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  • WCLC 2015

    16th World Conference on Lung Cancer

    Access to all presentations that occur during the 16th World Conference on Lung Cancer in Denver, Colorado

    Presentation Date(s):
    • September 6 - 9, 2015
    • Total Presentations: 2499

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    MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)

    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 14
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      MINI05.01 - A Progression Free Survival Score for EGFR Mutant Non-Small Cell Lung Cancer Patients Treat with First Line EGFR Tyrosine Kinase Inhibitors (ID 493)

      Y. Chen, M. Lin, W. Fang, C. Lie, H. Chang

      • Abstract
      • Presentation
      • Slides

      Background:
      As epidermal growth factor receptor (EGFR) mutation a strong predictor of EGFR tyrosine kinase inhibitor (TKI) responsiveness, there are still around 10% TKI-naïve patients early refractory to first line TKIs. We aimed to find clinical predictors of TKIs responsiveness in EGFR-mutant non-small cell lung cancer (NSCLC) patients and create a scoring system as progression free survival (PFS) prediction.

      Methods:
      This retrospective study evaluated 262 patients harboring EGFR mutation received TKIs as first line therapy for NSCLC between January 2011 and December 2013. Patients were assigned to test (N=131) and validation (N=131) by time sequence. Patients with age ≤ 40, uncommon EGFR mutation, poor performance status, more sites of distal metastasis, and lymphocyte to monocyte ratio ≤3 were independently associated with poor progression free survival. These five factors were included in the scoring system and 3 predictive groups were formed by total score. Table. 1 Univariate and Cox regression analysis of progression free survival

      Univariate analysis Multivariate analysis
      PFS (M) P value P value
      Age >40 ≤40 11.6 3.3 0.001 0.002
      BMI >24 ≤24 14.9 9.1 0.027 0.928
      Gender Male Female 9.3 12.0 0.292
      DM YES NO 9.1 11.5 0.500
      Smoking Never Former / current 11.5 7.6 0.413
      Performance status ECOG 0-2 ECOG 3-4 11.5 2.7 0.009 0.012
      Mutation Common Uncommon 11.5 4.1 <0.001 <0.001
      Tumor type Adenocarcinoma Non-adenocarcinoma 11.1 9.8 0.789
      No. of distal metastasis 0 1-2 >2 21.4 11.3 6.1 <0.001 <0.001 0.015 <0.001
      Malignant effusion Yes No 9.1 11.6 0.031 0.946
      Lymphocyte to monocyte ratio >3 ≤3 13.4 7.4 <0.001 0.047


      Results:
      Progression free survival in the test group were 15.7 months(m) for 0-1 points, 9.3 m for 2 points, 4.0 m for 3-6 points (p <0.001). In the validation test, Progression free survival in there predictive groups each were 13.7 m, 9.5 m, 4.8 m (p <0.001). Between the test and validation groups, no significant differences were found in each one of the three predictive groups. Figure 1



      Conclusion:
      The score appears valid and reproducible. It can stratify NSCLC patients harboring EGFR mutation using first line EGFR-TKIs into long, intermediate and short PFS groups.

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      MINI05.02 - Impact of ABCG2 Polymorphisms on the Clinical Outcome of TKIs Therapy in Chinese Advanced Non-Small-Cell Lung Cancer Patients (ID 591)

      X. Chen, D. Chen, S. Yang, Y. Pan, X. Li, S. Ma

      • Abstract
      • Presentation
      • Slides

      Background:
      ATP binding cassette superfamily G member 2 (ABCG2) has been demonstrated to be associated with the effect of chemotherapy/targeted therapy in non-small-cell lung cancer (NSCLC) and the single nucleotide polymorphisms (SNPs) of ABCG2 gene are supposed to affect the expression of ABCG2 protein. The purpose of this study was to investigate the correlation between SNPs of ABCG2 and outcome of tyrosine kinase inhibitions (TKIs) therapy in Chinese advanced NSCLC patients.

      Methods:
      SNP genotyping(34 G/A, 421 C/A, 1143 C/T and -15622 C/T)of ABCG2 gene in 100 patients was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The clinical characteristics of 100 patients were collected. A total of 70 patients were treated with TKIs(gefitinib, erlotinib and icotinib). The association between ABCG2 polymorphisms and clinical characteristics was evaluated. Kaplan-Meier survival curves were plotted for overall survival (OS) and analyzed with the log-rank test. Cox proportional hazards model was applied to evaluate the association between OS and clinical or genomic characteristics and estimated the adjusted HR and its 95 %CI.

      Results:
      The three polymorphisms of the ABCG2 34 G/A, 421 C/A and 1143 C/T occurred more frequently compared with -15622 C/T in Chinese advanced NSCLC patients. The allele A of 421C>A happened frequently in EGFR mutation positive patients (33.3% vs 9.1%, P=0.038). There was no association between ABCG2 polymorphisms and other clinical characteristics (p> 0.05).The median OS of patients with 34G>A mutant type (GA+AA) was 31.0 (95%CI: 22.9-39.1) months , which was significantly longer than those with wild type (GG) , 18.0 (95%CI: 14.9-21.1) months (p=0.005). No significant difference of OS was found in 421 C/A and 1143 C/T polymorphisms (p> 0.05).

      Conclusion:
      Our findings demonstrate a strong association between the ABCG2 34G>A polymorphism and the overall survival of NSCLC patients treated with TKI. It may be a possible predictor of the clinical outcome of TKIs therapy in NSCLC patients.

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      MINI05.03 - P53 Disruptive Mutation Is a Negative Predictive Factor in EGFR M+ NSCLC Treated with TKI (ID 903)

      A.C. Lueers, N. Neemann, R. Prenzel, D. Scriba, K. Wilborn, U. Stropiep, M. Falk, C. Hallas, M. Tiemann, F. Griesinger

      • Abstract
      • Presentation
      • Slides

      Background:
      p53 mutations are common in lung cancer, and have also been described in EGFR mutated patients. The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.

      Methods:
      267 patients from a single center diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing. P53 mutations were detected by Sanger Sequencing. Clinical characteristics including smoking status were available for all patients.

      Results:
      267 consecutive patients at the lung cancer center of the Pius-Hospital Oldenburg were studied. The overall EGFR mutation rate was 19% (51/267) in all patients, 80% (41/51) showing common mutations of exon 19 or 21. P53 disruptive mutation showed in 16% (8/51) and p53 nondisruptive mutation occurred in 11% (22/51) whereas p53 WT was found in 47% (24/51). In 8/51 (16%) patients p53 analysis was not successful. OS was 37 months in p53 disruptive mutation and p53 WT patients compared to 19 months in p53 nondisruptive mutation (p<0,05). PFS on 1st line TKI therapy was 18 months in p53 nondisruptive mutation and p53 WT patients and 6 months in p53 disruptive mutation (p<0,024). Similar results could be shown in the EGFR common mutation subgroup but not in the uncommon mutation subgroup.

      Conclusion:
      Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 mutation status. P53 mutational status is only predictive when disruptive and non-disruptive P53 mutations are differentiated. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.

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      MINI05.04 - Survival Outcome Assessed According to Tumor Burden & Progression Patterns in Patients with EGFR Mutant NSCLC Undergoing EGFR-TKIs (ID 886)

      Y.K. Cha, H.Y. Lee, M. Ahn, Y. Choi, J.H. Lee, K. Park, S. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs. Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs.

      Methods:
      A total of 224 patients with EGFR-mutant lung adenocarcinomas that were treated with EGFR-TKIs were retrospectively reviewed. Treatment outcomes were evaluated based on clinical factors, number of metastasis site and progression patterns.

      Results:
      The clinical factors associated with reduced progression-free survival (PFS) and overall survival (OS) by univariate analysis were ECOG performance status (PS) ≥ 2, intra- and extrathoracic metastasis, presence of extrathoracic metastasis, high number of metastasis sites, metastasis to liver or adrenal gland at baseline, and rapid progression of primary tumor at the time of progressive disease (PD). In multivariate analysis, factors that remained significantly associated with shorter PFS were ECOG PS ≥ 2 (Odds ratio [OR] 2.189 [95% CI, 1.374 – 3.437]; P < 0.001) and rapid progression of primary tumor at PD (OR 1.800 [95% CI, 1.059 – 3.058]; P = 0.030).

      Conclusion:
      Thus, tumor burden, expressed as the number of metastasis sites at the time of EGFR-TKI treatment, and rapid progression of primary tumor at PD are predictive of inferior survival in patients with lung adenocarcinoma with activating EGFR mutations.

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      MINI05.05 - Discussant for MINI05.01, MINI05.02, MINI05.03, MINI05.04 (ID 3531)

      F. Cappuzzo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI05.06 - A Phase Ib/II Study of Afainib plus Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib (ID 667)

      J.Y. Lee, S.H. Lim, H. Kim, K.H. Yoo, K.S. Jung, H. Song, M. Kwak, M. Han, J. Sun, S. Lee, J.S. Ahn, K. Park, M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background:
      Afatinib (A) is a potent irreversible EGFR TKI and nimotuzumab (N) is a humanized anti-EGFR mAb. In this phase Ib/II study, we aimed to assess the safety and activity of A plus N in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.

      Methods:
      Major inclusion criteria were advanced NSCLC with activating EGFR mutation or disease control for at least six months with previous gefitinib or erlotinib therapy. In the phase Ib study using classic 3+3 dose escalation method, patients were treated with A 40mg/d or 30mg/d in combination with N 100mg/w or 200mg/w. One cycle was composed of 4 weeks of treatment. In the phase II study, patients were treated with A plus N in the level of RP2D defined in the phase Ib study.

      Results:
      Overall, fifty pts were enrolled and treated: 13 in phase Ib and 37 in phase II. At the starting dose level (A 40mg/d + N 100mg/w), one out of 6 pts experienced end-of-cycle 1 DLT (G3 diarrhea), and the dose was up to the next level of A 40mg/d + N 200mg/w. Out of 6 pts at this level, 2 pts experienced DLTs (G3 diarrhea and G3 neutropenia, respectively), and RP2D was accordingly determined as A 40mg/d + N 100mg/w. In the whole treatment duration of the phase II, there was no treatment related death and 10 pts (20%) experienced any grade 3 adverse event, including diarrhea and skin rash. Out of evaluable 50 pts in the phase Ib/II study, the response rate was 36% (18 achieved partial response out of 50) and the median PFS was 4.4 months (95% CI:3.2-5.5 months).

      Conclusion:
      A and N showed an acceptable safety profile and promising antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.

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      MINI05.07 - Circulating Tumor Cells and Evaluation of Targeted Therapy Effect in EGFR Mutation/ALK Translocation Metastatic Non-Small Cell Lung Cancer (ID 1403)

      C. Su, X. Li, S. Ren, C. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Targeted therapies have considerably improved the prognosis of patients with non-small cell lung cancer (NSCLC).Although not precision enough, RESIST criteria was still the most often used response assessment method to reflecting the clinical benefits. We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values in EGFR mutation/ALK translocation advanced NSCLC.

      Methods:
      One hundred and thirty eight patients were enrolled in our study. Peripheral blood was analyzed for CTCs enumeration on negative enrichment by immunomagnetic beads. Changes of CTCs levels were correlated with radiological response. Sequential analyses were conducted to monitor CTC signals during therapy and correlate radiological effects with treatment outcome.

      Results:
      CTCs were detected (≥8.7CTC) in 84.8% of patients. Pretreatment and pro-treatment blood samples from all 118 EGFR-mutant (19deltion:56, L858R:57, G719x:3, L861Q:1, 19 deletion + L858R:1), 14 ALK translocation lung cancer patients and 6 EGFR wild type patients were collected. Of 89 eligible and evaluable patients, baseline CTC counts were not associated with response to treatment by RECIST (P=0.353). There is no difference between exon 19 deletion and L858R of baseline CTC values. (19deletion:19.4 CTCs, L858R:20.9 CTCs,P=0.222) The change of CTCs values increased correlation with radiological response (P=0.042) after treatment of targeted therapy. There is no significant difference between exon 19 deletion and L858R of CTCs values pre and pro EGFR-TKI treatment.(3.32 vs.12.1, P=0.783)

      Conclusion:
      This study confirms the predictive significance of CTCs in patients with EGFR mutation/ALK translocation NSCLC receiving targeted therapy. The change of CTCs value correlated significantly with radiological response. This strategy may enable non-invasive, specific biomarker assessment method for using CTC decreases as an early indication of response to targeted therapy and monitoring in patients undergoing targeted cancer therapies.

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      MINI05.08 - Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/L858R (ID 775)

      S.S. Ramalingam, K.J. O'Byrne, T. Mok, M. Boyer, P.A. Jänne, Z. Goldberg, C.B. Mather, I. Taylor, H. Zhang, L. Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background:
      To date there have been limited randomized comparisons of EGFR tyrosine kinase inhibitors (TKI) in EGFR mutant NSCLC. Dacomitinib is a potent, irreversible EGFR inhibitor that demonstrated robust activity in a phase 2 study for patients with common activating EGFR mutations. Additionally, preclinical data suggests greater activity in patients with common EGFR activating mutations in exon 19 or 21. ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) each compared the clinical activity of dacomitinib (D) versus erlotinib (E) in advanced NSCLC including patients with common activating EGFR mutations; pooled results are presented.

      Methods:
      Patients (pts) with locally advanced/metastatic NSCLC were randomized following progression with 1 or 2 prior chemotherapy regimens to treatment with dacomitinib (D) (45 mg PO QD) or erlotinib (E) (150 mg PO QD). The Phase 2 study (A7471028) was open label while the Phase 3 ARCHER 1009 study was double-blind and double dummy. Archived tumor tissue, ECOG performance status (PS) of 0-2, adequate organ function and informed consent were required. Results of the two studies were previously reported individually. Analyses were performed by pooling patients with common EGFR activating mutations from both studies to compare efficacy of D versus E.

      Results:
      121 patients with any EGFR mutation were enrolled into the two studies with 1 patient randomized but not treated; 101 (53 on D) pts had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median PFS was 14.6 months (95%CI 9.0–18.2) for D and 9.6 months (95%CI 7.4–12.7) for E and unstratified HR 0.717 (95%CI 0.458–1.124) with 1-sided p=0.073. The median OS was 26.6 months (95%CI 21.6–41.5) for D and 23.2 months (95%CI 16.0–31.8) for E and unstratified HR 0.737 (95%CI 0.431–1.259) with 1-sided p=0.132. The corresponding pooled analyses were conducted separately in exon 19 and exon 21. The adverse-event profile did not differ between the activating mutation subset and the overall population. Figure 1



      Conclusion:
      Dacomitinib may be associated with an improved PFS and OS compared to Erlotinib in patients with exon 19/21 EGFR mutations. A prospective P3 study comparing D to another EGFR TKI in 1L EGFR mutated NSCLC is ongoing to verify these observations (NCT01774721).

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      MINI05.09 - Discussant for MINI05.06, MINI05.07, MINI05.08 (ID 3323)

      R. Martins

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI05.10 - EGFR-TKI Alone or with Concomitant Radiotherapy for Brain Metastases in Lung Adenocarcinoma Patients with EGFR Gene Mutations (ID 1566)

      Y. Chen, J. Yang, X. Li, D. Hao, X. Wu, Y. Yang, X. Hu, C. He, W. Wang, J. Liu, J. Wang

      • Abstract
      • Presentation
      • Slides

      Background:
      Radiotherapy is the principal treatment modality for patients with brain metastases (BM), however, tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) shows therapeutic efficacy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. This study was conducted to compare the outcome of TKI alone with TKI plus concomitant radiotherapy in treatment of BM from EGFR-mutated lung adenocarcinoma patients.

      Methods:
      The inclusion criteria were as following: patients newly diagnosed with EGFR-mutant lung adenocarcinoma, presented with BM, TKI as first-line therapy, and ECOG PS 0-2.

      Results:
      From January 1, 2009 to September 1, 2014 at Zhengzhou University Affiliated Cancer Hospital, 516 lung adenocarcinoma patients with EGFR gene mutations were reviewed, and 132 cases (25.6%) with newly diagnosed BM were enrolled for the analysis. Among the 132 patients, more than half of them (n = 72; 54.5%) harbored a deletion in exon 19, 97 patients (73.5%) showed multiple intracranial lesions, and 50.8% (n = 67) had asymptomatic BM. 79 patients (59.8%) were treated with TKI alone, 53 with TKI plus concomitant radiotherapy (45 with whole brain radiotherapy, and 8 with stereotactic radiosurgery). The objective response rate of BM was significantly higher in TKI plus radiotherapy group (67.9%) compared with TKI alone group (27.8%, P<0.001). The median time to intracranial progression was 22.3 months. The median intracranial progression-free survival in patients who received TKI plus radiotherapy was 24.7 months, much longer than those treated with TKI alone which was 19.0 months, P = 0.005. Multivariate analysis showed brain radiotherapy (P = 0.012) and intracranial lesion number (P = 0.070) as important prognostic factors for intracranial progression-free survival. In addition, the data of overall survival will be presented at the conference.

      Conclusion:
      For EGFR-mutated lung adenocarcinoma patients with BM, TKI plus concomitant radiotherapy achieved higher response rate of BM and significant improvement in intracranial progression-free survival compared with TKI alone. Figure 1



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      MINI05.11 - Exon 19 Deletion Prolongs Survival in Brain Metastases from Non-Small Cell Lung Cancer (ID 417)

      H. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      Approximately 20-40% of non–small–cell lung cancer (NSCLC) patients develop brain metastasis (BM) and the survival is very poor with a median overall survival of 4-6 months following whole brain radiotherapy treatment. Recent studies have shown that oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were effective for the treatment of BM from NSCLC with EGFR mutation. However, the relationship between EGFR mutations and prognosis of NSCLC patients with BM remains to be determined. In this study, we investigated the impact of EGFR mutation status on the survival of BM patients from NSCLC

      Methods:
      730 NSCLC patients were retrospectively reviewed. 136 patients had developed BM during their course of disease. 33 of these 136 BM patients (24.3%) were confirmed to have exon 19 deletions, while 33 had exon 21 point mutation (L858R) (24.3%). Overall survival was evaluated by Kaplan-Meier method. Log-rank test and Cox proportional hazards model were used to analyze the impact of pretreatment and treatment variables on survival.

      Results:
      The median survival of NSCLC with BM was 8 months. Log-rank test analysis showed that ECOG PS at BM (p=0.000), control of primary tumor (p=0.005), pathology (p=0.01), EGFR mutations (p=0.045) and 19 exon deletion (p=0.007) were associated with a longer survival. In Cox proportional hazards model, EGFR exon 19 deletion (HR=0.558, 95%CI=0.325-0.957, p=0.034), control of primary tumor (HR=2.033, 95%CI=1.098-3.766, p=0.024), and ECOG PS at BM (HR=2.033,95%CI=1.145-1.287, p=0.006) were found to be independent prognostic factors. Moreover, there were significantly differences in the survival between different groups according to RTOG recursive partitioning analysis (RPA) classification system in this cohort of patients (p=0.000)

      Conclusion:
      Exon 19 deletion is an independent prognostic factor in BM from NSCLC. Our findings suggest that the status of exon 19 deletion may be integrated into the prognostic scoring classification system for NSCLC.

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      MINI05.12 - Erlotinib Combined with Chemotherapy versus Erlotinib Alone Treating Advanced Lung Adenocarcinoma with Brain Metastases (NCT01578668) (ID 620)

      H. Yang, Y. Zhang, M. Zhao, X. Xu

      • Abstract
      • Presentation
      • Slides

      Background:
      Erlotinib has a synergistic effect with pemetrexed when treating non-squamous non-small cell lung cancer. The aim of our study was to confirm the efficacy and safety of erlotinib (E) in combination with pemetrexed/cisplatin (E-P) in Chinese lung adenocarcinoma with brain metastases.

      Methods:
      This study is a prospecive, non-randomized cocurrent controlled study. Lung adenocarcinoma patients with brain metastases, who were erlotinib or pemetrexed treatment-naive and had adequate organ functions, were assigned in parallel to receive either erlotinib 150 mg/day or erlotinib on days 4-21 plus pemetrexed 500 mg/m[2] on day 1 and cisplatin 20 mg/m[2] on day 1-3 every 21 days up to 6 cycles and subsequent oral erlotinib, until progressive disease or unacceptable toxicity. The primary endpoint was intracranial overall response rate (ORRi). Previous data showed that about 56% of the patients treated with E and 78% of the patients treated with E-P, achieved an ORRi. We estimated the minimum sample size of 65 with 70% power (two-sided alpha 0.05).

