized algorithm based on binding energies and sequence homology, we assessed the potential binding of all miRNAs against target genes and XIST. We then determine the best candidates for sponging by XIST using XIST-high (female and male) and XIST-low (male) systems, and validate the presence of these candidate miRNAs in the nucleus.

      4c3880bb027f159e801041b1021e88e8 Result

      Our analysis yielded 543 genes that may be defended from miRNAs by XIST (DMX), with a predicted 804 miRNAs targeting both DMX genes and XIST. We compared the changes in miRNA-DMX relationships in XIST-high and XIST-low systems and discovera high-confidence set of 13 miRNA-DMX gene pairs. Interestingly, 5 of these miRNA-DMX gene pairs involve miRNA with validated nuclear localization.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A massive number of lncRNA sponging studies exist, but most only consider one miRNA in a singular type of cancer, are biased in their selection of this target, and limited in biological context. By analyzing the transcriptome of female and male LUAD, we show that the XIST-miRNA-DMX sponging axis is affected by expression of sex-specific genes and number of shared miRNA binding sites on DMX genes. Importantly, we identify that the miRNAs that mediate the XIST-DMX gene axis are enriched in the nucleus, co-localizing with XIST. In summary, our analysis provides both a comprehensive methodology for studying cancer-related miRNA sponge lncRNAs, and suggests the relevance of XIST in lung cancer.

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      P2.03-19 - RET-Mediated Activation of Ezrin is Associated with Cell Motility and Survival in a Subset of Lung Adenocarcinomas

      16:45 - 18:00  |  Presenting Author(s): Serisha Moodley  |  Author(s): Mathieu Crupi, Jenny Zhao, Brandy Hyndman, Taran Gujral, Lois M Mulligan

      • Abstract

      Background

      Lung cancer is the leading cause of cancer mortality worldwide with 40% of cases diagnosed as lung adenocarcinoma (LADC). Increased expression of RET has been reported in 10-20% of LADCs and is associated with metastasis and reduced survival. Alternative gene splicing of RET generates two co-expressed isoforms; RET9 and RET51, with unique C-terminal tails. The tails confer distinct protein binding opportunities with signaling proteins, known as scaffolds, to promote different signaling events and cell processes. RET9 interacts with the SHANK family scaffolds at a PDZ-binding motif and Enigma at tyrosine (Y) 1062, whereas, RET51 interacts with Grb2 at the unique Y1096. RET9 and RET51 are associated with distinct functions in thyroid cancer, where RET51plays a predominant role in cancer metastasis. Ezrin is a scaffold protein and tyrosine kinase substrate that bridges the plasma membrane to the actin cytoskeleton to promote adhesion, organization and migration. Overexpression of ezrin is associated with invasion and metastasis of osteosarcoma and pancreatic cancer cells. The roles of RET isoform-scaffold interactions in the progression of LADC has never been investigated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      HEK-293 cells were co-transfected with RET isoform or mutant constructs and Ezrin and/or Grb2 dominant negative (DN) constructs. A549 LADC cells were transfected with RET51 construct. SH-SY5Y neuroblastoma and HCC1833 LADC cells endogenously express Ezrin and RET. Cells were treated with RET/ Ezrin inhibitors and/or stimulated with glial-derived neurotrophic factor (GDNF) then fixed or harvested. Co-immunoprecipitation (Co-IP) or pull-down assays coupled to western blotting were used to investigate binding domains required for RET interaction with and activation of Ezrin or downstream effectors. Immunofluorescence confocal imaging was used to determine co-localization of RET and Ezrin and changes to cell morphology. GDNF-impregnated agarose bead live-cell fluorescence assays were used to measure cell growth, survival, spread and motility. SynTarget (cancer gene expression analysis tool) was used to assess co-expression of RET and Ezrin with respect to clinicopathological parameters and survival outcomes in LADC.