      Results:
      69 lung adenocarcinoma patients with brain metastases had received E (n=35) or E-P (n=34) from Jan 2012 through Nov 2014. Demographics and patient characteristics were well balanced between two groups, including EGFR status, gender, age, smoking status, ECOG performance status, brain metastases and number of prior treatments. ORRi, in the E-P arm was superior to that in the E arm (79% vs. 48%, P=0.008) (Table S). Especially in the patients with EGFR wild type or treated as first-line treatment could achieve much better ORRi. Patients treated with E-P arm, compared with E arm as first-line treatment, were associated with better intracranial PFS (PFSi) (median PFSi, 9 months vs. 2 months, P=0.02) and systemic PFS (median PFS, 8 months vs. 2 months, P=0.006).The most frequent adverse events related with erlotinib were higher in the combination arm. No new safety signals were detected. The side effects were tolerable and no-drug related deaths. Table S The ORRi between the E-P and E arm

      group (n) ORRi (n,%)
      Total patients E (35) 17,48.6%
      E-P (34) 27, 79.4%
      P value 0.008
      EGFR mutation E (18) 10,55.6%
      E-P (14) 12,85.7%
      P value 0.124
      EGFR negative E (7) 1, 14.3%
      E-P (11) 7, 63.6%
      P value 0.066
      EGFR unknown E (10) 6,60.0%
      E-P (9) 8,88.9%
      P value 0.303
      First-line treatment E (16) 7,43.7%
      E-P (18) 14 ,77.7%
      P value 0.08


      Conclusion:
      The combination of erlotinib and pemetrexed/cisplatin is effective and improved PFS as first-line treatment in Chinese lung adenocarcinoma with brain metastases. Toxicities are tolerable and the erlotinib-related side-effects were higher.

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      MINI05.13 - Treatment of EGFR/ALK-Driven Non-Small Cell Lung Cancer (NSCLC) Brain Metastases: Impact of First-Line Whole Brain Radiotherapy on Outcome (ID 1251)

      M.K. Doherty, G. Korpanty, P. Tomasini, M. Alizadeh, K. Jao, C. Labbe, C. Mascaux, P. Martin, S. Kamel-Reid, M. Pintilie, G. Liu, P. Bradbury, R. Feld, N. Leighl, C. Chung, F. Shepherd

      • Abstract
      • Presentation
      • Slides

      Background:
      Brain metastases (mets) in EGFR/ALK-driven NSCLC are common, and frequently pose treatment dilemmas. Effective systemic therapy with tyrosine kinase inhibitors (TKIs) controls extracranial disease in up to 70% of patients, but often radiotherapy is required for intracranial control. As whole brain radiation (WBRT) may be associated with neurocognitive toxicity, we aimed to evaluate the impact of molecularly targeted therapy and stereotactic radiotherapy (SRS) for EGFR/ALK-driven NSCLC on intracranial disease control with and without WBRT.

      Methods:
      This retrospective analysis included patients treated with EGFR/ALK-positive NSCLC at Princess Margaret Cancer Centre from 1998-2015, with brain mets at lung cancer diagnosis or during treatment/follow-up. Demographic data were collected from electronic patient records. Time to intracranial progression (TTIP) and overall survival (OS) were calculated from date of diagnosis of brain mets, using the cumulative incidence function and Kaplan-Meier methods respectively; differences between groups were tested with Gray’s or log-rank test.

      Results:
      From 1998-2015, 162 patients with brain mets from EGFR/ALK-driven NSCLC were identified: 138 in the EGFR cohort, 23 in the ALK cohort and one included in both cohorts for analysis, whose tumour carries both an EGFR mutation and ALK rearrangement. Table 1 contains clinical characteristics and treatment details. In the EGFR cohort, initial brain mets treatment consisted of systemic therapy alone in 19 patients (17 TKI, 2 chemotherapy), SRS +/- surgery in 27 patients and WBRT +/- SRS/surgery in 88 patients. 1-year intracranial progression rates were 26%, 32% and 12%, respectively, and median TTIP was 18, 16 and 40 months [p=0.12]. Median OS was 26, 27 and 34 months respectively [p=0.49]. In the ALK cohort, initial brain mets treatment consisted of systemic therapy alone in 4 patients (1 TKI, 3 chemotherapy), SRS/surgery alone for 4 patients and WBRT +/- SRS/surgery for 15 patients. 1-year intracranial progression rates were 50%, 50% and 13%, respectively, and median TTIP was 18, 14 and 69 months [p=0.028]. Median OS was 35 months, not reached and 51 months, respectively [p=0.75]. Multivariable analysis for the whole group showed that age [p=0.021], number of brain mets [p=0.012] and extracranial control [p=0.008] were significantly associated with OS, but not WBRT [p=0.61].

      Conclusion:
      In this cohort of patients with brain mets from EGFR/ALK-driven NSCLC, patients treated with WBRT trended to longer TTIP. Although not statistically significant, our data also show a trend towards longer survival in patients who received WBRT. These observations require further validation in this patient population.

      EGFR (N=139) ALK (N=24)
      Median Age (Range) 59(29-86) 53(31-77)
      Female Sex 93(67%) 15(62%)
      Ethnicity Asian Caucasian Other 58(42%) 63(45%) 18(13%) 7(29%) 13(54%) 4(17%)
      Smoking Never Smoker Former/Current Smoker Unknown 108(77%) 30(22%) 1(1%) 19(79%) 5(21%) 0
      ECOG PS (Diagnosis) 0 1 2-4 66(48%) 67(48%) 6(4%) 7(29%) 14(58%) 3(13%)
      Brain Mets at Stage IV diagnosis 93(67%) 13(52%)
      Number of Brain Mets 1 2-4 5+ N/A 32(23%) 39(28%) 62(45%) 6(4%) 9(38%) 6(24%) 9(38%) 0
      Symptomatic Brain Mets No Yes 78(56%) 61(44%) 16(67%) 8(33%)
      Initial Brain Mets treatment WBRT WBRT+SRS/Surgery SRS+/-Surgery Systemic Therapy None 71(51%) 17(12%) 27(19%) 19(14%) 5(4%) 13(54%) 3(12%) 4(17%) 4(17%) 0


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      MINI05.14 - Discussant for MINI05.10, MINI05.11, MINI05.12, MINI05.13 (ID 3324)

      B.J. Solomon

      • Abstract
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      Abstract not provided

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    MINI 06 - Quality/Prognosis/Survival (ID 111)

    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 15
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      MINI06.01 - Prognostic Impact of Visceral Pleural Invasion and Its Degrees in Non-Small Cell Lung Cancer: A SEER Database Analysis (ID 2256)

      L. Zhao, J. Zha, F. Zhou, K. Fei, C. Chen

      • Abstract
      • Presentation
      • Slides

      Background:
      Visceral pleural invasion (VPI) is reported to be associated with poor prognosis in non-small cell lung cancer (NSCLC). However, whether a tumor size larger than 3cm with VPI should be upgraded to the next T stage remains unclear. In addition, few studies have clarified the impact of VPI according to nodal status, and whether degree of VPI (PL1, PL2) affects survival is controversial. The objective of this study was to evaluate the influence of VPI and also develop a prognostic nomogram.

      Methods:
      We retrospectively reviewed the SEER database from 2004 to 2011. Inclusion criteria were defined as: first and only primary NSCLC treated with lobectomy; staging as T1-3N0-2M0, no other non-size-based T factors except VPI. Tumors were divided into 10 groups: A, 0-2cm, non-VPI; B, 0-2cm, VPI; C, 2-3cm, non-VPI; D, 2-3cm, VPI; E, 3–5cm, non-VPI; F, 3–5cm, VPI; G, 5–7cm, non-VPI; H, 5–7cm, VPI; I, >7cm, non-VPI; J, >7cm, VPI. Kaplan-Meier overall survival (OS) curves were compared using the log-rank test. A Cox proportional hazard model was used, and identified independent prognostic factors were entered into the nomogram.

      Results:
      A total of 26,315 patients were finally identified, 5,941 patients (22.6%) had VPI. VPI showed an adverse impact in all tumor size groups in N0 status (p<0.001). Cox regression showed that VPI is an independent risk factor (HR 1.25; 95%CI 1.19-1.31). In N0 status, the survival rates were significantly different between B with C and D with E groups (p<0.001), whereas not significantly between F with G (p=0.405) and H with I (p=0.506). In N1 and N2 status, only the A and B groups showed a distinct survival impact (p=0.001). Between 2010 and 2011, 5,632 patients performed the elastic stain for differentiating the degrees of VPI, and survival was not significantly different between PL1 and PL2 (p=0.568). The C-index of the nomogram was 0.68. The calibration curves showed optimal agreement between nomogram prediction and actual observation of OS.Figure 1



      Conclusion:
      The presence of VPI, rather than the extent (PL1, PL2) has an adverse impact on NSCLC patients and N0 status. In a future TNM staging system, VPI should lead to upstaging to the next T category in current 3-7cm tumors. VPI is more aggressive in early-stage tumors, while its prognostic impact in node positive and locally invasive tumors is less significant. We further established and validated a nomogram to provide individual prediction of OS. The nomogram could be helpful for clinicians in decision making.

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      MINI06.02 - T1a Lung Adenocarcinomas: Presence of Spread of Tumor through Alveolar Spaces (STAS), Micropapillary and Solid Patterns Determines Outcomes (ID 3068)

      T. Eguchi, K. Kadota, N.P. Rizk, K.M. Woo, C.S. Sima, B.J. Park, D.R. Jones, W.D. Travis, P.S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background:
      Our previous reports highlighting the significance of presence of micropapillary (MIP) (JNCI 2013), STAS- spread of tumor through alveolar spaces (JTO 2015), and predominant solid (SOL) (Modern Pathol 2011) histological subtype as poor prognostic markers in stage I lung adenocarcinomas (ADC) are reproduced by others. In this study, we hypothesized that presence of STAS, MIP or SOL patterns (≥5%) in small stage I lung ADC (≤2 cm) is a marker of invasion and poor prognosis, and can influence the recurrence patterns based on the type of surgical resection – lobectomy (LO) versus limited resection (LR).

      Methods:
      All available tumor slides from patients with therapy-naive, surgically resected small (≤ 2cm), solitary stage I lung ADC were reviewed (1995-2011; n = 909). STAS was defined as isolated tumor cells within alveolar spaces separate from the main tumor. MIP and SOL patterns were considered present in the tumor when it comprised ≥5% of the overall tumor. Cumulative incidence of recurrence (CIR; any types, locoregional or distant) was estimated using a cumulative incidence function. Differences in CIR between groups were assessed using Gray’s method.

      Results:
      Figure 1 The association of outcomes with the presence of STAS, MIP, or SOL patterns is shown in the table. The risk of developing any types of recurrence was significantly higher in patients with both STAS and MIP positive tumors than others (P < 0.001); and the risk of developing any types of recurrence was significantly lower in patients with both STAS and SOL negative tumors than others (P < 0.001). In the LR group, STAS, MIP and SOL patterns were independent prognostic factors for any types of recurrence (HR: 4.5, 1.4, and 1.3, respectively), locoregional recurrence (HR: 5.2, 1.3, and 1.3, respectively), and distant recurrence (HR: 3.1, 1.4, and 1.2, respectively).



      Conclusion:
      Tumor STAS, presence of MIP and SOL patterns are independent risk factors of recurrence especially in the LR group of small stage I lung ADC patients. Importantly, of these factors, tumor STAS was the strongest predictor of locoregional recurrence in this group. These results suggest that the identification of STAS in small lung ADC may identify LR patients who need further management, one of which may be completion lobectomy.

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      MINI06.03 - Improved Survival in Patients with Stage I-II NSCLC Treated with Surgery or Radiotherapy in the Department of Veterans Affairs (ID 1276)

      J.K. Salama, C.D. Williams, D. Moghanaki, M.J. Kelley

      • Abstract
      • Presentation
      • Slides

      Background:
      Recent advancements in surgical and radiotherapy techniques for early stage NSCLC have demonstrated improved outcomes in clinical trials and case series. However, their impact on large populations remains poorly studied. We therefore analyzed Department of Veterans Affairs (VA) data to evaluate temporal trends in survival within a large integrated healthcare system during the decade these techniques were introduced.

      Methods:
      Using VA Central Cancer Registry and vital status data, patients diagnosed with stage I-II NSCLC between 1/1/2001-12/31/2010 were identified. Patient characteristics assessed included age, race, stage, histology, Charlson comorbidity index, specific comorbid conditions, and smoking status. Descriptive and chi-square statistics were used to compare patient characteristics and outcomes.

      Results:
      18,442 patients were identified with stage I-II NSCLC. The primary modality of treatment was surgery in 10,754 (58%), radiotherapy in 3,708 (20%), and another or no therapy in 3,980 (22%). Patients treated with surgery were younger (median age 66 vs 72%, p<0.0001), were more likely to have a comorbidity index of 0 (28% vs 18%, p<0.0001), and were less likely to have COPD (41% vs 58%, p<0.0001), diabetes (22% vs 25%, p=0.0026), peripheral vascular disease (16% vs 20%,P<0.0001), and coronary vascular disease (9 vs 12%,p<0.0001). Surgery patients were more likely to be current (52% vs 45%, p<0.0001) and less likely to be former (39% vs 45%,p<0.0001) smokers. Equal percentages of surgery and radiation patients were black (14% vs 15%) and white (86% vs 85%). Compared to radiotherapy, surgery patients were more likely to have earlier stage disease (stage I: 79% vs 70%, p<0.0001), and adenocarcinoma (45% vs 22%, p<0.0001). The number of stage I-II NSCLC patients treated with radiotherapy or surgery increased by 50% (667 to 1,001) and 35% (1,845 to 2,496), respectively. The percentage treated each year with surgery increased from 56% in 2001 to a peak of 61% in 2004-2005, decreasing back to 56% in 2010. Inversely, the percentage treated each year with radiation decreased from 21% in 2001, to 17% in 2005 and increased to 24% in 2010. The use of other/no therapy remained unchanged. The Southern region comprised almost half of all treated lung cancer diagnoses (46%), followed by the Midwest (21%), the West (17%), and the Northeastern Region (14%). Between 2001-2010, the number of patients receiving therapy (radiation or surgery) increased each year (p=0.0017). The 4-year survival rate was 54% for surgery patients and 19% for radiotherapy patients (p<0.0001), which varied based on stage (stage I: 58% vs 22%; stage II: 41% vs 13%, respectively). Between 2001-2010, patients treated with either surgery or radiotherapy had a 12% absolute improvement in 4 year OS, representing a 100% survival improvement with radiotherapy (12% to 24%) and a 24% improvement with surgery (49% to 61%).

      Conclusion:
      The Department of Veterans Affairs is treating increasing numbers of patients with stage I-II NSCLC. Following a decade when advanced technologies were introduced for surgery and radiotherapy, survival rates have improved significantly for both treatment modalities. The largest gains were observed among patients treated with radiotherapy with a doubling of 4-year survival.

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      MINI06.04 - Impact of Attainment of the American College of Surgeons Commission on Cancer Quality Measure on Patient Survival After Lung Cancer Resection (ID 2177)

      X. Yu, N. Faris, R. Eke, M.P. Smeltzer, G. Relyea, F.E. Rugless, C. Fehnel, N. Chakraborty, C. Houston-Harris, F. Lu, E.T. Robbins, R.S. Signore, L. McHugh, B. Wolf, C. Mutrie, L. Deese, P. Levy, E. Crocker, L. Wiggins, R.U. Osarogiagbon

      • Abstract
      • Presentation
      • Slides

      Background:
      Institution-driven survival disparities persist among non-small cell lung cancer (NSCLC) patients who receive curative-intent surgical resection. Recently, the Commission on Cancer (CoC) established an institutional quality surveillance measure: the proportion of resected stage IA–IIB NSCLC with examination of ≥10 lymph nodes. We examined the potential impact of this measure on long-term patient survival.

      Methods:
      We analyzed all stage IA-IIB NSCLC resections in the Mid-South Quality of Surgical Resection cohort, a patient-level database of all lung cancer resections performed in 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, Northern Mississippi, and Western Tennessee from 2004-2013. We recorded pathologic staging details. Patients receiving pre-operative therapy were excluded. A trend analysis of quality and survival disparities was performed based on a Cox proportional hazard model, adjusted for age and pathologic stage.

      Results:
      Of 1,877 eligible patients, 77% were stage I and 23% stage II. The median number of lymph nodes retrieved during surgery was 6 (interquartile range [IQR]: 3-10). The CoC quality measure was achieved in 27.8% of cases. Conversely, 11% of resections had no lymph nodes examined (pNX). The proportion of cases meeting the CoC criteria increased from 18.8% in 2004 to 50% in 2013 (p<0.001). Large variations among institutions existed, ranging from 14% to 55% of institutional cases meeting the CoC measure. Compared to pNX resections, resections with at least one lymph node examined yielded some survival benefit (Hazard ratio (HR): 0.71, 95%CI: 0.54-0.93, p=0.014). Likewise, Patients with 10-12 lymph nodes examined had 43% overall survival benefit (HR: 0.57, 95%CI: 0.40-0.81, p=0.002), but survival did not significantly improve compared with 4-6 (the median) lymph nodes harvested (p=0.48). However, the survival benefit improved as more lymph nodes were examined, reaching an optimal point of a 72% benefit when 19-21 lymph nodes were harvested (HR: 0.28, 95%CI: 0.11-0.68, p=0.005). Compared with 4-6 lymph nodes, the survival benefit was 17% (p=0.06) (Figure 1). Furthermore, for those with any mediastinal lymph nodes sampled during the surgery, the survival benefit was 17% (HR: 0.82, 95%CI: 0.71-0.96, p=0.015). Figure 1



      Conclusion:
      Only 28% of NSCLC resections achieved the CoC measure, with large variations among institutions, but the overall rate of attainment has increased over time. Compared with no lymph nodes examined, meeting the CoC criteria provided a 43% overall survival benefit. However, more stringent measures, such as examining 20 lymph nodes (72%) or requiring mediastinal lymph node examination (17%), will have even greater survival impact.

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      MINI06.05 - Discussant for MINI06.01, MINI06.02, MINI06.03, MINI06.04 (ID 3398)

      D. Harpole

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      Abstract not provided

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      MINI06.06 - Early-Stage Lung Cancer Treatment and Survival: Impact of Race (ID 727)

      C.D. Williams, M.J. Kelley

      • Abstract
      • Presentation
      • Slides

      Background:
      Lower rates of surgical resection for early-stage lung cancer among blacks compared to whites are well-documented and have persisted for decades. It is suggested that the survival disparity is largely due to lower rates of surgery among blacks and that equivalent outcomes are possible for blacks and whites with similar treatment. The objectives of this work were to utilize a decade of data to evaluate trends in receipt of treatment among blacks and whites and examine the impact of race on survival outcomes.

      Methods:
      We used data from a national cohort of patients in the Veterans Administration diagnosed with Stage I-II non-small cell lung cancer (NSCLC) between 2001 and 2010. Chi-square statistics were used to compare treatment and outcomes by race. Cox proportional hazards models estimated hazard ratios (HR) with 95% confidence intervals (95%CI).

      Results:
      Among 18,442 patients with stage I-II NSCLC, the proportion of blacks and whites receiving surgery was 54% and 59% (p ≤ 0.0001), respectively. The black-white difference in surgery rates was 8% in 2001 and 1% in 2010. There was no racial difference in receipt of nonsurgical therapy; however, blacks were more likely than whites to have no treatment (22% vs. 18%, p ≤ 0.0001). Among surgical patients, type of surgical resection was similar by race, the 30-day mortality rate was 2% in both race groups, but 90-day mortality was significantly higher in whites than blacks (6% vs. 3%, p=0.0008). Also, 31% of blacks were diagnosed at the time of surgery compared to 27% of whites (p<0.0001). There was no racial difference in type of nonsurgical treatment, with 86% of all patients who did not have surgery receiving radiation therapy. Among all patients, the 4-year survival rate was 40% in blacks and 39% in whites (p=0.38), and the adjusted HR for blacks compared to whites was 0.91 (95%CI 0.84-0.98) among all patients. Corresponding HRs and 95% CI among patients receiving surgical treatment, nonsurgical treatment, or no treatment were 0.90 (0.83-0.97), 0.83 (0.76-0.91), and 0.91 (0.82-0.996), respectively.

      Conclusion:
      The racial disparity in receipt of surgery for early-stage lung cancer decreased between 2001 and 2010, with similar rates observed at the end of the study period. Previously reported racial differences in survival outcomes were not observed in this cohort. Despite overall lower surgery rates among blacks, the proportion of black and white patients surviving 4 years was similar although overall survival was slightly better among blacks, and this finding was consistent among patients with and without treatment.

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      MINI06.07 - High Incidence of PD-L1 Expression in Surgically Resected Pulmonary Lymphoepithelioma-Like Carcinoma Is Linked to Prognosis (ID 1495)

      Y. Yang, S. Hong, W. Fang, H. Zhao, Y. Huang, X. Wang, L. Zhang

      • Abstract
      • Presentation
      • Slides

      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. The prognostic significance of programmed cell death ligand 1 (PD-L1) in pulmonary LELC remains poorly understood.

      Methods:
      A total of 113 surgically resected pulmonary LELC in Sun Yat-sen University Cancer Center between January 2008 and December 2012 were included. Paraffin-embedded tumor sections were stained with PD-L1 antibody. H score were calculated by multiplying the percentage of positively stained cells by an intensity score. Tumors with >5% PD-L1 expression were deemed PD-L1 positive. The mRNA level of latent membrane protein 1 (LMP1) were determined by RT-PCR. Univariate and multivariate analyses were performed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS).

      Results:
      The positive rate of PD-L1 was 74.3%. Patients with PD-L1 (+) tumor were significantly younger than those with PD-L1 (-) (median age, 50 vs 58 years; p = 0.008). High PD-L1 expression (H-score > 30) was associated with impaired DFS (median: 33.8 months vs not reached; p = 0.008) compared with low PD-L1 expression (Figure 1). Multivariate analysis shows that PD-L1 expression level (p = 0.014), N stage (p = 0.039) and M stage (p= 0.024) were independent prognostic factors for DFS. N stage and M stage but not PD-L1 expression level were significantly associated with OS (Figure 2). Also, LMP1 mRNA level was significantly associated with PD-L1 expression level (p < 0.001).Figure 1Figure 2





      Conclusion:
      Our results reveal higher incidence of PD-L1 expression in pulmonary LELC than common lung cancer, which may be linked to EBV burden. PD-L1 was a negative prognostic factor for DFS but was not associated with OS in surgically resected pulmonary LELC. These findings may provide a rationale for immunotarget therapy in this virus-associated lung cancer.

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      MINI06.08 - Recognition Of 'Aggressive' Nodal Metastatic Behavior In 'Indolent' Ground Glass Opacity Lesions (ID 2345)

      J. Zha, L. Zhao, D. Xie, K. Fei, C. Chen

      • Abstract
      • Presentation
      • Slides

      Background:
      Radiologically characteristic ground-glass opacity (GGO) represents a special cohort of pulmonary adenocarcinomas that has been unanimously defined as biologically inert. Lymph node metastasis, however, occurs occasionally in these biologically "indolent" cancers. The incidence and underlying risk factors of nodal metastasis remain unknown.

      Methods:
      All surgically removed GGO lesions between Jan. 2008 and Dec. 2014 were reviewed from a single treatment institution. Pathologically-confirmed adenocarcinomas with systemic lymph node dissection or sampling were enrolled into the present study. All the lesions were classified into three groups according to the proportion of solid densities: Group I, pure GGO; Group II, 1% to 50%; and Group III, 50% to 100%. Risk factors analysis of lymph node involvement was performed by multivariate logistic regression.

      Results:
      Of the 867 patients eligible for this study, there were 566 (65.3%) females and 301 (34.7 %) males. 553 (63.7%) presented as pure GGOs (Group I) and 314 (36.2%) were mixed GGOs, of which 160 (18.5%) were in Group II and 154 (17.8%) group III. Lymph node metastasis was confirmed in 25 patients, including 12 pN1 and 13 pN2 cases. Among these 25 cases, 11 were Group II and 14 were Group III; 13 (13/367) had1-2cm tumors and 12 (12/136) had 2-3cm tumors, which also showed a significant statistical difference (p=0.016). Two of the 25 patients were deceased from lung cancer metastases at postoperative 23rd and 36thmonths, respectively. Statistical analysis revealed three predictors for lymph nodal metastasis: tumor size, preoperative serum carcinoembryonic antigen level, and proportion of the mix density. The ROC curves show cutoff values at 1.1cm, 2.75ng/ml and 21%, respectively.Figure 1

      Table1. Independent predictors of lymph node involvement by multivariate analysis
      Variables Odds Ratio 95%CI P
      Tumor size 2.544 1.271-5.092 0.008
      GGO status(Ratio) 3.272 1.759-6.089 <0.001
      CEA level 9.672 3.805-24.584 <0.001




      Conclusion:
      Among the majority of "indolent" GGO lesions, lymph node metastasis occurs occasionally at 2.9%. A larger size, mixed GGOs with a higher proportion of solid component, and elevated serum CEA level were associated with a higher preference for nodal metastasis.

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      MINI06.09 - Aerogeneous Spread Is a Predictive Factor of Recurrence in Stage I Lung Adenocarcinoma (ID 248)

      S. Shiono, N. Yanagawa

      • Abstract
      • Presentation
      • Slides

      Background:
      Previously, aerogeneous spread with floating cancer cell clusters (ASFC) was a prognostic factor and significantly related with local recurrence of the surgical margin after metastatic lung tumor (Shiono, Ann Thorac Surg 2005). However, ASFC in surgically resected lung cancer has not been investigated well. Since our institute examined ASFC in resected lung cancer specimens prospectively, we assessed the prognostic impact of ASFC and local recurrence in stage I lung adenocarcinoma cases.

      Methods:
      From July 2004 to November 2014, a total of 877 lung cancer patients underwent a surgery. Among them, 318 patients with pathological stage I adenocarcinoma cases were reviewed. We investigated the characteristics of ASFC and analyzed the relationship between ASFC and prognosis. The patients who received preoperative treatment or had multiple lung cancers were excluded.

      Results:
      Median follow-up time was 28 months. Of the 318 patients, 47 (14.8%) patients had ASFC. The local recurrence rate was 11 of 47 (23.4%) cases with ASFC and 10 of 271 (3.7%) cases without (p < 0.01). All 4 cases developing surgical stump recurrence had an ASFC. In patients with ASFC, the ratio of male, smoker, EGFR mutation negative, lymphovascular and pleural invasion were significantly high (p < 0.01). Standardized uptake value (SUV) (p < 0.01) was also significantly higher in ASFC positive cases. Surgical procedure did not influence development of ASFC. Multivariate analysis revealed that the ASFC were significantly related with EGFR negative mutation and lymphovascular invasion. As preoperative predictive factors for ASFC, SUV was a significant predictive factor (p = 0.01). Univariate analysis showed that overall 5-year survival of cases with ASFC was 62.7% and without was 91.1% (p < 0.01) and recurrence free 5-year survival of cases with ASFC was 54.4% and without 87.8% (p < 0.01). Multivariate analysis showed that age, pleural invasion and ASFC were significant prognostic factors for overall survival, and that these factors were significantly related to cancer recurrence after surgery.Figure 1



      Conclusion:
      In p-stage-I lung adenocarcinoma patients, ASFC was frequently found in invasive lung adenocarcinoma cases. Therefore, characteristics of these lung cancers may develop a poor prognosis. PET scan might have effective radiological examinations to find a lung adenocarcinoma with ASFC.

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      MINI06.10 - Discussant for MINI06.06, MINI06.07, MINI06.08, MINI06.09 (ID 3545)

      O.T. Brustugun

      • Abstract
      • Presentation
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      Abstract not provided

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      MINI06.11 - The Influence of Body Mass Index on Overall Survival following Surgical Resection of Non-Small Cell Lung Cancer (ID 2722)

      K.A. Gold, B. Sepesi, A.M. Correa, X. Liu, J.V. Heymach, A.A. Vaporciyan, E. Dmitrovsky

      • Abstract
      • Presentation
      • Slides

      Background:
      Population studies suggest that high body mass index (BMI) correlates with a reduced risk of death from lung cancer. The aim of our study was to evaluate the influence of BMI on long term overall survival (OS) in surgical patients with non-small cell lung cancer (NSCLC).

      Methods:
      Study population consisted of 1935 patients who underwent surgical resection for lung cancer at MD Anderson Cancer Center between 2000-2014. Patients with perioperative mortality, 90-day mortality, intraoperative transfusion, postoperative ICU days, postoperative pneumonia, and postoperative transfusion were excluded. Study variables included both patient and treatment related characteristics. Univariable and multivariable Cox regression analyses were performed to identify variables associated with overall survival. Propensity matching was performed to compare patients with BMI <25 and BMI≥30 matching on type of surgery, age, gender, histology, and pathological stage.

      Results:
      On univariable analysis, significant predictors of improved survival were higher BMI, pathologic tumor stage (stage I vs II, III, or IV), type of surgery (lobectomy/pneumonectomy vs wedge resection/segmentectomy), younger age, female gender, and adenocarcinoma histology (vs squamous) (all p<0.05). Patients considered morbidly obese (BMI≥35) had a trend towards better outcomes than those classified as obese (BMI ≥30 and <35), overweight (BMI ≥25 and <30), or healthy weight (BMI<25) (HR 0.727, 0.848, 0.926, and 1, respectively, p=NS). On multivariate analysis, BMI remained an independent predictor of survival (p=0.02, see Table). Propensity matching analysis demonstrated significantly better OS (p=0.008) in patients with BMI≥30 compared to BMI <25 (Figure).

      Multivariate Cox Regression Model
      N (%) Overall Survival HR (95% CI)
      BMI <25 (Reference) ≥25 646 (33.4%) 1289 (66.7%) 1.000 0.833(0.713-0.975)
      Age Continuous variable Median 66 (13-88) 1.024 (1.015-1.032)
      Gender Female (Reference) Male 984 (50.9%) 951 (49.1%) 1.000 1.236 (1.061-1.441)
      Stage I (Reference) II III IV 1149 (59.4%) 431 (22.3%) 299 (15.5%) 56 (2.9%) 1.000 1.839 (1.570-2.271) 2.653 (2.182-3.225) 2.737 (1.934-3.873)
      Surgery Wedge/Segmentectomy (Reference) Lobectomy/Pneumonectomy 198 (10.2%) 1737 (89.8%) 1.000 0.602 (0.479-0.755)
      Pre-op therapy No (Reference) Yes 1604 (82.9%) 331 (17.2%) 1.000 1.399 (1.160-1.686)
      Histology Adenocarcinoma (Reference) Squamous Other 1252 (64.7%) 472 (24.4%) 211 (10.9%) 1.000 1.225 (1.035-1.451) 0.959 (0.747-1.231)
      Figure 1



      Conclusion:
      In a large, single center series, after controlling for disease stage and other variables, higher BMI was associated with improved OS following surgical resection of NSCLC. Further studies are necessary to define the complex relationship between BMI and treatment outcomes.

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      MINI06.12 - Prognostic Impact of Cancer-involved Lymph Node Ratio in Resected NSCLC Differ between 'N1' or 'N2' Disease (ID 3209)

      W. Liang, J. He

      • Abstract
      • Slides

      Background:
      The extent of lymph nodes (LN) involvement and the adequacy of systematic LN sampling are significantly correlated with the prognosis of cancer patients. The index combing these two factors, cancer-involved LN ratio (LNR), has been proved a strong prognostic factor by extensive previous studies, including non-small cell lung cancer (NSCLC). However, intrapulmonary or mediastinal LNs associate with different examination strategy. It might not be appropriate to apply the LNR indistinguishably to all patients. Therefore, we sought to examine the performance of LNR separately.

      Methods:
      A consecutive cohort of patients who underwent radical resection with systematic lymph node sampling for NSCLC between Sep 2009 and Dec 2011 were collected. LNR for intrapulmonary and hilar LNs was recorded as LNR1, and LNR for mediastinal LNs was recorded as LNR2. LNR was incorporated in the Cox regression model as a continuous variable. Disease free survival (DFS) was the primary endpoint.

      Results:
      A total of 681 cases were included for analysis. Overall LNR was a significant prognostic factor in overall population (HR 11.75, 95% CI 6.99 to 19.75; P<0.001). For patients with ‘N2’ disease, overall LNR remained a prognostic factor (HR 3.07, 95% CI 1.22 to 7.74; P=0.02). However, further explorations revealed that LNR2 has prognostic impact (HR 3.59, 95% CI 1.68 to 7.67; P<0.01) but not LNR1 (HR 0.99, 95% CI 0.48 to 2.06; P= 0.99). For those with ‘N1’ disease, LNR1 was not a significant prognostic factor (HR 3.19, 95% CI 0.87 to 11.66; P=0.08) but the prognostic value of overall LNR is strong (HR 36.17, 95% CI 6.23 to 210.13; P<0.01).

      Conclusion:
      This study suggests that for pathological ‘N1’ NSCLC, overall LNR should be considered a prognostic value while for ‘N2’ disease, only medialstinal LNR should be included in prognostic stratification.

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      MINI06.13 - Multiple Lung Cancers: Is Their Survival Better or Worse Then Other Lung Cancers? (ID 3058)

      J. Naidoo, K. Woo, C.S. Sima, W.D. Travis, M. Arcila, D.J. Finley, V. Rusch, D.R. Jones, M.G. Kris, M.G. Zauderer

      • Abstract
      • Presentation
      • Slides

      Background:
      Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The prognosis of MLCs is not known. Herein, we evaluate the prognosis of patients with MLCs, one resected LC, and recurrent LC, to ascertain whether patients with MLCs have a distinct natural history compared to the other two groups.

      Methods:
      After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria and comprehensive pathologic assessment. Clinicopathologic data was collected. We used the Kaplan-Meier method and log-rank test to assess overall survival (OS) of patients with MLCs, one LC, or recurrent LC, from the time of surgery/pathologic confirmation of their MLC, one LC, or recurrent LC, respectively.

      Results:
      2352 patients were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113).Median OS and 2-year OS for patients in these subgroups stratified by stage, is depicted in Table 1. In patients with one LC, never smokers (p<0.001), adenocarcinoma histology (p<0.001), and surgery type (p<0.001) were associated with improved OS. In patients with recurrent LC, never smokers (p=0.015), and adenocarcinoma histology (p=0.009) were associated with favorable OS, compared to smokers and squamous histology respectively. In patients with MLCs, adenocarcinoma histology was associated with improved OS when compared to squamous histology (p=0.049).

      Pathologic Stage (n) Median Overall Survival (months, 95% CI) Two-Year Overall Survival p value
      One Lung Cancer (n=2238) All Not Reached (75.2-NA) 0<0.001
      IA 0.914
      IB 0.841
      IIA 0.789
      IIB 0.755
      IIIA 0.691
      Multiple Lung Cancers(n=113) All 55.5 (49.4-NA) 0.32
      IA 0.810
      IB 0.806
      II/III 0.830
      Recurrent Lung Cancer (n=348) All 10.4 (9.1-12.3) 0.077
      IA 0.263
      IB 0.180
      IIA 0.273
      IIB 0.351
      IIA 0.083


      Conclusion:
      Martini-Melamed criteria and comprehensive pathologic assessments successfully identify patients with MLCs. Prognostic data for patients with MLCs, one LC and recurrent LC, highlight that these patients have a long natural history. MLCs have a long survival stage for stage, which underscores a definitive therapeutic approach where possible, based on favorable prognosis of these patients.

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      MINI06.14 - The Impact of Serum EGFR Levels on Survival of Resected Patients with Non-Small Cell Lung Cancer (ID 3237)

      E. Hekimoglu, Y. Oltulu, I. Yaylım, K. Kaynak, A. Turna

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is an important cause of cancer mortality. Mutations of the EGFR gene may cause deranged activation leading to cell proliferation and the inhibition of apoptosis and metastases. Screening for EGFR mutation plays a key role for managements of lung cancer cases. The aim of our study is to determine a possible relationship between EGFR gene mutations in exon 19,20,21, along with serum EGFR levels and non small cell lung cancer.

      Methods:
      A total of 35 patients; 29 (%82.9) male and 6 (%17.1) female with non small cell lung cancer who underwent surgical resection between February 2011 and July 2013 were analyzed.Mean age of the patients was 60.1(41-79) Mediastinoscopy was performed to all patients prior to the resection. Lobectomy, pneumonectomy and bilobectomy were performed to 30(%85.7), 4(%11.4) and 1 (%2.9) patients respectively. The most common tumour histopathology was adenocarcinoma(%55.6). EGFR gene mutations were analyzed for exon 19,20 and 21 by direct sequencing. In addition, serum EGFR levels were determined by ELISA in non small cell lung cancer patients and control group

      Results:
      Exon 19,20 and 21 aminoacid substitutions that could cause significant mutations were detected.At exon 19,20 and 21, totally 17 mutations were detected in 10 different regions.One of these mutations were (2237-MT) E746- T751>V, E746-T751VA, E746-S752>V on exon 19. In one sample 5 different regions of exon 20 mutations were detected. On exon 21 two mutations that cause aminoacid changes were detected which includes Leu 861 Gln ve Leu 861 Arg. In our study there was no significant difference in survival rates between the cases who have EGFR mutations or who have not(p=0.21). Serum EGFR average levels of non small cell lung cancer patients and healthy control groups were calculated respectively as, 341,49±125,41 pg/ml ve 574,9±125,96 pg/ml and the difference was found statistically significant (p<0,001). According to the EGFR levels survival rate at 3 years was %45 and mean survival time is 19 (%95 confidence interval :14-29 months)and 23 (%95 confidence interval 18-29 months)month in patients with serum EGFR levels higher and lower than 400 pg/ml respectively. The patients with high serum EGFR levels (>400 pg/ml) have better survival time than the ones who had low serum EGFR levels (p=0.04).

      Conclusion:
      EGFR mutation did not lead to survival difference in resected patients with lung adenocarcinoma.. However, survival of patients with higher serum EGFR levels seems better. The modus operandi of this effect and validation of the data need further studies.

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      MINI06.15 - Discussant for MINI06.11, MINI06.12, MINI06.13, MINI06.14 (ID 3471)

      G. Wright

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      Abstract not provided

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    MINI 07 - ChemoRT and Translational Science (ID 110)

    • Type: Mini Oral
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 15
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      MINI07.01 - A Randomized Phase II Study of S-1 and Cisplatin vs Vinorelbine and Cisplatin with Concurrent Radiotherapy for Locally Advanced NSCLC: WJOG5008L (ID 544)

      J. Shimizu, T. Kodaira, T. Seto, T. Sasaki, T. Yamanaka, N. Kunitake, F. Ohyanagi, T. Kozuka, M. Takeda, K. Nakamatsu, T. Takahashi, H. Harada, N. Yoshimura, S. Tsutsumi, H. Kitajima, M. Kataoka, K. Nakagawa, Y. Nishimura, Y. Nakanishi

      • Abstract
      • Presentation
      • Slides

      Background:
      Cisplatin-based chemotherapy and concurrent radiotherapy is the standard treatments for locally advanced non-small cell lung cancer ( LA-NSCLC). This trial evaluated two experimental regimens of chemotherapy with concurrent radiotherapy.

      Methods:
      Eligible patients (pts) with unresectable stage III NSCLC, 20 to 74 years of age, and ECOG PS of 0­–1 were randomized to either Arm SP, S-1 (40 mg/m[2]/dose per oral, b.i.d, on days 1-14) and cisplatin (60 mg/m[2] on day 1) repeated every 4 weeks or Arm VP, vinorelbine ( 20mg/m[2] on day 1, 8) and cisplatin (80 mg/m[2] on day) repeated every 4 weeks with early concurrent thoracic radiotherapy of 60Gy at 2 Gy per daily fraction. The primary endpoint was overall survival rate at 2-year (2yr-OS). A pick-the-winner design was used to identify the treatment regimen most likely to be superior. The planned sample size was 55 patients per arm, assuming in each arm that the null hypothesis for 2yr- OS was 50% versus an alternative hypothesis for 65% with one-sided alpha of 0.10 and power of 80%. All the radiation treatment plans were reviewed at quality assurance committee meetings. (Study ID: UMIN000002420)

      Results:
      One hundred eleven patients were registered between Sep 2009 and Sep 2012. Of 108 patients for efficacy analysis, the 2yr-OS was 76% (95% CI, 62-85%) for SP and 69% (95% CI, 54-79%) for VP. The hazard ratio (HR) of death between the two arms was 0.85 (0.48-1.49). The median progression-free survival (PFS) was 14.8 months for SP and 12.3 months for VP with a HR of 0.92 (0.58-1.44). 80% and 48% of pts completed the protocol treatment in SP and VP, respectively. Common grade 3-4 toxicities of both SP and VP were neutropenia 33%, 75%, platelets 9%, 4%, hemoglobin 26%, 28%, febrile neutropenia 9%, 17%, diarrhea 6%, 0% respectively. There were 4 and 5 treatment-related deaths in Arms SP and VP, respectively. The quality assurance committee judged that 74% of radiation treatment plans had no deviation and 24% had a minor deviation.

      Conclusion:
      Both arms rejected the null hypothesis for 2yr-OS. In this study Arm SP was declared the winner in terms of 2yr-OS, PFS, treatment completion, and toxicity.

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      MINI07.02 - Chemoradiotherapy versus Radiotherapy Alone in Elderly Patients with Stage III Non-Small Cell Lung Cancer: A Systematic Review (ID 3163)

      D.E. Dawe, D. Christiansen, R. Zarychanski, A. Abou-Setta, P.M. Ellis, A. Swaminath, J. Rothney, R. Rabbani, S. Mahmud

      • Abstract
      • Presentation
      • Slides

      Background:
      Approximately 30% of non-small cell lung cancer (NSCLC) patients present with locally advanced (stage III) disease, and half are elderly (age ≥70). Young, fit patients with stage III NSCLC have improved survival with the use of combined chemotherapy and radiation therapy (CRT) over radiation therapy (RT) alone – HR 0.74 in a 2010 Cochrane systematic review. Elderly patients have more comorbid illnesses and suffer greater treatment toxicity, thus it is unclear whether they benefit more from CRT over RT. The objective of this systematic review is to explore the evidence base for using CRT in elderly patients with stage III NSCLC.

      Methods:
      We performed a systematic review including trials identified in MEDLINE, EMBASE and CENTRAL databases from inception to March 8, 2015, plus relevant conference proceedings since 2000. We included randomized controlled trials (RCTs) of elderly patients (≥70 years old) with stage III NSCLC or elderly subgroups from individual patient meta-analyses comparing CRT versus RT alone. We excluded studies that treated patients with palliative intent, included surgical patients, or in which both arms received chemotherapy. We did not restrict language. Two reviewers independently extracted summary outcome data. Risk of bias was assessed using the Cochrane Risk of Bias tool. We used a random effects model and inverse variance method to pool time-to-event outcomes. We calculated Peto Odds Ratios (POR) using RevMan 5.3 to pool dichotomous outcomes with a zero cell and otherwise calculated Risk Ratios (RR).