      4c3880bb027f159e801041b1021e88e8 Result

      Ezrin binds kinase active RET51 with Grb2. GDNF-stimulation promotes the formation of cytoskeletal outgrowths with increased co-localization of Ezrin and RET. GDNF-activation of RET results in scaffold-mediated activation of Rho-family GTPases to promote cell motility. Like RET, overexpression of Ezrin is associated with poor overall survival in LADC patients and overexpression of both RET and Ezrin has a negative synergistic effect on overall survival in a subset of LADC patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      RET interaction with Ezrin identifies a distinct functional role of RET as an oncogenic driver in lung adenocarcinoma.

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      P2.03-20 - Factor XIIIA-Expressing Inflammatory Monocytes Promote Lung Squamous Cancer through Fibrin Cross-Linking

      16:45 - 18:00  |  Presenting Author(s): Chad Victor Pecot

      • Abstract

      Background

      Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      See results

      4c3880bb027f159e801041b1021e88e8 Result

      Using computational analyses of The Cancer Genome Atlas(TCGA) dataset, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. Multiplex immunohistochemistry for CD14/CCR2/pan-cytokeratin revealed that dual-positive CD14+/CCR2+ cells predominately reside in the stromal LUSC compartment and not cancer cell islets. Using immunogenomics, we found that amongst 9 immune subsets expressing CD14, IMs had the strongest relationship with CD14 expression and poor LUSC survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is driven by TNFa-mediated activation of the NFkB pathway. Furthermore, tumor production of CCL2 isnecessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment with a potent CCR2 inhibitor (PF-04136309) had substantial anti-metastatic effects, which was not due to inhibition of tumor-associated macrophages (TAMs) but rather by blockade of IMs in the blood and tumor microenvironment. Notably, in contrast to TAMs, we show that IMs express high levels of Factor XIIIA (FXIIIA). We demonstrate that FXIIIA is packaged into podosome-like structures in IMs, and when in contact with fibrin the IMs are capable of rapidly creating fibrin cross-linkages. We show that FXIIIA-mediated IM fibrin cross-linking creates a scaffold for LUSC cell invasion, migration and metastases. Consist with this observation, we found clinical LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor relapse-free survival.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Given the rapidly evolving landscape of precision immune-oncology, these findings identify IMs as a novel context-specific vulnerability of LUSC and provide an important insight into the mechanisms through which this immune cell type determines a poor prognosis.

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      P2.03-21 - Mechanistic Investigation of DRD1 in Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Leila Toulabi  |  Author(s): Christopher Grant, Adriana Zingone, Khadijah A Mitchell

      • Abstract

      Background

      The D1 dopamine receptor (DRD1) is a G protein-coupled receptor (GPCR) for the catecholamine dopamine (DA). Historically, DA was thought to function mainly within the central nervous system (CNS), and there have been no prior reports linking the DA pathway (DAP) to lung cancer biology. Our group previously discovered an epidemiological association between a DRD1 gene polymorphism and risk of developing lung cancer. Since this association was observed in never smokers,it suggested that DRD1 may play a direct role in the pathogenesis of lung cancer. We have been investigating this novel function of DRD1.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The DAP has never been fully characterized in lung. We therefore examined the presence of DAP-related proteins, including dopamine receptors, metabolizing and synthesizing enzymes, and dopamine transporter in normal human lung tissue. To understand the mechanistic role of DRD1 in lung cancer, we generated stable lung cancer cell lines in which DRD1 was overexpressed or knocked down and performed proliferation, transcriptome, and kinome analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that dopamine-related proteins are expressed throughout the respiratory tract in normal human tissue. Further, we observed that DRD1 expression is significantly downregulated in lung cancer using samples from the on NCI-MD case control study and replicated this with TCGA. Methylation analyses in NCI-MD and TCGA showed that DRD1 is hyper-methylated in lung cancer and that there is a negative correlation between DRD1 mRNA and methylation. DRD1 methylation and methylation are associated with patient outcome.