      Results:
      We screened 2951 citations identifying 68 articles for full text evaluation, 16 of which have not been accessible yet. Four reports of three studies met inclusion criteria (n = 407 elderly patients). All trials were evaluated as having a high risk of bias due primarily to lack of blinding. Overall survival in elderly patients was superior in those treated with CRT compared to RT (HR 0.66, 95%CI 0.53 to 0.82, I[2] 0%, p 0.0009). Progression-free survival was also improved with CRT (HR 0.67, 95%CI 0.53 to 0.85, I[2] 0%, p 0.001). Toxicity assessments were available in two studies with 119 patients receiving CRT and 121 RT. Treatment-related death occurred in 6 (5%) with CRT and 5 (4%) with RT (RR 1.22, 95%CI 0.38 to 3.88) and grade ≥3 pneumonitis was seen in 6 patients in each group, (RR 1.01, 95%CI 0.34 to 3.06) – neither was significantly different between treatments. Neutropenia – 57% v 2% (POR 14.38, 95%CI 8.26 to 25.04) and thrombocytopenia – 30% v 3% (RR 7.62, 95%CI 2.09 to 27.79) were more common with CRT. Febrile neutropenia occurred in 3 (2.5%) patients with CRT and zero patients with RT, but this did not meet significance (POR 7.54, 95%CI 0.78 to 72.82). No studies included patient-reported quality of life.

      Conclusion:
      CRT in elderly patients with stage III NSCLC results in improved survival as compared to RT alone, at the expense of increased treatment-related hematologic toxicity. Quality of life assessment should be included in any future trial design. CRT can be considered for fit patients ≥70 years of age with stage III NSCLC.

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      MINI07.03 - The NARLAL2 Phase III Trial: Heterogeneous FDG-Guided Dose Escalation of Advanced NSCLC. A Clinical Trial by the Danish Lung Cancer Group (ID 2248)

      D.S. Møller, J.L. Andersen, A.L. Appelt, C. Brink, O. Hansen, L. Hoffmann, N.K.G. Jensen, M. Josipovic, A.A. Khalil, M.M. Knap, M.D. Lund, C.M. Lutz, M.S. Nielsen, S.K. Nielsen, T.B. Nielsen, C.H. Nyhus, W. Ottosson, G.F. Persson, P. Sibolt, K. Wedervang, T. Schytte

      • Abstract
      • Presentation
      • Slides

      Background:
      Locally advanced lung cancer lacks effective treatment options and requires aggressive radiotherapy (RT) with higher doses. In the light of RTOG 0617, multi-center dose escalation trials should avoid increasing organ at risk (OAR) toxicity and require strict quality assurance (QA). Exploiting the predictive value of FDG-PET, sub-volumes can be dose escalated, and by implementing image-guided adaptive RT, the total treatment volume (PTV) can be reduced. Incorporating these elements, the randomized multicenter trial NARLAL2 aims at increasing loco-regional control at 30 months without increasing major toxicity.

      Methods:
      Figure 1 In the standard arm, the PTV is treated with a homogenous dose of 66 Gy/33 fractions. In the experimental arm, the dose is heterogeneously escalated to the FDG-PET avid volumes, with mean doses up to 95 Gy/33 fractions and 74 Gy/33 fractions to the escalated volumes in the tumor and malignant lymph nodes, respectively. The escalation dose will be limited in favor of OAR constraints. A standard and an experimental treatment plan with similar mean lung doses of maximum 20 Gy are made for each patient prior to randomization. Quality Assurance: FDG-PET scans of a standard phantom (NEMA) and PET signal processing software from all centers were compared and acceptable agreement achieved. Multicenter delineation of OARs was performed and consensus achieved. Treatment planning and adaptive strategy consensus were based on a study including five patients with repeated CT-scans, requiring several steps before the achievable level of dose escalation and the number of patients needed in the trial could be defined. Daily online tumor set-up and adaptive strategies were mandatory. A QA committee for evaluation of RT plans and treatments and a central committee for evaluation of all non-biopsy-verified recurrences were established.



      Results:
      A mean dose of 91,9 Gy to the FDG-PET avid part of the tumor and 80 Gy to the clinical target volume was achieved in the planning study, corresponding to 16% estimated increase in locoregional control at 30 months. Assuming a loco-regional control of 56% at 30 months in the standard arm, a total of 330 patients were needed in order to resolve this effect with a power of 80% (95% significance level). Recalculation of escalated plans on CT-scans acquired at fraction 20 revealed an increase in OAR doses of 4-7Gy for two of five patients, endorsing the need for adaptive strategies.

      Conclusion:
      A dose escalation trial with strict QA has been set up. Patient enrollment started January 2015.

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      MINI07.04 - Dynamic Changes in Cell-Free Circulating Tumor DNA to Track Tumor Response and Risk of Recurrence in Stage III Non-Small Cell Lung Cancer (ID 2499)

      S.H. Lin, T. Xu, J. He, K. Banks, R.B. Lanman, D. Sebisanovic, A.A. Talasaz, C. Lu, T. Buchholz, S. Hahn, R.U. Komaki, Z. Liao

      • Abstract
      • Presentation
      • Slides

      Background:
      While the curative management of unresectable stage III non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy, clinical outcomes remain poor. Cellular heterogeneity in tumors is correlated with therapeutic resistance and poor prognosis. We hypothesize that tumor-specific mutant allelic frequency in cell-free DNA from plasma quantifies tumor heterogeneity and that tracking allelic evolution via blood from patients during and after treatment can serve as a non-invasive means to monitor treatment response and recurrence.

      Methods:
      Between 2009-2013, 156 patients with unresectable NSCLC who received definitive radiotherapy or chemoradiotherapy were consented to have blood drawn at baseline before starting radiotherapy, once or twice during treatment, and once or twice during follow up visits. Cell-free plasma DNA was sequenced using a cell-free circulating tumor DNA (ctDNA) next generation sequencing (NGS) assay (Guardant360) that uses digital sequencing to report single nucleotide variants (SNVs) in 68 genes and amplifications in 16 genes. This ctDNA assay has high sensitivity (detects 85%+ of the SNVs detected in tissue in advanced cancer patients) and analytic specificity (>99.9999%). Over 670 serial samples were collected from these patients. Here we report the initial analysis of the first 26 patients of this ongoing study.

      Results:
      Among this initial cohort, 23 (88%) had a recurrence (PFS ranged from 1.2 – 27.9 months) and three (12%) had no evidence of recurrence as of last contact (32.8 – 42.8 months post-radiotherapy completion). Twenty-one patients (81%) had ctDNA alterations present pre-radiotherapy, of which six had a classic driver mutation: KRAS G12F x2; KRAS G12S; PIK3CA E545K x2; PIK3CA H1047R. These six patients had significantly shorter PFS compared to patients without a driver mutation present pre-radiotherapy: average PFS of 4.2 months (1.2 - 8.3) vs. 18.6 months (4.4 - 42.8) respectively (p=0.002). All six had the driver mutation disappear during radiotherapy, four had new alterations appear during and/or post-treatment. One patient had the driver mutation reappear in ctDNA post-radiotherapy and had the shortest PFS (1.2 months) of all patients. Ten patients (38%) had no ctDNA alterations present in the post-radiotherapy blood sample and a trend was observed of improved PFS among patients without ctDNA alterations post-treatment (average PFS 52.3 vs. 75.5 months respectively) however this was not statistically significant (p=0.1). Of note, the three patients without evidence of recurrence as of last contact had no ctDNA alterations identified in the post-treatment sample. This trend is anticipated to become significant with larger sample size.

      Conclusion:
      In this interim analysis, we found that the dynamic alterations of specific mutant alleles strongly correlated with clinical response and that persistence of ctDNA mutant allele concentrations post-definitive treatment is likely a marker of early metastatic recurrence. Undetectable ctDNA in post-treatment sample was seen in the three patients with approximately three years of PFS. These initial results suggest that serial ctDNA analysis may be useful to monitor treatment response and identify patients at high risk for early recurrence who may benefit from additional systemic therapy.

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      MINI07.05 - Discussant for MINI07.01, MINI07.02, MINI07.03, MINI07.04 (ID 3311)

      J. Schiller

      • Abstract
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      Abstract not provided

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      MINI07.06 - Pattern of Loco-Regional Failure after Definitive Chemo Radiotherapy for NSCLC. Results from NARLAL, a Phase II Randomized Trial (ID 1042)

      T. Schytte, T.B. Nielsen, M. Knap, A. Khalil, C. Nyhus, T. McCulloch, B. Holm, C. Brink, O. Hansen

      • Abstract
      • Presentation
      • Slides

      Background:
      Concurrent chemo-radiotherapy (CRT) is the treatment of choice in loco-regional advanced non-small cell lung cancer (LA-NSCLC). Even though the patients are treated with curative intend the loco-regional control at 2 year is only about 30% in clinical trials. The aim of this study is to compare the loco-regional failure in patients treated with 66 Gy vs 60 Gy in the randomized phase II trial, NARLAL. Furthermore to analyze the localization of relapse compared to the original treatment plan.

      Methods:
      From 2009-2013 117 patients with LA-NSCLC were randomized in a national multicentre protocol between 60 Gy/ 30 F (arm A) and 66 Gy/ 33 F (Arm B), 5 FW. Navelbine[®] 50 mg 3 days a week was given as concomitant regimen. Patients were followed with CT scans every 3[rd] month in 2 years and hereafter every 6[th] month for another 3 years. As part of the protocol a PET-CT scan was performed 9 months after randomization. In case recurrent disease was suspected a biopsy was done from the lesion if possible. The recurrence gross tumor volume will be delineated and registered with the original radiation treatment plan to identify the site of failure.

      Results:
      Fifty-nine patients were treated in arm A and 58 patients in arm B. The median local recurrence free interval was 10 months in arm A and 10.9 months in arm B (p=0.57). At the end of this analysis 22 patients were alive with no evidence of loco-regional disease, 16 patients had died with no evidence of loco-regional failure. Loco-regional failure in high-dose area was diagnosed in 60 (51%) patients (33 patients in arm A and 27 patients in arm B). Loco-regional failure outside high-dose area was diagnosed in 19 patients. Fig 1. Treatment plan 60 Gy/ 30 F and PET-CT with relapse (verified by biopsy) Figure 1



      Conclusion:
      Although this treatment was with curative intend, the loco-regional control was disappointingly poor in both treatment arms. This is in line with other newly published clinical dose-escalations trials for NSCLC. In order to improve loco-regional control and hopefully survival homogeneous dose-escalation is not the choice. Inhomogenous dose-escalation may be an alternative. A phase III trial on this subject has just started enrolment in Denmark (NARLAL II, www.clinicaltrials.gov). Acknowledgements Supported by CIRRO- The Lundbeck Foundation Center for Interventional Research in Radiation Oncology.

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      MINI07.07 - Risk Factor of Morbidity and Mortality of Surgical Resection after Induction Therapy in Patients with Stage IIIA-N2 Lung Cancer (ID 1762)

      J.H. Cho, J. Kim, H.K. Kim, Y.S. Choi, J.I. Zo, Y.M. Shim, K. Kim

      • Abstract
      • Presentation

      Background:
      Surgical resection after neoadjuvant chemoradiation therapy for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) carries high postoperative complications. Careful selection of candidate for surgery should be based on analysis of proven risk factors.

      Methods:
      We retrospectively reviewed all consecutive patients with clinical stage IIIA-N2 non-small cell lung cancer who underwent surgical resection after neoadjuvant chemoradiation therapy from 1997 to 2013. Preoperative, perioperative, and outcome variables which related to the morbidity and mortality were assessed. Univariate and multivariate analysis was done to identify predictors of postoperative morbidity and mortality.

      Results:
      During the study period, 574 patients underwent major pulmonary resection after induction therapy. The median time interval between the end of induction therapy and surgery was 33 days (range, 5-79 days). Thirty-day and ninety-day postoperative mortality were 1.4% (8 patients), and 7.1% (41 patients), respectively. The most common cause of In-hospital mortality was acute respiratory distress syndrome (n=6, 4.5%). Morbidity rate was 34.7 % (199 patients). Median hospital stay was 8 days (interquartile range, 7-11 days). Significant predictors of morbidity by multivariable analysis included patient age more than 70 years (odds ratio- 1.82;p=0.040), low body mass index <18.5 (odds ratio - 2.62;p=0.022), and pneumonectomy (odds ratio – 1.8;p=0.026). Significant predictors of mortality by multivariable analysis included patient age more than 70 years (odds ratio – 1.82; p=0.022), and pneumonectomy (odds ratio – 3.256; p=0.003). Ninety-day mortality was 15.8 % (9/57) in patient age more than 70 years, and 17.8 % (13/73) in patients who underwent pneumonectomy.

      Conclusion:
      Surgical outcomes after neoadjuvant CCRT for patients who are older than 70 year or undergo pneumonectomy are relatively poor. For those patients, there should be extra concern about the respiratory complications. And for the elderly patients with limited pulmonary reserves, other possible alternative treatment options, such as definitive CCRT rather than surgery should be considered.

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      MINI07.08 - Mutation Profile Prognostic Value in Stage III Non Small Cell Lung Cancer (NSCLC) Patients Treated with Chemo-Radiotherapy (CRT) (ID 2262)

      A. Boros, L. Lacroix, B. Lancas, J. Adam, J. Pignon, C. Caramella, D. Planchard, A. Levy, V. De Montpreville, E. Deutsch, B. Besse, C. Le Pechoux

      • Abstract
      • Presentation
      • Slides

      Background:
      Molecular profiling is a standard procedure in advanced non squamous NSCLC. Gene alteration in EGFR, BRAF or ALK gene can lead to prescription of targeted therapies and prolongs survival. The influence of molecular abnormalities on the survival of stage III NSCLC patients definitely treated by CRT is unknown.

      Methods:
      We reviewed all consecutive patients that received CRT or RT with a curative intent for stage III NSCLC in a single institution. Paraffin embedded tissue block were collected. DNA was extracted for gene mutation analysis by next generation sequencing and ALK, ROS1 and RET rearrangements were detected by FISH analysis. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method.

      Results:
      Between January2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Platinum-based chemotherapy was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Seventy-eight patients were evaluable for mutation profile, 20 (26%) were female, 47 (60%) were current smoker, 40 (51%) had adenocarcinoma and there were 47/31 stage IIIA/IIIB. Mutations were positive as follow: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/66), PI3KCA 2% (1/58), HER2 0% (0/65), NRAS 3% (1/32), CTNNB1 3% (1/32). FISH was positive for ALK in 5% (3/56) of the NSCLC. In 32 NSCLC for which the test was performed, there was no alteration in ROS1, RET, HRAS and AKT1. Median Follow-up was 3.1 years (minimum 0.9 year). EGFR mutated or ALK+ (EGFR/ALK) group (n=11) and other mutation group (n=17) had a poorer progression free survival (median 0.8[95%CI: 0.6 ; 0.9] year and 0.5 [0.4 ; 0.8] year ; multivariate hazard ratio (HR)= 1.8 [0.8 ; 3.8] and 2.8 [1.5 ; 5.1] respectively, p=0.004) compared to the wild group (n=50) (median 1 year [0.9;1.3]). There was no significant difference (p=0.23, multivariate Cox) in overall survival: median 2.4 years [1.3 ; NR] for EGFR/ALK group, 1.1 [0.6 ; 2.5] for other mutation group and 1.9 [1.5 ; 2.5] for wild type. In multivariate analysis, only the dose of radiotherapy was significantly associated with overall survival (HR=0.5 [0.3 ; 1.0], p=0.04 in contrast with performance status or stage.

      Conclusion:
      This study suggests that selected gene alterations could be associated with a poorer survival in stage III NSCLC patients treated by combined modality treatment or radiotherapy alone. Their prognostic and/or predictive value should be further evaluated in a larger population.

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      MINI07.09 - Incorporating Erlotinib Into Chemoradiation Therapy for Unresectable Stage IIIA/B NSCLC: Interim Results of Ongoing Phase II Randomized Trial (ID 1761)

      J.S. Lee, S.H. Moon, K.Y. Lim, B. Nam, G.K. Lee, Y. Lee, H.T. Kim, T. Yun, K. Cho, S.J. Yoon, J. Han

      • Abstract
      • Presentation
      • Slides

      Background:
      Combined chemoradiotherapy (CCRT) improves long-term outcome of patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC). However, most pts die from distant failure due to preexisting occult metastases. Based on the premise that EGFR-TKI would improve the outcome of pts with stage III NSCLC that harbors sensitive EGFR mutations, as for the pts with stage IV NSCLC, we initiated a randomized phase II pilot trial that incorporated erlotinib (E) into CCRT treatment paradigms.

      Methods:
      Eligible pts over 18 years old with unresectable stage IIIA or IIIB NSCLC, ECOG PS 0–1, and adequate organ function were screened for EGFR mutation in axons 18–21 in the tumor sample. Those with EGFR mutation (+) tumors were randomized upfront to receive 3 cycles of 3-weekly E 150 mg/day treatment, and then either E x2 cycles concurrently with CCRT and x6 more cycles after CCRT (Arm A) or CCRT with 2 cycles of irinotecan-cisplatin (IP) but no additional therapy after CCRT (Arm B). When disease progression (PD) is documented during follow-up, E was re-instituted. Pts with EGFR mutation (-) or unknown tumors were randomized to receive either 3 cycles of IP induction followed by CCRT concurrently with 2 cycles of IP (Arm C) or CCRT with IP x2 first then consolidation with IP x3 (Arm D). IP chemo dose-schedule was irinotecan 60 mg/m[2] and cisplatin 30mg/m[2] iv on days 1 and 8 when given concurrently with RT (2.4 Gy/fx, total 60 Gy); irinotecan 65 mg/m[2] and cisplatin 30 mg/m[2] iv on days 1 and 8 when given every 3 weeks as induction or consolidation. The primary endpoint was overall response rate (ORR), toxicity, and overall survival (OS).

      Results:
      From 02/2008 to 03/2015, 59 pts (44 men and 8 women) with median age of 62 years (range: 37-78) were enrolled. There were 13 never smokers, 28 had adenocarcinoma, and 44 had IIIB tumors. EGFR mutation was (+) in 12, (-) in 28, and unknown in 19. There was apparent imbalance in histology and smoking status between the pts assigned to Arms A&B and C&D. ORR after induction E therapy was 75.0% for the 12 pts with EGFR mutation(+) tumors (Arm A, n=7; B, n=5). ORR after IP induction therapy was 63.6% for pts with EGFR mutation(-) or unknown tumors in Arm C (n=22). After completion of upfront CCRT therapy with IP in Arm D (n=25), ORR was 68.0%. There were no noticeable unusual side-effects. Median PFS for Arm A, B, C, and D, was 11.84, 8.09, 8.36, and 11.81 months respectively, with a trend toward better OS for pts with EGFR mutation(+) tumors (Arm A: not reached, B: 31.18 mos) than those EGFR mutation(-) or unknown tumors (Arm C: 17.93 mos, Arm D: 25.33 mos).

      Conclusion:
      The combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC patients. Although the number is rather small, pts with EGFR mutation (+) tumors seem to be a distinct subset with better overall survival than the others, which warrants careful consideration in chemoradiation therapy trial design and outcome evaluation.

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      MINI07.10 - Discussant for MINI07.06, MINI07.07, MINI07.08, MINI07.09 (ID 3312)

      B. Loo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract

      Background:
      RTOG 0617 investigated standard dose radiotherapy (RT) versus higher dose in the context of concurrent chemoRT with no advantage to higher dose treatment. IDEAL CRT investigated an alternative RT dose-escalation strategy with concurrent chemoRT in locally advanced NSCLC. Dose-per-fraction-escalation was used to achieve intensification without treatment prolongation. The trial would determine the maximum tolerable dose (MTD) deliverable to esophagus, and assess toxicity and early clinical outcomes for the schedule.

      Methods:
      Patients were enrolled to 2 groups, depending on maximum esophageal dose. Tumor doses were determined by esophageal constraints in Group 1 and other normal tissue constraints in Group 2. Patients received 63-73Gy in 30 once-daily fractions / 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. Group 1 esophageal dose-escalation followed a 6+6 design, increasing maximum dose to 1cc esophagus from 65Gy, 68Gy then 71Gy in successive cohorts, defining MTD by early and late toxicity. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and tumor response.

      Results:
      8 centres recruited 84 patients, treating 13, 12 and 10 in 65Gy, 68Gy and 71Gy group 1 cohorts. Prescribed RT doses are shown in figure 1. Median follow-up 24 months. 57 patients (68%) were stage IIIa and 21 (25%) IIIb. 5 grade 3 esophagitis events observed across both groups and 3 grade 3 pneumonitis. Following 1 fatal esophageal perforation in the 71Gy cohort, 68Gy was declared as esophageal MTD. Overall Survival (OS) and Progression Free Survival (PFS) were 87.8% and 72.0% at 1 year, and 67.1% and 50.4% at 2 years, median OS 39.3 months. OS is shown in figure 2. Figure 1 Figure 2





      Conclusion:
      Acceptable toxicity rates and promising survival were achieved. The isotoxic design proved practical, allowing significant treatment intensification and definition of MTD with relatively few patients. Results from longer follow-up are required and will be presented at the meeting.

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      MINI07.12 - Stage III NSCLC in the Elderly: Patient Characteristics Predictive for Tolerance and Survival of Chemoradiation in Daily Clinical Practice (ID 1512)

      E. Driessen, G. Bootsma, L. Hendriks, F. Van Den Berkmortel, B. Bogaarts, J. Van Loon, A. Dingemans, M. Janssen-Heijnen

      • Abstract
      • Presentation
      • Slides

      Background:
      Although the mean age at diagnosis of stage III non-small cell lung cancer (NSCLC) is 70 years, trials mainly include younger patients. Therefore, a lack of knowledge remains regarding tolerance and survival of standard treatment (concurrent chemoradiation (cCHRT)) and other treatment options for the elderly. The aim of this study was to evaluate administered treatment, assess motivations to omit cCHRT, and determine predictors for treatment tolerance and survival among unselected elderly with stage III NSCLC.

      Methods:
      In this multicenter retrospective study, all stage III NSCLC patients aged ≥70 and diagnosed in 2009-2013 in three Dutch teaching hospitals were included. Data on patient and tumor characteristics were derived from the Netherlands Cancer Registry and medical records regarding treatment details, geriatric patient characteristics, tolerance (completing treatment and/or no unplanned hospitalizations) and survival. Treatment and motives for omitting cCHRT were described. Univariate and multivariable analyses were performed to gain insight into predictive factors.

      Results:
      In the 219 included patients, mean age was 76 years, 78% was male and 51% had squamous cell carcinoma. Sixty-eight percent had a WHO Performance Status (PS) of 0-1, 22% PS 2, and 11% PS 3. Serious co-morbidity (severe organ decompensation or ≥2 moderate decompensations) was present in 59%, average co-morbidity (moderate organ compensation or ≥2 mild decompensations) in 16%, mild co-morbidity (mild organ decompensation) in 11% and 15% had no co-morbidities. Chemoradiation (CHRT) was administered in 55% of patients (33% cCHRT and 22% sequential CHRT (sCHRT)), 16% received only radical radiotherapy (RT) and 29% Best Supportive Care (BSC). CHRT was less often administered to patients aged ≥75 and those with a PS 2-3 (p<0.001). Also, patients with serious co-morbidity were less likely to receive CHRT, although not significant (p=0.10). The most common motives for omitting cCHRT were co-morbidity and/or poor PS (57%) and patient refusal (15%). Multivariable analyses showed that treatment and co-morbidity were predictive for tolerance. In comparison to cCHRT, tolerance was significantly better for RT (Odds Ratio (OR) = 5.1(95% Confidence Interval (95%CI) 2.1-13)) and non-significantly better for sCHRT (OR=2.2 (0.97-4.9)). Patients with serious co-morbidity had significantly worse tolerance compared to no co-morbidity (OR=0.28 (0.11-0.68). Even when corrected for patient characteristics, survival was not significantly better after cCHRT compared to sCHRT (Hazard Ratio (HR) = 1.1 (95%CI 0.76-1.7)) or compared to RT (HR=1.3 (0.81-2.0)). The 1-and 3-year Overall Survival (OS) rates for cCHRT were respectively 56% and 17%, for sCHRT 54% and 16%, and for RT 48 % and 9%.

      Conclusion:
      Co-morbidity, poor PS and patient refusal were the most common motives for omitting cCHRT. Although relatively fit and younger elderly were assigned to cCHRT, treatment tolerance was worse. OS was not significantly different between cCHRT, sCHRT and even RT. Since limited information on geriatric characteristics was available in this retrospective study, prospective studies including geriatric assessments are urgently needed to gather evidence on treatment options, resulting in the most optimal balance between quality of life and survival.

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      MINI07.13 - Clinical Impact of Frequent Surveillance Imaging in the First Year following Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer (ID 2538)

      N.K. Harandi, M.E. Daly

      • Abstract
      • Presentation
      • Slides

      Background:
      Uncertainty exists regarding the optimal surveillance strategy following definitive chemoradiation (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) with regards to both frequency and modality. We sought to determine the efficacy of frequent (q2-4 month) post-treatment imaging in detecting asymptomatic recurrent disease and document the clinical impact of frequent surveillance imaging.

      Methods:
      The records of all patients treated with CRT for stage IIIA/IIIB NSCLC between August 1999 and April 2014 at our institution were reviewed. Patients were included if they underwent frequent (Q2-4 month) chest computed tomography (CT) or positron emission tomography (PET/CT) for routine surveillance following CRT for at least one year following CRT or until disease progression or death. Radiographic findings and clinical interventions from the first year following CRT were identified.

      Results:
      We identified 145 patients with LA-NSCLC treated with CRT, 65 of whom underwent Q2-4 month surveillance imaging for at least one year or until progression or death. Median age was 63.6 years (range, 41.0-86.9 years). Forty-nine (75.4%) also underwent an initial baseline CT within the first 6 weeks following CRT. An asymptomatic recurrence was detected by surveillance imaging within the first year in 40 (61.5%) patients, 31 (77.5%) by CT and 9 (22.5%) by PET/CT. Among these patients, 21 (52.5%) initiated palliative systemic therapy. Three (7.5%) underwent attempted definitive therapy for isolated disease, including one patient treated with definitive lobectomy for what was found to be a histologically distinct new primary early stage NSCLC, and two patients treated with stereotactic ablative radiotherapy for isolated recurrences, both of whom subsequently developed metastatic disease. Urgent palliative local therapies (radiotherapy and bronchoscopy) were performed in 2 patients for impending neurologic and airway compromise, respectively. Ten patients (25%) with recurrences detected on surveillance imaging were not candidates for or declined additional cancer-directed therapy. Seven patients (10.8%) developed a symptomatic recurrence detected between planned scans. Five patients (7.7%) underwent additional diagnostic procedures for false-positive surveillance imaging findings.

      Conclusion:
      Frequent surveillance imaging within the first year following CRT for LA-NSCLC detected asymptomatic recurrences in a high proportion of patients in our population. However, definitive interventions were attempted in less than 5%, and were successful in only one patient. The predominant potential benefit of frequent radiographic surveillance appears to be the expedient initiation of palliative systemic therapy. Evidence-based algorithms for follow-up imaging among this population are needed, and should account for patient-specific factors including expected tolerance of, benefit from, and willingness to undergo systemic therapies.

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      MINI07.14 - Endostatin Combined with Paclitaxel, Carboplatin, and Radiotherapy in Patients with Unresectable Locally Advanced Non-Small Cell Lung Cancer (ID 2830)

      X. Sun, Q. Deng, X. Yu, Y. Ji, Y. Zheng, H. Jiang, Y. Xu, S. Ma

      • Abstract
      • Presentation
      • Slides

      Background:
      Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC).

      Methods:
      Nineteen patients with unresectable stage III NSCLC, ECOG performance status 0-l, and adequate organ function were treated with 60–66 Gy thoracic radiation therapy over 30–33 fractions concurrent with weekly 7.5 mg/m[2] endostatin for 14 days, 50 mg/m[2] paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m[2] endostatin for 14 days, 150 mg/m[2] paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment (Fig.1). The objective response rate was recorded according to the RECIST criteria, and the toxicity was evaluated using the NCI Common Toxicity Criteria. Figure 1



      Results:
      Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 13 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% [95% CI, 51%–97%]. The median progression-free survival was 10 months (95% CI, 7.6–12.3 months), and the median overall survival was 14 months (95% CI, 10.7–17.2 months) (Tab.1). The toxicity analysis of 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity. Figure 1



      Conclusion:
      The results demonstrated no evidence of the efficacy of endostatin concurrent with chemoradiotherapy of locally advanced unresectable NSCLC. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined.

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      MINI07.15 - Discussant for MINI07.11, MINI07.12, MINI07.13, MINI07.14 (ID 3325)

      C.J. Langer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 08 - Prognostic/Predictive Biomarkers (ID 106)

    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 15
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      MINI08.01 - Quantitative Mass Spectrometry Proteomics Identifies FRalpha and GARFT as Predictive Biomarkers in NSCLC Patients Treated With Pemetrexed (ID 1685)

      A.A. Alshehri, E. An, F. Cecchi, T. Hembrough, P.C. Ma, M. Smolkin, S. Wen, M. Monga

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer remains the leading cause of cancer mortality in United States and globally. Pemetrexed combined with platinum chemotherapy is specifically indicated for treatment of non-squamous non-small cell lung cancer (non-sq NSCLC). Pemetrexed is a folate-analog metabolic inhibitor that disrupts folate-dependent processes essential for cell replication. Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Folate receptor alpha (FRalpha) is a folate/antifolate transporter protein that is overexpressed by a number of epithelial tumors. The purpose of this study is to identify proteomic biomarkers predictive of response to pemetrexed-based chemotherapy in non-sq NSCLC.

      Methods:
      Patients with advanced non-sq NSCLC who received pemetrexed-based chemotherapy at West Virginia University from 2009 to 2014 were retrospectively identified. Formalin-fixed, paraffin-embedded tumor biopsies were laser microdissected, solubilized, enzymatically digested and subjected to quantitative proteomic analysis. A multiplexed, selected reaction monitoring (SRM) mass spectrometry (MS) assay was used to determine the absolute levels of 46 different candidate proteomic markers, including those in the folate receptor pathway. The Kaplan-Meier method and log-rank test were used in statistical analysis of overall survival (OS) and progression-free survival (PFS).

      Results:
      The 74 patients included in the study had a median follow-up of 26 months, a median OS of 16.6 months (95%CI: 11.6 - 43.4), and a median PFS of 9.61 months (95%CI: 8.43, 12.98). There were 65 patients who received pemetrexed-based regimen as a first line therapy and 9 patients as subsequent salvage treatment. In a comparison between patients who survived >24 months and < 8 months, there were no significant differences between the two groups in terms of sex, age, ECOG performance status, TNM stage at diagnosis, and smoking history. Among the 37 patients with sufficient tumor specimens available for multiplexed proteomic analysis, 30 biomarkers were detected with varying levels of expression. Sixteen additional biomarkers were undetectable. TS protein expression was detected in only 2 patients. Patients whose tumors expressed low levels of GARFT protein (≤900 amol/µg; n=7) had statistically significantly longer median PFS than those whose tumors expressed high levels of GARFT (>900 amol/µg; n=30) (40.6 vs. 11.4 months; p= 0.014). Patients with high FRalpha protein expression (>1510 amol/µg, n=9) had significantly longer median PFS than those with low FRalpha expression (≤1510 amol/µg; n=28) (>50 vs. 11.4 months; p= 0.021). Moreover, the 23 patients with both high GARFT expression (>900 amol/µg) and low FRalpha expression (≤1510 amol/µg) faired considerably worse than the remainder of patients (median PFS 10.1 vs. 40.6 months; p=0.0003).

      Conclusion:
      Multiplexed mass spectrometry-based proteomics offers a feasible and promising approach for tumor biomarker profiling and quantification to predict therapeutic response. Of note, our results show that FRalpha and GARFT protein expression may be predictive of response to pemetrexed-based treatment in patients with non-sq NSCLC. Further investigation is needed to validate the utility of these biomarkers for guiding personalized treatment decisions in clinical practice.

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      MINI08.02 - Prediction of Response to Pemetrexed in NSCLC by Immunohistochemical Phenotyping Based on Gene Expression Profiles (ID 2793)

      S. Visser, J. Hou, K. Bezemer, L. De Vogel, B. Stricker, J. Philipsen, J.G. Aerts

      • Abstract
      • Presentation
      • Slides

      Background:
      A major challenge in the treatment of advanced non-small cell lung cancer (NSCLC) is to identify specific tumor properties that predict response to chemotherapy. Although thymidylate synthase (TS) immunohistochemical (IHC) staining has been extensively studied as a predictive marker for pemetrexed (PEM) sensitivity, its clinical value remains limited. We investigated IHC stainings of different molecular markers linked to the folate metabolic pathway (FMP) identified with gene expression profiling (Hou et al, JTO 2012;7:105-114). We used a population with advanced NSCLC treated with PEM for external validation.

      Methods:
      Resected tumor samples from PEM-naïve NSCLC patients were collected. Gene expression profiling with respect to predicted sensitivity to PEM was based on genes related to FMP. Based on differentially expressed genes, patients were divided into predicted responders (Rs) and non-responders (NRs). Genes showing a strong correlation with these FMP genes and for which IHC stainings were commercially available, were selected for measurement of corresponding protein expressions by IHC stainings. A semiquantitative scoring method was applied, which was used to construct a prediction model for response to PEM. Subsequently, a retrospective cohort of patients with advanced NSCLC was selected, who had received at least two cycles of PEM-based chemotherapy as first-line treatment. IHC staining scores for the same proteins were obtained from tumor tissue. The performance of the prediction model was tested in this population.

      Results:
      From 91 patients resected tumor samples were collected. The majority of patients had early or locally advanced NSCLC (96.3%). Gene expression profiling revealed five markers that showed mRNA levels strongly correlating to FMP genes mRNA levels: TPX2, CPA3, EZH2, MCM2 and TOPO2a. Of 63 patients IHC staining scores of these markers were obtained, which all correlated to their corresponding mRNA levels. The scores were significantly different between predicted NRs and Rs (p<0.05). Testing the IHC markers showed an optimized prediction model with CPA3 (OR=1.71, 95%CI (0.94-3.08)), EZH2 (OR=0.57, 95%CI (0.35-.093)) and TPX2 (OR=0.55, 95%CI (0.29-1.03)) included. With this model 86.5% of the predicted Rs and 72.7% of the predicted NRs were correctly classified. The ROC showed an AUC of 0.883 representing a good discriminatory performance. In the external study population (n=23) the majority of patients had metastatic NSCLC (95.7%). Partial response (PR) was established in 26.1%. Considering patients with PR as responders the prediction model classified 16.7% of the observed Rs and 88.2% of the observed NRs correctly. The ROC showed an AUC of 0.750.

      Conclusion:
      Using external validation this prediction model with IHC staining of FMP correlated markers shows a good specificity, but lacks sensitivity. Again this study shows the limited value of IHC markers as response predictors for PEM in clinical practice. This may be ascribed to the poor relation between IHC and protein activity but the biological significance of FMP genes may also be less important than other factors influencing PEM activity, like pharmacodynamics of PEM e.g. the formation of metabolites. Metabolomics may offer better understanding in cellular processing of PEM and could provide new insights for tailored chemotherapy. Supported by an unrestricted grant from Eli-Lilly, the Netherlands

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      MINI08.03 - Discussant for MINI08.01, MINI08.02 & MINI08.02b (ID 3546)

      D.R. Spigel

      • Abstract
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      Abstract not provided

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      MINI08.04 - VeriStrat® and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib +/- Erlotinib in Non-Small Cell Lung Cancer (ID 552)

      S.K. Padda, P. Lara Jr., S.N. Gettinger, J.A. Engelman, P.A. Jänne, H. West, L.Y. Zhou, D.S. Subramaniam, J.W. Leach, M.B. Wax, J.W. Neal, D.O. Clary, L.J. Goodman, H.A. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background:
      VeriStrat is a blood-based multivariate proteomic test that predicts response to second line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy in non-small cell lung cancer (NSCLC). We report a retrospective blinded analysis of VeriStrat classification in plasma samples from a phase 1b/2 trial of cabozantinib (C) +/- erlotinib (E) in metastatic NSCLC patients who had all progressed after benefiting from EGFR TKI therapy. Cabozantinib inhibits the MET/hepatocyte growth factor (HGF) pathway, and VeriStrat may be a surrogate marker for this pathway.

      Methods:
      Patients enrolled into phase 1b (1A:60 mg C+150 mg E, 2A:60 mg C+100 mg E, 3A:100 mg C+100 mg E, 4A:100 mg C+50 mg E, 2B:40 mg C+150 mg E) and phase 2 (Arm A:100 mg C, Arm B:100 mg C+50 mg E). EGFR mutation (EGFRm) status was tested on archival tissue and/or plasma when available. The primary objective was to determine if pre-treatment VeriStrat (VS) classification, good or poor, was prognostic for patients treated with cabozantinib +/- erlotinib. Kaplan-Meier method and log-rank test was used to compare progression-free survival (PFS) of VS-good v. VS-poor patients. Outcomes were stratified by EGFRm status (mutated v. wild type WT/unknown UNK).

      Results:
      Of 79 evaluable patients, 71 were classified as VS-good and 8 as VS-poor. 55.7% had an activating EGFRm (majority exon 19 del/exon 21 L858R) and 12.7% had UNK EGFRm status. There were no significant differences in patient characteristics between VeriStrat-groups. VS-good patients had a statistically improved PFS: VS-good 3.7 mo. (95% CI 3.5-5.4) v. VS-poor 1.9 mo. (95% CI 1.1-3.4), p=0.014. This was still true after excluding 14 patients who had received cabozantinib alone (p=0.005). There was no difference in PFS for VS-good patients when stratified by EGFRm status. There was also no difference in PFS for VS-poor patients with WT/UNK EGFR v. VS-good patients irrespective of EGFRm status. However, VS-poor patients with WT/UNK EGFR had improved PFS compared to VS-poor patients with an EGFRm (3.1 mo. v. 1.6 mo., HR 0.15, 95% CI 0.03-0.68).

      Conclusion:
      VeriStrat is a strong prognostic marker in this study. This study suggests cabozantinib neutralized the worse prognosis of VS-poor patients with WT/UNK EGFR. Given the heterogeneity of treatment dosing, the small number of VS-poor patients, and a high proportion of unknown EGFRm (including T790M) status, this analysis should be considered exploratory.

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      MINI08.05 - A Survival Comparison Study of Chinese Patients with Primary Lung Adenocarcinoma Harboring ALK Rearrangements Detected in Different Methods with Crizotinib Treatment (ID 3227)

      S. Lu, X. Niu, Z. Chen, Z. Zhou, Z. Li, X. Ye, Y. Yu, Y. Xu, M. Liao

      • Abstract
      • Presentation
      • Slides

      Background:
      EML4-ALK is a new driver gene of non-small cell lung cancer (NSCLC) and is associated with response to inhibition with crizotinib. ALK break apart fluorescence in situ hybridization (FISH) assay, Ventana immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR) can all be used as the primary assay for detecting ALK fusion events in tumor samples of lung cancer patients with SFDA approval in China. The objective of this study was to analyze the association of ALK rearrangements with clinical outcomes in different ALK testing methods, including FISH, Ventana IHC, and RT-PCR.

      Methods:
      ALK status was assessed by FISH, IHC and RT-PCR in 75 patients with advanced ALK-positive lung adenocarcinoma who had received crizotinib treatment from 2011, May to 2014, Nov in China. Clinicopathologic data and survival outcomes were analyzed. Kaplan-Meier cumulative probability was used to assess different testing methods for survival.

      Results:
      Of all 75 ALK-positive lung adonocarcinoma, there are 23 FISH-positive ALK patients (23/75, 30.7%), 35 IHC-positive ALK patients (35/75, 46.7%) and 17 RT-PCR-positive ALK patients (17/75, 22.7%). 75 patients received crizotinib treatment with IHC-positive and FISH-positive had better progression-free survival (PFS) (P=0.049, Fig A), compared with those with RT-PCR-positive, but not for overall survival (OS) (P=0.074). The median PFS survival for all these 75 patients was 16m, 14m, 8m, respectively, based on the IHC, FISH, and RT-PCR test (Fig A). 23 patients received first-line crizotinib treatment with IHC-positive and FISH-positive had better PFS (P=0.030), compared with those with RT-PCR-positive, but not for OS (P=0.061), either. The median PFS survival for these 23 patients with first-line crizotinib treatment was 12m, 18m, 4.8m, respectively, based on the IHC, FISH, and RT-PCR test. Of all 17 RT-PCR-positive ALK patients, there are 10 E13:A20 fusion type (10/17, 58.8%), 4 E6:A20 fusion type (4/17, 23.5%), 2 E18:A20 fusion type (2/17, 11.8%), and 1 E2:A20 fusion type (1/17, 5.9%). 4 different fusion-type ALK-positive patients detected by RT-PCR received crizotinib treatment with no crizotinib-related PFS significant difference (P=0.312) and no OS difference (P=0.149).Figure 1



      Conclusion:
      ALK-positive patients confirmed by IHC and FISH assay, compared with RT-PCR, maybe have better crizotinib-related PFS. RT-PCR method needs to be further evaluated in clinical practice to identify its role in guiding targeted therapy using crizotinib. And there is no survival difference for different ALK fusion type detected by RT-PCR in our cohort, which need further validation in a large group.

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      MINI08.06 - Prognostic Significance of FGFR1 Amplification in Patients with Lung Squamous Cell Carcinoma (ID 814)

      Q. Zhang, X.-. Zhang, Z. Xie, J. Su, Q. Zhou, X.-. Yang, W.-. Zhong, J.-. Yang, Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      The Fibroblast Growth Factor Receptor(FGFR) pathway especially FGFR1 gene copy number gain have attracted continuous attention of researchers for several years. Whereas due to different test methods and distinguishing criteria whether FGFR1 amplification related to patients smoking status or prognosis is still controversial.