      Modulation of DRD1 in multiple cell line model systems affects cell proliferation. Transcriptome and kinome profiling revealed that this modulation is mediated through EGFR and downstream MAPK and AKT signaling. Immunofluorescent staining shows that EGFR and DRD1 colocalize at the cell membrane. Ongoing work is aimed at establishing the exact nature of the DRD1/EGR interaction.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Collectively, this work suggests that DRD1 acts like a tumor suppressor in lung cancer, that inherited susceptibility in the DRD1 gene contributes to lung cancer and agents that modulate the bioavailability of dopamine could modulate patient survival. Understanding the possible crosstalk between DRD1, EGFR and MAPK signaling may be very valuable for lung cancer therapeutic strategy. The majority of patients receiving EGFR inhibitors eventually develop resistance. Using DRD1 agonists as combinatorial agents may help bypassing anti-EGFR resistance.

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      P2.03-22 - OCT4&amp;SOX2 Specific CTLs Plus PD-1 Inhibitor Had Synergistic Effect on Killing CSC And Treating Drug-Resistant Lung Cancer Mice

      16:45 - 18:00  |  Presenting Author(s): Fang Hu  |  Author(s): Xueyan Zhang, Xiaoxuan Zheng, Bo Zhang, Huimin Wang, Guangyu Tao, Jianlin Xu, Yanwei Zhang, Baohui Han

      • Abstract

      Background

      This study aimed to investigate the synergistic effect of OCT4&SOX2 specific cytotoxic T lymphocytes (CTLs) and PD-1 inhibitor on killing lung cancer stem-like cells (LCSCs) and their efficacy in treating drug-resistant lung cancer (DRLC) mice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      OCT4&SOX2 specific CTLs and PD-1 inhibitor with differed doses were applied to treat PC9 cells and PC9 LCSCs. CCK8 assay and flow cytometry (FCM) assay with CFSE staining target cells before treatment and PE staining died cells after treatment were conducted to detect the cytotoxic activity. DRLC mice were constructed by injection of PC9 LCSCs suspension and Matrigel into left lung of SD mice. DRLC mice was randomly divided into 5 group: Control group, CMV pp65 CTLs group, OCT4&SOX2 CTLs group, PD-1 inhibitor group and OCT4&SOX2 CTLs+PD-1 inhibitor group.

      4c3880bb027f159e801041b1021e88e8 Result

      In vitro, Both CCK8 assay and FCM assay disclosed that OCT4&SOX2 specific CTLs plus PD-1 inhibitor presented with elevated cytotoxic activity on PC9 cells and PC9 LCSCs. In vivo, tumor volume and tumor weight were decreased, while tumor necrosis and tumor apoptosis were increased in OCT4&SOX2 CTLs group than CMV pp65 CTLs group and control group, and in OCT4&SOX2 CTLs+PD-1 inhibitor group than OCT4&SOX2 CTLs group and PD-1 inhibitor group. In addition, CD8 expression was increased while OCT4 and SOX2 expressions were decreased in OCT4&SOX2 CTLs+PD-1 inhibitor group than OCT4&SOX2 CTLs group and PD-1 inhibitor group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, OCT4&SOX2 specific CTLs and PD-1 inhibitor presented with synergistic effect on killing LCSCs in vitro and treating DRLC mice in vivo.

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      P2.03-23 - MicroRNA-30e Inhibits Cell Proliferation and Invasion in Non-Small Cell Lung Cancer via Directly Targeting SOX9

      16:45 - 18:00  |  Presenting Author(s): Lei Zhao  |  Author(s): Zhao Shilei, Chundong Gu, Yixiang Zhang, Zhe Sun

      • Abstract

      Background

      Previous studies reported that microRNA-30e (miR-30e) was dysregulation in multiple human cancers. However, the expression, functions and molecular mechanism of miR-30e in NSCLC remains unknown. In this study, we found that miR-30e expressed at low levels in NSCLC tissues and NSCLC cell lines.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      figure.jpgThe miR-30e expression was texted in NSCLC tissues and cell lines by RT-qPCR. We then overexpressed miR-30e expression in NSCLC cells to evaluate its effects in regulating NSCLC proliferation and invasion in vitro. Moreover, the mechanisms underlying the biological roles of miR-30e in NSCLC were investigated using luciferase reporter assay.