      Methods:
      We used fluorescence in situ hybridization (FISH) to detect the gene copy number in paraffin-embedded tissue sections from 200 cases of pulmonary squamous cell carcinoma patients who underwent surgery in Guangdong Lung Caner Institute(GLCL) from 2008 to 2013. All samples had been identified as primary squamous cell carcinoma by postoperative pathology and informed consent. A tumor is defined as FGFR1 amplification positive when FISH results meet one of the following criteria after reviewing at least 100 tumor cells: (1) FGFR1/CEP-8 ratio≥2; (2) mean number of FGFR1 signals≥6; or if (3) ≥10% tumor cell containing more than 15 FGFR1 signals or large clusters. Among them, sample accord with the 3rd standard was defined as focal amplification.

      Results:
      Figure 1 We used fluorescence in situ hybridization (FISH) to detect the gene copy number in paraffin-embedded tissue sections from 200 cases of pulmonary squamous cell carcinoma patients who underwent surgery in Guangdong Lung Caner Institute(GLCL) from 2008 to 2013. All samples had been identified as primary squamous cell carcinoma by postoperative pathology and informed consent. A tumor is defined as FGFR1 amplification positive when FISH results meet one of the following criteria after reviewing at least 100 tumor cells: (1) FGFR1/CEP-8 ratio≥2; (2) mean number of FGFR1 signals≥6; or if (3) ≥10% tumor cell containing more than 15 FGFR1 signals or large clusters. Among them, sample accord with the 3rd standard was defined as focal amplification.



      Conclusion:
      Our results suggested that FGFR1 focal amplification might be an independent risk factor for patients overall survival. Patients with FGFR1 amplification were more likely to disease recurrence. Clinical characteristic including smoking status were not found in association with FGFR1 amplification, suggesting patients with FGFR1 amplification might not be fully enriched through only clinical factors.

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      MINI08.07 - Discussant for MINI08.04, MINI08.05, MINI08.06 (ID 3327)

      P. Hammerman

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      Abstract not provided

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      MINI08.08 - VEGF-Mediated Cell Survival in NSCLC: Implications for Epigenetic Targeting of VEGF Receptors as a Therapeutic Approach (ID 2721)

      M.P. Barr, K.J. O'Byrne, N. Al Sarraf, S. Cuffe, S. Finn, S.G. Gray

      • Abstract
      • Presentation
      • Slides

      Background:
      We have recently shown that VEGF, at least in part, is an autocrine growth factor for NSCLC cells, mediating its survival effects via VEGFR2 (KDR) in addition to the more novel receptor, Neuropilin-1 (Barr et al., Mol Cancer, 2015). In this study, we evaluated the potential therapeutic utility of histone deacetylase (HDAC) inhibitors in targeting the VEGF-VEGFR signalling axis in non-small cell lung cancer (NSCLC) cells.

      Methods:
      The effect of the HDAC inhibitor, Trichostatin-A (TSA) on modulating the expression of the VEGF receptors, VEGFR1, VEGFR2, NP1 and NP2, in A549 and SKMES-1 cells was examined and validated at the mRNA level and protein levels using RT-PCR and Western blot analysis. Gene expression was further validated by quantitative real-time PCR. To investigate the effect of TSA on the viability of NSCLC cells, these were treated with increasing concentrations of TSA (2.5 ng/ml-250 ng/ml) for 24h. Cell proliferation and apoptosis was measured by BrdU and Annexin V/PI (FACS), respectively. VEGF protein secretion in response to TSA was assessed in conditioned media from lung tumour cells by ELISA. To determine if the effects of TSA on VEGFR receptors were mediated through immediate to early responses, cells were pre-treated with cycloheximide (10 µg/ml) for 2 h followed by treatment with TSA (250 ng/ml) for 24 h. To confirm whether the observed effects of HDAC inhibition by TSA were due to increased histone hyperacetylation at the VEGFR1 and VEGFR2 gene promoters, chromatin immunoprecipitation (ChIP) analysis was carried out following treatment with TSA.

      Results:
      NP1 and NP2 mRNA levels were decreased in both A549 and SKMES-1 lung cancer cells in response to TSA and induced the expression of VEGFR1 and VEGFR2 at higher concentrations. TSA however, had no effect on VEGF mRNA expression. Critically, the effect of TSA was more marked at the protein level, with complete loss of Neuropilin-1 protein. HDAC inhibition resulted in a significant decrease in the viability of A549 and SKMES-1 cells in a dose-dependent fashion. While TSA induced significant apoptosis of both lung tumour cell lines, VEGF was unable to rescue cells from TSA-induced cell death. VEGF secretion was significantly decreased in both cell lines. Treatment with cycloheximide was unable to abrogate the TSA-mediated increase in the VEGF receptors examined, indicating that de novo protein synthesis is not required for these observed effects, but may be due to direct effects at the promoter level. Direct histone acetylation of histones H3 and H4 was observed, indicating an increase in histone hyperacetylation of VEGFR1 and VEGR2 promoters. A significant trend in the modulation of the VEGF receptors similar to that seen in response to TSA was shown when treated with Vorinostat (SAHA).

      Conclusion:
      Epigenetic targeting of the Neuropilin receptors may offer an effective treatment for NSCLC patients in the clinical setting. The possibility of novel targeted agents decreasing the levels, or function, of tumour VEGF receptors, in particular NP1, may lead to more successful treatments and prolonged overall survival in these patients.

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      MINI08.09 - Anti-Tumor Efficacy of Interleukin-27 in Non Small Cell Lung Cancer (ID 551)

      G. Cipollone, I. Airoldi, M.G. Tupone, S. Esposito, M.V. Russo, G. Barbarito, E. Di Carlo

      • Abstract
      • Presentation
      • Slides

      Background:
      Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) constitute the commonest lung cancer histotypes, but current therapies still fail to significantly increase their survival rate. An effective immunotherapy to apply alternatively or together with specific treatments may be of great value. Here we asked whether Interleukin (IL)-27, which has revealed powerful antitumor activity in different tumor types and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients.

      Methods:
      Human lung AC and SCC cell lines were used to assess IL-27’s effect on cancer cell viability, by flow cytometry, and on malignancy-related gene expression, by qRT-PCR. Its effects on tumor growth were assessed in pre-clinical models and examined histopathologically. Expression of IL-27Receptor(R) in clinical samples was assessed by laser capture microdissection followed by qRT-PCR, and by immunohistochemistry.

      Results:
      In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROg/MIP2b expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with the Epithelial to Mesenchymal Transition (EMT)-related genes NESTIN, SNAI1/Snail, SNAI2/Slug and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R was expressed by the majority of AC, 90%, and SCC, 84%. Its expression by the primary tumor was significantly associated with advanced stages of disease (P = 0,02) as assessed by Fisher’s exact test. IL-27R was also expressed by pre-cancerous lesions, microvessels, and by infiltrating immune cells as CD15[+]granulocytes, CD68[+]monocytes/macrophages and CD11c[+]myeloid dendritic cells scattered in the stroma or within the lymph node–like structures, known as tertiary-lymphoid-structures (TLS).

      Conclusion:
      Altogether, our results highlight novel aspects of IL-27’s antitumor potential, specifically in NSCLC, such as the ability to drive myeloid cells towards antitumor activities, and down-regulate stemness genes, particularly in SCC cells, thus suppressing their self-renewal potential. IL-27 may thus be proposed for clinical trials with the prospect of its clinical use in immune-defective or advanced NSCLC patients.

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      MINI08.10 - Co-Occurrence of Driver Mutations of MAPK and PI3K Pathways in Non Small Cell Lung Cancer: A Report from Lung Cancer Genomics Ireland (LCGI) Study (ID 2627)

      S. Rafee, Y. Elamin, S. Toomey, K. Gately, A. Carr, S. Cuffe, S. Nicholson, S.P. Finn, R. Ryan, V. Young, J. Crown, O. Breathnach, P. Morris, E. Kay, A. O'Grady, B. Hennessy, K.J. O'Byrne

      • Abstract
      • Presentation
      • Slides

      Background:
      The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are frequently altered in human cancers. Targeting these pathways is an attractive therapeutic strategy in malignant disease. The frequency of single and dual pathway alterations varies substantially across various cancers. Co-occurrence of the MAPK and PI3K pathway aberrations is reported in 5-7% of melanomas, gastric and colorectal cancers, and is associated with a worse clinical outcome. In this report we aim to determine the co-occurrence of the MAPK and PI3K pathway mutations in a large cohort of surgically resected NSCLC tumors.

      Methods:
      We used the platform of Sequenom’s MassArray to perform genotyping for 548 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways in surgically resected NSCLC tumors. MAPK pathway genes that were screened include: KRAS, HRAS, BRAF, RAF1, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP2K1, MAP2K2, MAP2K3, and PTPN11. PI3K pathway genes that were screened include: PIK3CA, PIK3R1, PIK3R2, PTEN, PDPK1, AKT1, AKT2, and MTOR. Fisher’s exact test was used to determine the statistical significance of association between the MAPK and PI3K pathway mutations. The strength of association was determined in the form of odds ratio.

      Results:
      NSCLC tumors from 356 patients (258 squamous cell, 98 adenocarcinomas) were tested using Sequenom’s MassArray. The frequency of mutations in the MAPK and PI3K pathways was 22.5% (n=80) and 22.8% (n=81) respectively. Among these patients, 38 patients had mutations in both pathways (i.e: 47.5% of patients with a MAPK pathway mutation also had a mutation in the PI3K pathway, and 46.9% of patients with a PI3K pathway mutation also had a mutation in the MAPK pathway, see table 1). Fisher’s exact test revealed that mutations in the MAPK and the PI3K pathways are mutually inclusive (p<0.0001, odds ratio=4.95, 95% CI 2.9-8.5) Table 1: The co-occurrence of MAPK and PI3K pathway mutations in NSCLC

      Pathway/no of patients PI3K WT PI3K MT
      MAPK WT 235 43
      MAPK MT 42 38


      Conclusion:
      38 (10.7%) of 356 NSCLC patients included in the LCGI study had hotspot somatic mutations in both the MAPK and PI3K pathways. Contrary to previous reports, we observed that activating mutations of the MAPK and PI3K pathways are mutually inclusive in NSCLC. These findings may have implications in designing clinical trials of targeted therapies in lung cancer.

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      MINI08.11 - Genome-Wide Association Analysis Identifies Novel Genetic Determinants of Cancer Metastasis in Korean Lung Adenocarcinoma (ID 2363)

      Y. Hwang, H.Y. Son, Y.J. Jung, S.B. Lee, Y.H. Kim, H.J. Lee, I.K. Park, C.H. Kang, J. Kim, Y.T. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) is characterized by poor prognosis, and few molecular markers were proven to be associated with cancer metastasis. The aim of the study is to identify the associations between single-nucleotide polymorphisms (SNPs) and distant metastasis of adenocarcinoma of the lung in Korean population.

      Methods:
      We conducted a genome-wide association study (GWAS) of in 499 Korean lung adenocarcinomas comparing 4,653,588 SNPs genotypes. Analyses were performed to investigate the association between the germline variations in all genes and cancer metastasis, survival and cancer recurrence.

      Results:
      We undertook a gene-metastasis interaction analysis in a GWAS of lung cancer using a case-control study. (18cases and 481controls) The combined analyses identified two susceptibility loci for metastasis risk in lung adenocarcinoma: SYNE1 [rs117050208, p-value = 1.91 x 10[-14], odds ratio (OR) = 87] and QSOX1 (rs148150589, p-value = 4.46 x 10[-9], OR = 56.5). SYNE1 was known to play crucial roles in the dynamics of genetic progression in colorectal adenocarcinoma and QSOXI was considered a prognostic indicator of metastatic potential in the breast cancer. (Figure1) However, no significant association was found between SNPs and either survival or recurrence. Figure 1



      Conclusion:
      Our data suggest that the SYNE1 rs117050208 and the QSOX1 rs148150589 may serve as potential biomarkers to influence cancer metastasis in the Korean lung adenocarcinoma. The analysis of the rs117050208 and rs148150589 polymorphism can help identify patients at high risk of distant metastasis of lung adenocarcinoma.

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      MINI08.12 - Proteomic Profiling of Pulmonary Cancer with Squamous Cell Histology (ID 1377)

      H. Bohnenberger, D. Yepes, K. Pan, A. Emmert, H. Henric-Petri, F. Bremmer, J. Strecker, A. Lois, L. Fischer, S. Küffer, M. Hinterthaner, H. Wolff, M. Canis, M. Sebastian, B. Danner, P. Ströbel, H. Serve, H. Urlaub, T. Oellerich

      • Abstract
      • Slides

      Background:
      Pathologic differentiation of neoplastic lesions in the lung with squamous cell histology is challenging as appropriate diagnostic immunohistochemical biomarkers are lacking. In particular patients with head and neck cancer and a smoking history can develop both lung metastases and primary lung cancer. Differentiation of primary lung cancer and lung metastases of head and neck cancer is clinically important for therapy and risk stratification. Furthermore, molecular targeted therapies for squamous cell carcinoma of the lung are largely lacking to date. Recent genetic studies uncovered multiple genetic subgroups of squamous cell carcinoma of the lung and moreover potential drug targets. However, the correlation between protein-expression/signaling activation patterns and genetic alterations is strongly influenced by co- and post-transcriptional as well as post-translational regulation. We characterized a broad panel of primary patient-derived formalin-fixed squamous cell carcinomas from lung and head and neck cancer by quantitative mass spectrometry to identify proteomic diagnostic biomarkers, signaling patterns and potential novel drug targets.

      Methods:
      Proteins were extracted from formalin-fixed paraffin-embedded (FFPE) microdissected patient-derived cancer tissues by using the “filter-aided sample preparation (FASP)” method. Purified proteins were subsequently mixed with a cancer-matched isotope labeled quantification standard (Super-SILAC standard) that allows for identification and quantification of thousands of proteins and their phosphorylation sites by high-end mass spectrometry. Using bioinformatics we determined the protein expression and signaling patterns. The biomarkers discovered were validated by immunohistochemistry in additional independent tumor tissues.

      Results:
      In this study we quantitatively characterized the proteomes of 60 primary patient-derived non-small cell lung cancer specimens with squamous cell histology and 25 squamous cell carcinomas from the head and neck region derived from patients that developed lung tumors with similar histology in the course of their disease. Using the Super-SILAC-based mass spectrometric approach we were able to identify and quantify around 2500 proteins per sample. Unsupervised clustering- and principal component analyses revealed that the detected protein expression patterns show a strong correlation with the cellular origin of the analyzed carcinomas. Furthermore, secondary lesions with similar histological morphology in the lung in patients with squamous cell carcinoma of the head and neck region could be classified as primary or metastatic cancer according to their protein expression profiles.

      Conclusion:
      Collectively, this study provides a large set of proteomic biomarkers that can be used to improve lung cancer diagnostics in the future. In particular the differential diagnosis of squamous cell carcinoma/metastases in the lung, that has so far been difficult due to the lack of biomarkers, will be improved by the biomarker panels presented here. Moreover, the expression and activation patterns of kinases discovered in our study is of interest regarding potential novel lung cancer therapies as overexpression or hyperactivation of certain kinases can potentially contribute to the malignant phenotype of lung cancer cells.

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      MINI08.13 - Driver Mutation Status in Resected Stage I Lung Adenocarcinoma: Correlation with Radiographic CT Findings (ID 3251)

      H.Y. Zhou, C.C. Wu, M. Mino-Kenudson, L.F. Tapias, M. Lanuti

      • Abstract
      • Presentation
      • Slides

      Background:
      To indentify the correlation of chest computed tomography appearance and the presence of oncogenic driver mutations in resected stage I lung adenocarcinoma

      Methods:
      Patients with resected stage I lung adenocarcinoma were analyzed from 2008-2012 and categorized into 3 groups: pure ground glass (GGO), mix-solid and ground glass, and solid patterns. All patients underwent driver mutation analysis (26 genes and 89 point mutations) using a multiplex PCR-based assay from paraffin embedded tumors. Disease free survival (DFS) and overall survival (OS) were compared between patients with EGFR, KRAS and the wild-type tumors using Kaplan-Meier methods and Cox regression models.

      Results:
      237 patients who underwent curative resection for stage I lung adenocarcinoma were analyzed with a median follow-up 34 months. Female gender was observed in 68% (160/237) and 21% (50/237) were nonsmokers. Pure GGO was indentified in 9% (n=21), mixed solid in 69% (n=164), and solid in 22% (n=52) of cases. EGFR and KRAS mutation rates were 18.6% (n= 44) and 34.6% (n= 82), respectively. Univariate analysis showed that KRAS-mutated tumors (HR 1.91, 95% CI 1.37-2.67; p<0.01), solid component > 50%, (HR 2.65, 95% CI 1.03-6.8; p=0.04), and smoking status (HR 3.59, 95% CI 1.1-11.8; p=0.03) were associated with worse DFS. In multivariate analysis only KRAS-mutated tumor (HR 1.84, 95% CI 1.31-2.59; p<0.01) was significant for worse DFS. KRAS-mutated tumor was also associated with worse OS in both univariate (HR 1.72, 95% CI 1.14-2.59; p=0.009) and multivariate (HR 1.65, 95% CI 1.09-2.49; p=0.018) analysis. Tumors that harbored >50% solid component on CT chest with a KRAS mutation were associated with worse DFS (HR 2.87, 95% CI 1.4-5.92; p=0.004) and OS (HR 2.51, 95% CI 1.03-6.1; p=0.04) in multivariate analysis compared to wild type tumors that were < 50% solid.

      Conclusion:
      KRAS mutation status and percent solid component on chest CT were predictive of worse outcome in surgically resected stage I lung adenocarcinoma

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      MINI08.14 - Discussant for MINI08.08, MINI08.09, MINI08.10, MINI08.11, MINI08.12, MINI08.13 (ID 3328)

      J.F. Gainor

      • Abstract
      • Presentation

      Abstract not provided

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      MINI26.01 - Tumour Molecular Profiling and Quantitative Detection of Circulating Biomarkers in Patients with Non-Small Cell Lung Cancer (NSCLC) (ID 317)

      E. Karampini, H. Farah, N. Kamal, P. Cane, J. Moorhead, S. Pomplun, J. King, T. Sethi, J. Spicer, F. McCaughan

      • Abstract
      • Presentation
      • Slides

      Background:
      The introduction of targeted therapy has transformed the care of patients with lung cancer by incorporating tumour genotyping into therapeutic decision making. Recent improvements in sequencing technology have allowed for a rapid and broad snapshot of a tumour’s genetic landscape. Circulating cell-free tumour DNA (cfDNA) can be detected in patients with solid organ malignancies and has the potential to be used as a non-invasive biomarker (“liquid biopsy”). By integrating the two approaches, it is possible to detect specific mutational events in diagnostic samples, assess tumour burden, longitudinally monitor the response to therapeutic intervention and detect disease recurrence. As we have shown previously, it may also facilitate the detection of emergent subclonal populations, including variants that confer resistance to specific therapeutic agents.

      Methods:
      30 unselected treatment-naive patients with lung cancer were recruited from clinic. Paired DNA from tumour biopsies and plasma was obtained. Targeted next-generation sequencing (NGS) was performed on the tumour biopsy DNA. Primer sets and probes for identified mutations were optimised and validated on a microdroplet digital PCR (mdPCR) system.

      Results:
      25 of 30 patients in our test cohort had stage IIIB/IV non-small cell lung cancer. 25 of 30 patients (83%) of patients had mutations identified in their diagnostic specimen. 4 out of the 5 patients with no identifiable mutation in their diagnostic specimen presented with early disease and underwent curative surgery. The diagnostic specimens included endobronchial ultrasound (EBUS) samples, percutaneous and pleural biopsies, surgical resection specimens and a brain biopsy. The corresponding mutation was then assayed in cfDNA and was detected in the pre-treatment plasma samples in 90% of patients. Results to date from this cohort will be presented in detail. There has been complete concordance between mutations identified as part of the clinical standard-of-care and our targeted NGS data.

      Conclusion:
      It is feasible to perform a targeted NGS analysis on DNA from standard diagnostic lung cancer specimens and design generic and patient-specific biomarkers for use in a mdPCR assay of cfDNA. We aim to validate this approach and embed it in future clinical trial protocols.

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    MINI 09 - Drug Resistance (ID 107)

    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI09.01 - Inhibiting Tankyrase Prevents Epithelial-To-Mesenchymal Transition and Synergizes with EGFR-Inhibition in Wnt-Dependent NSCLC Lines (ID 2850)

      H.A. Scarborough, B.A. Helfrich, M. Casas-Selves, Z. Zhang, D.C. Chan, A. Schuller, S. Grosskurth, P.A. Bunn, Jr, J.V. DeGregori

      • Abstract
      • Slides

      Background:
      Despite their promise, therapies targeting driver receptor tyrosine kinases (RTKs) rarely produce complete responses and have shown modest clinical benefit in NSCLC. This suggests the presence of escape mechanisms that allow cells to survive and proliferate despite inhibition of an oncogenic driver.

      Methods:
      Using a genome-wide shRNA screen, we identified that the canonical Wnt/β-catenin pathway contributes to the survival of NSCLC cells during inhibition of the epidermal growth factor receptor (EGFR). In order to evaluate the effects of inhibiting the Wnt pathway on EGFR-inhibited cells, we categorized NSCLC cell lines as “Wnt-responsive” or “Wnt-non-responsive” based on their ability to upregulate β-catenin-dependent targets in response to treatment with exogenous Wnt3a. Using both shRNA knockdown and a novel tankyrase inhibitor, AZ1366, we evaluated the ability of tankyrase inhibition to synergize with EGFR-inhibition in multiple Wnt-responsive and Wnt-non-responsive cell lines. We then evaluated the effects of the combination of gefitinib and AZ1366 on the survival and tumor progression in an orthotopic mouse model. In order to comprehensively query transcriptional changes brought about by treatment, we performed RNA-seq on cells treated with gefitinib, AZ1366, or the combination of the two drugs.

      Results:
      We have demonstrated that inhibition of tankyrase, a key player in the canonical Wnt pathway, significantly increases the induction of senescense and/or apoptosis mediated by EGFR-inhibitors in cell lines with a Wnt-responsive phenotype, and that the ability of the tankyrase inhibitor to synergistically eliminate NSCLC cells is dependent on its actions within the canonical Wnt pathway. In Wnt-non-responsive cell lines, tankyrase inhibition did not synergize with inhibition of EGFR. We have further demonstrated that Wnt-responsive cell lines show evidence of EMT in response to Wnt ligand stimulation, and that this can be prevented with tankyrase-inhibitor treatment. Additionally, we have shown that mice orthotopically implanted with Wnt-responsive cell lines and treated with a combination of a tankyrase inhibitor and an EGFR inhibitor have a substantially reduced tumor burden and a significant improvement in survival when compared to treatment with an EGFR inhibitor alone. When Wnt-non-responsive cell lines were used, we noted no improvement in survival or reduction in tumor burden. RNA-seq analysis revealed that while most transcriptional changes present in the combination were driven by gefitinib, AZ1366 had the effect of significantly amplifying many of the changes thought to be instrumental in resistance to EGFR inhibition including increased expression of TP53 and apoptosis signaling machinery, increased expression of NF-kB signaling components, and a strong decrease in cell cycle drivers. Furthermore, treatment with AZ1366 alone resulted in decreased expression of Axl and its ligand, Gas6, a known mechanism of resistance to EGFR inhibition.

      Conclusion:
      Taken together, these results indicate that tankyrase inhibition impinges on multiple mechanisms of escape from EGFR-inhibition, and that its ability to synergize with EGFR-inhibition is dependent on its actions within the canonical Wnt pathway. As the goal of these studies is the development of combination therapies with EGFR inhibition, this suggest tankyrase as a promising target in the subset of NSCLC with known dependencies on signaling through the canonical Wnt pathway.

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      MINI09.02 - Transcriptome-Metabolome Reprogramming of EGFR-Mutant NSCLC Contributes to Early Adaptive Drug-Escape via BCL-xL Mitochondrial Priming (ID 3085)

      P.C. Ma, P. Thiagarajan, W. Zhang, X. Wu, P. Leahy, I. Shi, Y. Feng, M.L. Veigl, D. Lindner, D. Danielpour, L. Yin, Z. Zhang, R. Rosell, T. Bivona

      • Abstract
      • Slides

      Background:
      Precision therapy using EGFR small molecular inhibitors is the current standard-of-care in treatment of advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations. Nonetheless, emergence of acquired resistance to therapy invariably occurs despite effective initial response. Classical rebiopsy studies of EGFR-mutant pts at clinical tumor progression based on RECIST criteria have identified diverse resistance mechanisms involving T790M-EGFR, MET amplification or activation and AXL upregulation. Tumor cells within minimal or microscopic residual disease during drug response may constitute founder cells for future disease relapse. The mechanisms of molecular changes intrinsic to these early therapeutic survivors are not yet well-understood. Our studies focus on tumor cells adaptation early during therapy to map the initial course of molecular drug resistance emergence and evolution.

      Methods:
      Drug-sensitive model studies of EGFR-mutant lung cancer were performed using HCC827 and PC-9 cells (exon 19 deletions EGFR) under erlotinib, and H1975 (T790M/L858R-EGFR) cells under CL-387,785 inhibition. Affymetrix microarray profiling was performed in triplicate at 0h, 8h, 9d and 9d tyrosine kinase inhibitor (TKI) followed by 7d drug-washout. Both in vitro and in vivo xenograft analyses, immunofluorescence, immunohistochemistry, time-lapse video microscopy analysis were conducted. Mass-spectrometry based global metabolomics profiling was also conducted under similar conditions as in gene expression profiling.

      Results:
      We identified an early adaptive and reversible drug-escape within EGFR-mutant cells that could emerge as early as 9 days during course of effective therapy with molecular drug resistance. Principal component analysis (PCA) of gene expression profiling data identified distinct transcriptome signatures in each cell state. Of note, the prosurvival cell state was independent of MET pathway activation, and had a TKI cytotoxicity escape at 100x higher IC50. The drug resistant cell state was associated with reversible cellular quiescence, suppressed Ki-67 expression, and profoundly inhibited cellular motility and migration. Transcriptome gene expression profiling revealed a remarkable adaptive genome-wide signature reprogramming, centered on the autocrine TGFβ2 cascade that involved pathways of cell adhesion, cell cycle regulation, cell division, glycolysis, and gluconeogenesis. Global metabolomic profiling of cellular metabolites in HCC827 cells under erlotinib inhibition also revealed a concurrent adaptive reprogramming of cellular metabolism during the early drug-resistant cell state, with suppression of glycolysis, TCA cycle, amino acids metabolism, and lipid bioenergetics. Our studies identified a direct link of TGFβ2 within the drug escaping cells, with the metabolic-bioenergetics quiescence, reverse Warburg metabolism and mitochondrial BCL-2/BCL-xL priming. Furthermore, this adaptive drug-resistant cell state also displayed an increased EMT and cancer stem cell signaling as adaptation to the drug treatment and that could be overcome by broad BCL-2/BCL-xL BH3 mimetic ABT-263, but not BCL-2 only mimetic ABT-199.

      Conclusion:
      We identified and characterized the emergence of early adaptive drug-escape within EGFR-mutant NSCLC cells amid an overall precision therapy excellent response, through a MET-independent mechanism. The profoundly drug-resisting prosurvival cell state undertook remarkable cellular transcriptome-metabolome adaptive reprogramming coorindated through autocrine TGFβ2 signaling augmentation. Our study results have important implications in lung cancer drug-resistant minimal/microscopic disease and future therapeutic remedies in precision therapy.

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      MINI09.03 - Characterization of Afatinib or EGFR T790M Specific Inhibitor (WZ8040 or AZD9291) Resistant Lung Cancer Cells (PC9) (ID 1065)

      A.M. Lin, M. Huang, T. Yu, H. Tsai, J. Lee, J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer patients harboring epidermal growth factor receptor (EGFR) mutation respond well to EGFR tyrosine kinase inhibitors (TKI). However, all patients develop resistance to EGFR TKI after long term use. EGFR T790M mutation can be found in about half of the resistant re-biopsy tumors. Afatinib is an irreversible EGFR TKI with in vitro activity against resistant T790M mutation. However, afatinib has little activity in EGFR TKI resistant patients whose tumors developed T790M mutation. A novel alinino-pyrimidine based WZ8040 has been developed to specifically inhibit phosphorylation of EGFR with T790M mutation and not on wild type EGFR. Similar compounds such as CO1686 or AZD9291 has demonstrated high activity against T790M mutations. We plan to develop afatinib or AZD9291, WZ8040 resistant PC9 cells to study afatinib or AZD9291 resistance.

      Methods:
      PC9 cells were grown in culture media containing escalating concentrations of afatinib, WZ8040 or AZD9291. When cells can grow in high concentrations of drugs, cells were cloned, expanded and grew in drug-free media for more than two weeks to obtain stable afatinib, WZ8040 or AZD9291 resistant clones. Gefitinib, afatinib, WZ8040, AZD9291. Cells viability were determined by surforodamine bromide method. PC9 parental and EGFR TKI resistant cells were treated with gefitnib, afatinib, WZ8040 or AZD9291 for one hour and EGFR, AKT, ERK phosphorylation were determined by Western blot. DNA repair capacity were compared between sensitive and resistant cells after exposure of cells to ultraviolet light and measured by pGL3-luciferase plasmid transfection methods. Epithelial mesenchyma transition of these cells were tested by snail, slug, vimentin and E-cadherin western blot. Autophagy was measured by LC3-II levels by Western blot. EGFR exon 18-21 sequence of each clones were determined by Sanger’s direct sequencing.

      Results:
      We developed afatinib resistant PC9 cells, PC9/AFAb2, PC9/AFAc3 and WZ8040 resistant PC9/WZd7, PC9/WZf6. PC9/AFA cells were more than 100-fold resistant to afatinib and PC9/WZ cells were more than 50-fold resistant to WZ8040. 10nM of afatinib treatment inhibits EGF-induced EGFR, AKT and EKR phosphorylation in PC9 cells, but phosphorylation of these kinases were only partially inhibited in PC9/AFA cells. Phosphorylation was completely blocked at 100nM afatinib. MEK inhibitor plus afatinib did not reverse resistance to afatinib in PC9/AFA cells. On the other hand, WZ8040 or AZD9291 alone completely reversed resistance in PC9/AFA cells. EGFR, AKT and ERK phosphorylation can be blocked by 100nM WZ8040 in PC9 and PC9/WZd7 cells. However, it is curious that phosphorylation of these proteins can be inhibited by 100nM gefitinib as well. EGFR T790M mutation was only detected in PC9/AFA cells and not in PC9/gef, PC9/WZ cells. None of the PC9/WZ cells have EGFR C797S mutation. We did not detect any other EGFR resistance mechanism in PC9/AFA cells. Other of comparing EMT, autophagy and DNA repair capacity of PC9 and their resistant cells are ongoing.

      Conclusion:
      We developed multiple gefitinib, afatinib, WZ8040, AZD9291 resistant PC9 cells. Only afatinib resistant cells develop EGFR T790M. We demonstrated that EGFR T790M was the predominant resistant mechanism in PC9/AFA cells. The characteristics of PC9/WZ and PC9/AZD9291 are still under investigation.

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      MINI09.04 - Identification of Effective Drug Combinations to Prevent or Delay Resistance to the EGFR Mutant Selective Inhibitor Rociletinib (CO-1686) (ID 3010)

      A. Simmons, H.J. Haringsma, M. Nguyen, L. Robillard, A. Allen, T.C. Harding

      • Abstract
      • Presentation
      • Slides

      Background:
      Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type (WT) EGFR. Although rociletinib has generated compelling objective responses in heavily-pretreated T790M positive and negative NSCLC patients, acquired resistance to rociletinib monotherapy has also been observed. We are currently exploring preclinical combinations to delay or prevent resistance to rociletinib.

      Methods:
      To study acquired resistance in an unbiased fashion, rociletinib resistant populations and clones were generated from the EGFR mutant NSCLC cell lines PC-9 (del19 EGFR), HCC827 (del19 EGFR), and NCI-H1975 (L858R/T790M EGFR) by chronic in vitro and/or in vivo exposure of rociletinib. Compound library screening was performed with rociletinib resistant cell lines to identify drug combinations that could restore rociletinib sensitivity. In vitro and in vivo validation, mechanism of action, and combination studies were performed to evaluate the potency of these combinations in rociletinib sensitive and resistant preclinical models. In addition, combination studies with therapies commonly used in NSCLC, including radiotherapy (RT), an anti-EGFR antibody, and anti-PD-1/L1 antibodies were also explored.

      Results:
      Multiple mechanisms of resistance were observed in rociletinib resistant cell lines, including MET amplification and an epithelial-mesenchymal transition (EMT). In a PC-9 resistant population (designated 2A10) generated by in vitro and in vivo selection, multiple agents including the aurora kinase inhibitor MLN8237, the MEK inhibitor trametinib, and an anti-EGFR antibody restored rociletinib sensitivity in cell viability assays. Western blot analysis demonstrated that the levels of p-ERK in the parental PC-9 cell line were comparable to p-ERK levels in 2A10 cells grown in the presence of 1 mM rociletinib. The combination of rociletinib and trametinib in the 2A10 cell line suppressed p-ERK signaling, concomitant with increased levels of apoptotic markers such as PARP cleavage. The combination of rociletinib and trametinib also demonstrated potent in vivo activity in the 2A10 xenograft model. In vitro and in vivo studies performed with additional cell lines and combinations are ongoing and will also be presented.

      Conclusion:
      Resistance to all 3[rd] generation EGFR inhibitors is likely to be observed, and identifying tolerable and effective combinations to delay or prevent resistance is critical in extending the clinical benefit of these therapies. In vitro and in vivo studies reported here highlight multiple combinations that restore the activity of rociletinib in rociletinib resistant models. In particular, the combination of trametinib and rociletinib restored MAPK pathway suppression and anti-tumor activity in the rociletinib resistant 2A10 model. These nonclinical data support the ongoing Phase 1/2 evaluation of the combination of trametinib and rociletinib.

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      MINI09.05 - Discussant for MINI09.01, MINI09.02, MINI09.03, MINI09.04 (ID 3313)

      C. Lovly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI09.06 - Oncogenic Drivers including RET and ROS1 plus PTEN Loss and MET by IHC in Patients with Lung Adenocarcinomas: Lung Cancer Mutation Consortium 2.0 (ID 2114)

      B.E. Johnson, M.G. Kris, I.I. Wistuba, L. Berry, M.A. Socinski, S.S. Ramalingam, B. Glisson, G. Otterson, J. Schiller, J. Cetnar, J.R. Brahmer, L.V. Sequist, C. Lovly, J. Minna, P.A. Bunn, Jr, D.J. Kwiatkowski, K. Kugler, S. Waqar, K. Politi, E.B. Garon, E. Haura

      • Abstract
      • Presentation
      • Slides

      Background:
      The Lung Cancer Mutation Consortium (LCMC) 1.0 demonstrated multiplexed genomic platforms can assay 10 oncogenic drivers in tumor specimens from patients with lung adenocarcinomas. 28% of the patients with oncogenic drivers could be effectively targeted. The survival of these 275 patients treated with targeted agents was longer than the patients who were not treated with a targeted agent (Kris and Johnson JAMA 2014). The efficiency of Next-Generation Sequencing enables more comprehensive testing of additional aberrations with less tumor tissue. LCMC 2.0 was initiated to test tumor specimens for 12 oncogenic drivers and to provide the results to clinicians for treatment decisions and research purposes.

      Methods:
      The 16 site LCMC 2.0 is testing tumors from 1000 patients with lung adenocarcinomas in CLIA laboratories for mutations in KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, and NRAS, MET DNA amplification, and rearrangements in ALK as done in LCMC 1.0. The new genes that were added because of emerging information about potential therapeutic targets include MAP2K1 mutations, RET and ROS1 rearrangements, PTEN (MAb 138G4) loss and MET (MAb SP44) overexpression by immunohistochemistry (IHC). All patients were diagnosed with stage IIIB/IV lung adenocarcinoma after May 2012, had a performance status 0-2, and available tumor tissue.

      Results:
      Of 1073 patients registered, data is now reported for 759. The median age of the patients is 65 (23-90). The population includes 369 (55%) women; 164 (24%) never smokers, 399 (59%) former smokers, and 73 (11%) current smokers; 26 (4%) Asians, 58 (9%) African American, 548 (81%) Caucasian, and 43 (6%) of other races. As of April 2015 information on genomic and immunohistochemical changes for 675 eligible patients were recorded in our database. Alterations in oncogenic drivers were found in 45% of samples as follows: 159 KRAS (24%), 88 EGFR (13%), 25 ALK (4%), 19 BRAF (3%), 17 PIK3CA (3%), 9 HER2 (1%), 4 NRAS (1%) 0 AKT1, 28 had ≥ 2 findings (4%) and 25 MET DNA amplification (4%). The new genes studied in LCMC 2.0 revealed 1 MAP2K1 mutation (<1%), 19 RET (3%) and 9 ROS (1%) rearrangements, 94 had PTEN loss (14%), and 362 with MET overexpression (54%). As expected, PIK3CA mutations and PTEN loss by IHC were mutually exclusive in 109 of 111 (98%) patients’ tumors. Seventeen of the 23 (74%) with MET DNA amplification studied thus far with IHC had MET overexpression. Next-Generation platforms were used at 13 of 16 LCMC 2.0 sites.

      Conclusion:
      Next-Generation Sequencing is rapidly becoming routine practice at LCMC 2.0 centers with use going from 0 to 81% of sites since 2012. LCMC 2.0 identified additional targets (RET and ROS1 rearrangements and PTEN loss). PIK3CA and PTEN were largely mutually exclusive and an actionable oncogenic driver has been identified in the 45% of initial lung adenocarcinoma specimens. Supported by Free to Breathe

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      MINI09.07 - Activation of the MET Kinase Confers Acquired Resistance to FGFR-Targeted Therapy in FGFR-Dependent Squamous Cell Carcinoma of the Lung (ID 1212)

      Y.W. Moon, S. Kim, H. Kim, H.R. Kim, S.M. Lim, B.C. Cho

      • Abstract
      • Presentation
      • Slides

      Background:
      Fibroblast growth factor receptor (FGFR) tyrosine kinase plays a crucial role in cancer cell growth, survival, and resistance to chemotherapy. FGFR1 amplification occurs at a frequency of 10-20% and is a novel druggable target in squamous cell carcinoma of the lung (SCCL). A number of FGFR-targeted agents are currently being developed in SCCL harboring FGFR alterations. The aim of the study is to evaluate the activity of selective FGFR inhibitors (AZD4547, BAY116387) and the mechanisms of intrinsic and acquired resistance to these agents in SCCL.

      Methods:
      The antitumor activity of AZD4547 and BAY116387 was screened in a panel of 12 SCCL cell lines, among which 4 cell lines harbored FGFR1 amplification. To investigate mechanisms of acquired resistance, FGFR1-amplified H1581 cells which were exquisitely sensitive to FGFR inhibitors, were exposed to AZD4547 or BAY116387 to generate polyclonal resistant clones (H1581-AR, H1581-BR). Characterization of these resistant clones was performed using receptor tyrosine kinase (RTK) array, immunoblotting and microarray. Migration and invasion assays were also performed.

      Results:
      Among 12 SCCL cell lines, two FGFR1-amplified cells, H1581 and DMS114, were sensitive to FGFR inhibitors (IC~50~<250 nmol/L). Compared with resistant cells, sensitive cells showed increased phosphorylation of FRS2 and PLC-γ, but decreased phosphorylation of STAT3. There was no noticeable difference in FGFR1-3 protein expression level between sensitive and resistant cells. Importantly, phosphorylation of ERK1/2 was significantly suppressed upon treatment of FGFR inhibitors only in sensitive cells, suggesting phospho-ERK1/2 as a pharmacodynamic marker of downstream FGFR signaling. RTK array and immunoblots demonstrated strong overexpression and activation of MET in H1581-AR and H1581-BR, in comparison to almost nil expression in parental cells. Four different SCCL cells with intrinsic resistance to FGFR inhibitors also showed intermediate to high MET expression, suggesting that MET may be involved in both intrinsic and acquired resistance to FGFR inhibitors. Gene-set enrichment analysis against KEGG database showed that cytokine-cytokine receptor interaction pathway was significantly enriched, with MET contributing significantly to the core enrichment, in H1581-AR and H1581-BR, as compared with parental cells. Stimulation with HGF strongly activated downstream FGFR signaling or enhanced cell survival in the presence of FGFR inhibitors in both acquired and intrinsic resistant cells. Quantitative PCR on genomic DNA and fluorescent in situ hybridization revealed MET amplification in H1581-AR, but not in H1581-BR. MET amplification led to acquired resistance to AZD4547 in H1581-AR by activating ERBB3. The combination of FGFR inhibitors with ALK/MET inhibitor, crizotinib, or small interfering RNA targeting MET synergistically inhibited cell proliferation in both H1581-AR and H1581-BR, whereas it resulted in additive effects in SCCL cells with intrinsic resistance to FGFR inhibitors. Acquisition of resistance to FGFR inhibitors not only led to a morphologic change, but also promoted migration and invasion of resistant clones via inducing epithelial to mesenchymal transition phenotype, as documented by a decrease in E-cadherin and an increase in N-cadherin and vimentin.

      Conclusion:
      MET activation is sufficient to bypass dependency on FGFR signaling and concurrent inhibition of these two pathways may be desirable when targeting FGFR-dependent SCCL.

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      MINI09.08 - Secondary C805S Mutation in HER2 Gene Confers Acquired Resistance to HER2 Kinase Inhibitors in HER2 Mutant Lung Cancer (ID 2181)

      T. Kosaka, H. Endoh, C. Repellin, J. Tanizaki, D. Ercan, M. Capelletti, P.A. Jänne

      • Abstract
      • Presentation
      • Slides

      Background:
      Activating mutations in the HER2 kinase domain are detected in 2-4% of non-small cell lung cancers (NSCLC), and are oncogenic in both in vitro and in vivo models. Current clinical strategies to target mutant HER2 include the use of covalent HER2 inhibitors afatinib, dacomitinib and neratinib; all of which have limited single agent activity. We evaluated how drug sensitive models of HER2 mutant lung cancer develop acquired resistance in vitro to gain biological insights and to predict how acquired resistance may develop in the clinic.