      4c3880bb027f159e801041b1021e88e8 Result

      In NSCLC cell lines, enforced expression of miR-30e inhibited cell proliferation and invasion in vitro. In addition, miR-30e negatively regulated SOX9 expression through directly binding to the 3'UTR of SOX9, and an inverse correlation was found between miR-30e and SOX9 mRNA expression level in NSCLC tissues. Moreover, SOX9 knockdown led to decreased proliferation and invasion of NSCLC cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      miR-30e is downregulated in NSCLC and inhibits cell proliferation and invasion, possibly by directly targeting SOX9.

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      P2.03-24 - CD90 Enhances Metastasis by Epithelial-Mesenchymal Transdifferentiation in Lung Adenocacinoma

      16:45 - 18:00  |  Presenting Author(s): Xiangdong Zhou  |  Author(s): Liu Pan

      • Abstract

      Background

      The specific mechanism of lung cancer remains unclear. The existence of cancer stem cells(CSCs) reflects the cellular heterogeneity within tumors,and we presume that CD90pos lung adenocarcinoma(LA) cells play the role of CSCs.

      The epithelial-to-mesenchymal transition (EMT) is a de-differentiation process that has been implicated in metastasis and generation.In this study, CD90pos CSC were isolated and characterized from LA cell line A549, and we discovered that the specific subtype displayed CSCs and epithelial-mesenchymal transition phenotypes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Section not applicable

      4c3880bb027f159e801041b1021e88e8 Result

      1. CD90pos CSC was isolated and characterized from LA cell line A549.

      1)FACS assay was utilized to isolated CD90pos cells from LA cell line A549 ,we found that adherent A549 cells possess much lower proportion of CD90 than A549 sphere cells, indicating that CD90 maybe the potential CSCs marker.

      2) CD90pos cells expressed higher stemness genes Oct4 and Nanog via Western blot analysis. Also the clonal formation and sphere formation assay by CD90pos and CD90neg cells was performed, and the former highly expressed proliferation capability.

      3) The tumorigenicity assay in nude mice showed CD90pos cells highly expressed tumorigenicity in vivo, which possessed shorter latency stage and formed larger xenograft nodes.

      2. CD90pos cells possessed highly metastasis and invasiveness associated with epithelial mesenchymal transition.

      1) Migrative and invasive ability of CD90pos cells was measured by migration and Transwell invasion assay, and we found that CD90pos cells with higher migrative and invasive ability in vitro compared with CD90neg cells.

      2) To further confirm upper observation, an experimental tail vein metastasis model was performed in vivo,and CD90pos cells displayed a superior ability to metastasize to the lung.

      3) RT-PCR measurement of gene expression related with EMT showed same tendency compared with Western blot analysis and immunofluorescence assay.MMP2 was higher expression in CD90pos cells, also transcription factors Twist increased significantly, in which mould be involved in the EMT phenotype maintaining.

      3. CD90 expression has important clinical significance for patients with LA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CD90 is a effective marker for isolation and enrichment of LCSCs. CD90pos cells highly expressed stem cell related genes, self-renewal capability in vitro, showed stronger tumorigenicity in vivo. Furthermore, CD90pos cells possesse higher metastasis and invasiveness, which is associated with EMT.CD90pos cells are endowed with EMT phenotype and show an decreased expression of E-cadherin, and increased expression of N-cadherin, vimentin, MMP2, which would be associated with Twist. Expression of CD90 is negatively correlated with survival time in the metastatic sites instead of primary sites.

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      P2.03-25 - Loss of Expression Rather Than Cytoplasmic Mislocalization of RUNX3 Predicts Worse Outcome in Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Xiaohui Chen  |  Author(s): Yujie Deng, Yi Shi, Weifeng Zhu, Kunshou Zhu, Xiongwei Zheng, Gen Lin

      • Abstract

      Background

      Functional inactivation of RUNX3 through epigenetic silencing was well-documented in many cancers. Added to gene mutation and promoter hypermethylation, cytoplasmic mislocalization was another major manifestation of RUNX3 dysfunction in malignancies like gastric cancer. We aimed to investigate whether NSCLC patients with different RUNX3 expression patterns would have differrent OS, and the associations of different patterns with clinicopathologic parameters and clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Expressions of RUNX3 and Ki-67 were immunohistochemically detected in normal lung tissue (n=5) and surgically resected NSCLC patients (n=188). The optimal cutoff of RUNX3 was determined by X-tile software related to their survival. Apoptotic index in cancerous tissue was evaluated by TdT mediated dUTP-biotin nick end labelling (TUNEL) method. The prognostic significance of different expression patterns of RUNX3 was determined by means of Kaplan-Meier survival estimates and log-rank tests.

      4c3880bb027f159e801041b1021e88e8 Result

      Loss of RUNX3 expression in NSCLC was correlated with low cancerous apoptotic index (P<0.001), shorter OS and worse prognosis (P=0.0142), while no statistical difference of apoptotic index (P=0.73) or survival (P=0.3781) had been determined between patient subgroups with different localization of RUNX3 expression.

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      8eea62084ca7e541d918e823422bd82e Conclusion

      Loss of expression rather than cytoplasmic mislocalization of RUNX3 predicted worse outcome in NSCLC, which was quite different from what it manifested in other cancer types.

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      P2.03-26 - A Prospective Cohort Study of TMB and Determinants of ctDNA Detection by Comprehensive Genomic Profiling in Stage I Lung Adenocarcinomas

      16:45 - 18:00  |  Presenting Author(s): Kezhong Chen  |  Author(s): Heng Zhao, Jing Bai, Fan Yang, Lianpeng Chang, Yanfang Guan, Xin Yi, Lin Feng, Shujun Cheng, Jun Wang

      • Abstract

      Background

      Plasma tumor mutational burden (TMB) is a predictor of immune checkpoint inhibitors treatment in advanced lung cancer patients. A preliminary study has shown the feasibility of PD-1 treatment in resectable lung cancer. However, few studies investigated TMB and plasma circulating tumor DNA detection in stage I lung adenocarcinomas.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We prospectively enrolled 67 consecutive patients with pulmonary nodule who intended to undergo curative lung resection (NCT03320044). Comprehensive genomic profiling were used to identify somatic variants in both tissue and matched blood samples. Tissue clonal mutations were defined if mutations were in the cluster with the highest mean variated allele frequency with PyClone.

      4c3880bb027f159e801041b1021e88e8 Result

      Mean effective depth of coverage of 1045x and 27410x were obtained in tissue and plasma samples, respectively. Resected stage I lung adenocarcinoma patients were included (4 IA1, 20 IA2, 9 IA3, 12 IB)(Fig.1). An increasing tissue TMB was detected in Stage IA1, Stage IA2, Stage IA3 ( 1.5mut/Mb, 3mut/Mb, 4mut/Mb, p<0.05). Mixed invasive subtype appeared the highest TMB, followed by invasive adenocarcinoma and minimally invasive adenocarcinoma (4mut/Mb, 3mut/Mb, 1mut/Mb, p<0.05). A significant rise of TMB was identified in pure ground-glass nodule, subsolid nodule and solid nodule (1.5mut/Mb, 2 mut/Mb, 4 mut/Mb, p<0.05). 30.3 % (10/33) patients were demonstrated to be ctDNA-positive with a mean ctDNA abundance of 0.0415% (ranged from 0.012 to 0.119%). A series of factors such as gender, pleural invasion and solid tumor size affected ctDNA detection. 50% patients detected clonal alterations in plasma. Unlike tissue, blood TMB showed no relation with clinical-pathological characteristics.

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      8eea62084ca7e541d918e823422bd82e Conclusion

      We evaluated the feasibility of TMB and determinants of ctDNA detection in stage I lung adenocarcinomas. TMB was related to the invasiveness of tumor, while no such correlation were found in ctDNA. Improving the sensitivity of ctDNA detection, such as incorporated methylation or cancer-related antibodies detection, may be necessary in early stage patients.

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      P2.03-27 - Polymorphisms in Folate Metabolism Related Genes Affect the Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer

      16:45 - 18:00  |  Presenting Author(s): Sun ha Choi  |  Author(s):