      Methods:
      Murin Ba/F3 cells expressing duplication/insertion of four amino acids (YVMA) between codon 775 and 776 in exon 20 of HER2 gene (A775_G776insYVMA (insYVMA)) were exposed to N-ethyl-N-nitrosourea mutagenesis and expanded in the presence of neratinib and dacomitinib. Total RNAs were extracted from resistant clones and sequencing of the HER2 tyrosine kinase domain was performed. Drug resistance was confirmed with cell growth assays and western blotting.

      Results:
      Total 5 clones for Neratinib and 7 clones for Dacomitinib were expanded from each 300 wells. Sequencing analysis revealed that all resistant clones retained original insertion mutation and acquired same substitution of Cysteine to Serine change in codon 805 (C805S) in exon 20 of HER2 gene. This mutation is analogous to the EGFR C797S mutation that mediates resistance to 3[rd] generation EGFR inhibitors. Next, we generated Ba/F3 cells co-expressing activating mutations; insYVMA and a dacomitinib hypersensitive insertion mutation (insertion of three amino acids (WLV) after codon 774 with deletion of M774 (M774del insWLV (insWLV))), in cis with the C805S mutation. Cell growth assay revealed these double mutants were resistant to all three second generation inhibitors for EGFR family; neratinib, dacomitinib, and afatinib, compared to parental cells which only have activating mutation. They were also resistant to 3[rd] generation EGFR inhibitors; WZ40002 and AZD9291. Phosphorylation of HER2 was not completely inhibited by these drugs. Resistant cells showed moderate sensitivity to mTOR inhibitor; rapamycin alone. Combination treatment with afatinib and rapamycin effectively inhibited growth of these cells.

      Conclusion:
      The C805S secondary HER2 mutation results in acquired resistance to covalent HER2 inhibitors in HER2 mutant NSCLC. Our results provide insights into drug resistance mechanisms and help predict likely clinical mechanisms of resistance to HER2 targeted therapies in HER2 mutant NSCLC.

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      MINI09.09 - Discussant for MINI09.06, MINI09.07, MINI09.08 (ID 3314)

      E.B. Garon

      • Abstract
      • Presentation
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      Abstract not provided

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      MINI09.10 - Tumor Angiogenesis in LKB1-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 3059)

      I. Guijarro, M. Nilsson, A. Poteete, P. Tong, H. Sun, W. Denning, D. Xia, F. Skoulidis, J. Wang, E. Roarty, J.V. Heymach

      • Abstract
      • Presentation
      • Slides

      Background:
      LKB1 is a critical regulator of cell growth, metabolism and EMT, and it is mutated in 20-30% of non-small cell lung cancers (NSCLC). LKB1 mutations co-occur with KRAS-activating mutations in 7%-10% of all NSCLC and results in an aggressive phenotype and a worse response to chemotherapy compared to KRAS-mutated tumors. Because LKB1 activates AMPK (AMP-activated protein kinase) which functions as a cellular energy sensor, LKB1-deficient cells are unable to appropriately sense metabolic and energetic stress. LKB1 is also known to regulate angiogenesis, but the mechanism(s) by which this occurs remains unclear. Bevacizumab, the human anti-VEGF antibody approved for the treatment of NSCLC, improves the progression-free and overall survival of NSCLC patients combined with chemotherapy, but often the benefit is transient, and therapeutic resistance occurs. Our laboratory has previously identified phenotypical differences in vasculature patterns in A549 NSCLC tumors resistant to bevacizumab (LKB1 mutant), when compared to H1975 tumors, (LKB1 wild-type). In addition, LKB1 mutant NSCLC cell lines are highly vulnerable to agents acting on energetic pathways. These results may indicate that loss of LKB1 in NSCLC could alter the tumor vasculature and regulate sensitivity to anti-angiogenic therapies. Here, we investigate the hypothesis that combinations of energetic-depleting compounds along with blockade of tumor angiogenesis would be more effective in NSCLC LKB1 mutant tumors.

      Methods:
      mRNA and protein expression of 584 angiogenesis-related genes were analyzed in wild-type and LKB1 mutant NSCLC (TCGA, RPPA and PROSPECT databases). In vitro validation was performed using qPCR, immunohistochemistry and western blot analysis as well as pairs of isogenic LKB1 mutant cell lines with overexpressed or silenced LKB1. Endothelial cells were incubated with conditioned medium of wild-type and LKB1 mutant NSCLC cell lines, and tube formation matrigel, proliferation and migration (Boyden chamber) assays were performed.

      Results:
      We identify a group of new and classic angiogenesis-related molecules: VEGFA, VEGFR1, KDR, NRP1, PDGFB, PDGFRA-B, HIF-1A, C-KIT, VCAM1, hypoxia related molecules: HIF1AN, EGLN1, HIF3A, CA12, EPAS1 and immune related molecules: TNFSF11, NFKB1, CD47, PDL1 differentially expressed in LKB1-wild type and LKB1 mutant NSCLC (p<0.05 and fold-change ≥ or ≤1.5). LKB1 mutant cell lines showed higher protein expression of phospho-cKIT, a tyrosine-kinase receptor involve in cell proliferation and angiogenesis, and CA12 (Carbonic anhydrase 12), a known HIF-1α regulated molecule, involved in maintaining cellular pH homeostasis. Also, LKB1 mutant cells exhibit different quantitative vascular patterns in matrigel assays like number of nodes, junctions, length and branching of the endothelial matrix (p<0.05). Human endothelial cells exhibited an increase rate of proliferation and migration when incubated with conditioned medium from LKB1 mutant NSCLC cell lines compared with conditioned media from LKB1-wild type NSCLC cell lines (p<0.05).

      Conclusion:
      There are biological differences in vasculature patterns in LKB1 mutant NSCLC tumors and in LKB1 mutant cell lines comparing with wild-type LKB1. These differences are translated in biological alterations of human endothelial cells in vitro suggesting an important role of LKB1 in resistance to anti-angiogenic treatments in vivo.

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      MINI09.11 - Adaptor Re-Programming and Acquired Resistance in RET-Fusion Positive NSCLC (ID 2891)

      S. Nelson, L. Schubert, A.T. Le, K.A. Ryall, S. Kako, A. Tan, M. Varella-Garcia, R.C. Doebele

      • Abstract
      • Presentation
      • Slides

      Background:
      RET gene fusions were identified as a novel oncogenic driver of ~1-2% of non-small cell lung cancer (NSCLC) patients and clinical trials investigating the use RET TKI therapy are underway. Like all NSCLC patients treated with TKI therapies, it is expected that drug resistance will emerge in this patient population. The mechanisms that drive acquired resistance to RET TKI therapy are still unknown. The objective of this study is to advance current understanding of RET signaling in NSCLC and to identify the cellular mechanisms of acquired RET TKI resistance that will eventually emerge in RET fusion positive NSCLC patients by using in vitro models of drug resistance.

      Methods:
      The LC-2/ad is a lung adenocarcinoma cell line that harbors the CCDC6-RET fusion. We created three distinct ponatinib resistant (PR) LC-2/ad cell lines (PR1, PR2, PR3) derived from three different dose-escalation strategies. RET break-apart fluorescence in situ hybridization (FISH) was performed on the parental LC-2/ad and PR-derivatives. Interactions between the RET kinase domain and known adaptor signaling molecules were assessed via proximity ligation assay (PLA) in parental LC-2/ad cells and resistant lines. Formation of RET-adaptor signaling complexes were confirmed via immunoprecipitation and western blot analysis. Next-generation RNA sequencing in conjunction with a high-throughput small molecule inhibitor screen were performed to elucidate the signaling pathways that drive resistance to RET-inhibition. Pathways and candidate molecules identified by these screens were validated using siRNA knockdown and pharmacologic inhibition in the context of a cell-proliferation MTS assay. Western blot analysis was utilized to identify the downstream signaling programs responsible for proliferation and survival in the RET-inhibition resistant cell lines.

      Results:
      MTS cell proliferation assay confirmed that all three ponatinib resistant cell lines are significantly less sensitive to ponatinib than parental LC-2/ad cells. RET FISH analysis demonstrated that the CCDC6-RET gene was retained in the PR1 and PR2 cell lines, but lost in the PR3 cell line. RT-PCR and western blot analysis confirmed the loss of the CCDC6-RET fusion in the PR3 cell line. DNA sequencing demonstrated no RET kinase domain mutations in either the PR1 or PR2 derivatives. Further, profound changes in the RET-signaling program have emerged in the PR1 and PR2 cell lines. Using a RET-GRB7 PLA, we have demonstrated that PR1 cells no longer form RET-GRB7 signaling complexes, while PR2 cells retain RET-GRB7 complexes even in the presence of ponatinib. Next-generation RNA sequencing of the PR1 cell line revealed an increase in expression of several known EMT markers including caveolin-1, vimentin, and ADAMTS1.

      Conclusion:
      Like many other targeted therapeutic strategies, resistance to small molecule Ret-inhibition in RET-fusion positive lung cancer cells can be driven by multiple mechanisms. Changes in the RET-adaptor programming appear to mitigate resistance in both the PR1 and PR2 cell lines, suggesting that RET-resistant cells may have successfully undergone an oncogenic switch to rely upon another known oncogenic driver in lieu of the CCDC6-RET fusion. Further, EMT reprogramming of the LC-2/ad cell may have contributed to the resistance phenotype in the PR1 cell line.

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      MINI09.12 - HDAC Inhibitors Overcome New Generation EGFR-TKI-Resistance Caused by Homozygous BIM Polymorphism in EGFR Mutant Lung Cancer (ID 885)

      S. Yano, A. Tanimoto, S. Arai, K. Fukuda, S.T. Ong, S. Takeuchi

      • Abstract
      • Slides

      Background:
      The BIM deletion polymorphism in intron 2 was found in a significant percent (~13%) of the Asian population, with 0.5% of individuals being homozygous for this deletion. Patients with EGFR mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to 1[st] generation EGFR-TKIs, gefitinib and erlotinib. We recently reported that the histone deacetylase (HDAC) inhibitor vorinostat can epigenetically restore BIM function and death sensitivity of EGFR-TKI, in cases of EGFR mutant lung cancer where resistance to 1[st] generation EGFR-TKI is associated with a heterozygous BIM polymorphism. Here, we examined 1) whether BIM polymorphism associated with resistance to new generation EGFR-TKIs and 2) whether vorinostat could overcome EGFR-TKI resistance in EGFR mutant lung cancer cells with a homozygous BIM polymorphism.

      Methods:
      We used EGFR mutant lung cancer cells lines, PC-9, PC-9[i2BIM-/-] (a genetically engineered subclone that was homozygous for BIM deletion polymorphism), and PC-3 (heterozygous for BIM deletion polymorphism). These cell lines were treated with gefitinib, afatinib (2[nd] generation), and AZD9291 (3[rd] generation). Apoptosis was evaluated by FACS and expression of cleaved-caspase 3/7 and PARP by western blot.

      Results:
      While PC-9 cells were sensitive to all EGFR-TKIs in terms of apoptosis induction, both of PC-3 and PC-9[i2BIM-/- ] cells were resistant to 1[st] generation EGFR-TKIs and new generation EGFR-TKIs as well. Vorinostat combined with new generation EGFR-TKIs induced apoptosis of PC-3 and PC-9[i2BIM-/- ] cells in vitro. In the subcutaneous tumor model, AZD9291 regressed the tumors produced PC-9 cells but not PC-9[i2BIM-/- ] cells, indicating in vivo resistance of PC-9[i2BIM-/- ] cells to EGFR-TKIs. Combined use of vorinostat with AZD9291 successfully decreased the size of tumors produced by PC-9[i2BIM-/-] cells by inducing tumor cell apoptosis.

      Conclusion:
      These observations indicated that BIM deletion polymorphism is associated with apoptosis resistance caused not only by 1[st] generation EGFR-TKIs but also by new generation EGFR-TKIs. Moreover, combined use of HDAC inhibitor may overcome EGFR-TKI resistance associated not only with heterozygous deletion but also with homozygous deletion in the BIM gene.

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      MINI09.13 - Neuropilin-2 Promotes Acquired Resistance to EGFR-TKI Associated with the Epithelial–Mesenchymal Transition in Lung Cancer (ID 1271)

      P. Nasarre, J. Nair-Menon, A. Dimou, T. Yoshida, H. Uramoto, E. Haura, R.M. Gemmill, H.A. Drabkin

      • Abstract
      • Slides

      Background:
      Lung cancer accounts for one-fifth of cancer deaths worldwide with invasion, metastases and drug resistance representing major causes of mortality and barriers to cure. While lung cancers with activating mutations in the EGF receptor (EGFR) are susceptible to tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, the efficacy of these agents is limited by the inevitable development of resistance. The epithelial-mesenchymal transition (EMT), by which epithelial cells acquire a mesenchymal and invasive phenotype, is one mechanism promoting EGFR-TKI resistance, including resistance to 3[rd] generation T790M-specific inhibitors. However, the molecular connections between EMT and resistance are not well understood. Here we report that upregulation of Neuropilin-2 (NRP2) is crucial for development of EGFR-TKI resistance associated with the EMT. NRP2 is a cell surface receptor for SEMA3F, a secreted semaphorin with tumor suppressor activity that is down-regulated during EMT. NRP1 and NRP2 are also co-receptors and signaling enhancers for several growth-promoting ligands such as VEGF, HGF and FGF. We previously reported that NRP2 was induced by TGFβ as part of an EMT response in lung cancers and that NRP2 knockdown suppressed the EMT phenotype, including local tumor invasion in a subcutaneous xenograft model.

      Methods:
      Immunohistochemistry (IHC) was performed for NRP2 on patient biopsies, before and after development of gefitinib resistance. EGFR mutant NSCLC cell lines, transfected with control or NRP2-specific shRNAs, were selected for gefitinib/erlotinib resistance in vitro, using progressively increasing concentrations or continuous exposure to IC~50~ levels of EGFR TKIs. Western blot analysis confirmed changes in NRP2 expression along with selected markers of EMT. MTS viability assays determined drug sensitivity while migration and invasion were assessed using Boyden chambers. Growth as spheroids was assessed in 1% methylcellulose medium in low-adherence plates.

      Results:
      Increased NRP2 was observed in lung tumor biopsies following acquisition of EMT-associated gefitinib-resistance, and in HCC4006-ER cells, which acquired a stable erlotinib-resistant EMT phenotype. In vitro, using multiple EGFR mutant cell lines, NRP2 knockdown blocked acquired gefitinib-resistance, arising both spontaneously following growth in IC~50~ concentrations or after exposure to TGFβ. Of interest, spontaneously-resistant cells exhibited increased migration similar to cells stimulated with TGFβ. NRP2 knockdown also blocked tumorsphere formation, which has been associated with stem-cell characteristics and drug resistance.

      Conclusion:
      Collectively, our results demonstrate that NRP2 is a mediator of acquired EGFR-TKI resistance. The results also suggest that NRP2 blocking antibodies could be useful for enhancing the duration of response to EGFR inhibitors, including those targeting the T790M mutation.

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      MINI09.14 - Discussant for MINI09.10, MINI09.11, MINI09.12, MINI09.13 (ID 3315)

      C. Mathias

      • Abstract
      • Presentation
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      Abstract not provided

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    MINI 10 - ALK and EGFR (ID 105)

    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 15
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      MINI10.01 - Frequency of Concomitant EGFR, EML4-ALK or KRAS Alterations in NSCLC Patients and Correlation with Response to Treatment (ID 942)

      P. Ulivi, E. Chiadini, C. Dazzi, A. Dubini, M. Costantini, L. Medri, M. Puccetti, L. Capelli, D. Calistri, A. Verlicchi, A. Gamboni, M. Papi, M. Mariotti, N. De Luigi, E. Scarpi, S. Bravaccini, G.M. Turolla, D. Amadori, L. Crinò, A. Delmonte

      • Abstract
      • Presentation
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) and KRAS mutations, and echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation are generally considered to be mutually exclusive. However, some reports show that a number of patients may have concomitant mutations, and it is not yet clear what impact these double mutations could have on response to targeted therapy.

      Methods:
      We took into consideration 380 NSCLC patients who underwent non-sequential testing for EGFR and KRAS mutations and EML4-ALK translocation between January 2010 and December 2013. EGFR mutation and EML4-ALK translocation analysis were performed on the entire case series and KRAS mutation analysis was performed on 282 cases.

      Results:
      EGFR mutation and EML4-ALK translocation were present in 44 (11.6%) and 32 (8.4%) of patients, respectively. Ninety-two patients (32.6%) showed a KRAS mutation. Two concomitant mutations among EGFR, KRAS or EML4-ALK genes were observed in 16 patients. In particular, 6 of the 380 (1.6%) patients analyzed had concomitant EGFR mutation and EML4-ALK translocation. Of the 282 patients who also underwent KRAS mutation, 3 (1.1%) showed a concomitant EGFR and KRAS mutation and 7 (2.5%) a concomitant EML4-ALK and KRAS alteration. Of the 44 EGFR-mutated patients, 28 received a TKI-based treatment (24 with gefitinib and 4 with erlotinib) as first-line therapy, and 6 of these also had an EML4-ALK translocation. Among the 22 patients with EGFR mutation only, we observed 2 complete response (CR) (9%), 16 partial response (PR) (72.7%) and 4 progressive disease (PD) (18%). Of the 6 patients who also had an EML4-ALK translocation, one had CR (17%), 3 PR (50%) and 2 PD (33%). No differences were seen in terms of overall survival (OS). Of the 32 patients harboring the EML4-ALK translocation, 6 (those also carrying the EGFR mutation) were treated with a TKI as first-line therapy, while the others received chemotherapy. Twelve patients received crizotinib as second-line treatment and 7 progressed within 3 months of starting therapy. Of these, 2 showed a concomitant KRAS mutation (G12C) and one a concomitant EGFR mutation (exon 19 del). Two patients had stable disease, one of whom also showed a KRAS mutation (G12V). Two patients had PR and one had CR, all of whom showed a EML4-ALK translocation only. The median OS of the patients carrying an EML4-ALK translocation alone or a concomitant KRAS mutation was 57.1 (range 10.7-nr) and 10.7 (range 4.6-nr) months, respectively.

      Conclusion:
      The concomitant presence of EGFR, EML4-ALK or KRAS mutations is a possible event in NSCLC. KRAS mutation in patients with EML4-ALK translocation represents the most common double mutation and seems to confer a poor prognosis.

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      MINI10.02 - Intratumoral Heterogeneity of ALK-Rearranged and ALK/EGFR Co-Altered Lung Adenocarcinoma (ID 685)

      W. Cai, C. Zhou, D. Lin, C. Wu, X. Li, C. Zhao, L. Zheng, K. Fei, F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background:
      Genetic intratumoral heterogeneity has a profound influence on the selection of clinical treatment strategies and addressing resistance to targeted therapy. The purpose of our study is to explore the potential effect of intratumoral heterogeneity on both the genetic and pathologic characteristics of ALK-rearranged lung adenocarcinoma (LADC).

      Methods:
      We tested ALK fusions and EGFR mutations in 629 LADC patients by using laser capture microdissection (LCM) to capture spatially separated tumor cell subpopulations in various adenocarcinoma subtypes and test for ALK fusions and EGFR mutations in ALK-rearranged, EGFR-mutated, and ALK/EGFR co-altered LADCs in order to compare the oncogenic driver status between different tumor cell subpopulations in the same primary tumor.

      Results:
      Among the 629 patients, 30 (4.8%) had ALK fusions, 364 (57.9%) had EGFR mutations, and 2 had ALK fusions coexisting with EGFR mutations. Intratumoral heterogeneity of ALK fusions was identified in 9 patients by RT-PCR. In the 2 ALK/EGFR co-altered patients, intratumoral genetic heterogeneity was observed both between different growth patterns and within the same growth pattern. Genetic intratumoral heterogeneity of EGFR mutations was also identified in EGFR-mutated NSCLC. ALK fusions were positively associated with a micropapillary pattern (P=0.002) and negatively associated with a lepidic pattern (P=0.008) in a statistically-expanded analysis of 900 individual adenocarcinoma components, although they appeared to be more common in acinar-predominant LADCs in the analysis of 629 patients.

      Conclusion:
      Intratumoral genetic heterogeneity was demonstrated to co-exist with histologic heterogeneity in both single-driver and EGFR/ALK co-altered LADCs. As for the latter, one of the dual altered drivers may be the trunk-driver for the tumor.

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      MINI10.03 - Evolution of Concurrent Driver Mutations in Lung Adenocarcinoma Patients on EGFR TKI Therapy Uncovered by Comprehensive Molecular Profiling (ID 2848)

      C.M. Blakely, S. Asthana, E. Pazarentzos, V. Olivas, L. Lin, J. Flanagan, A. Caulin, P. Giannikopoulos, T. Bivona

      • Abstract
      • Slides

      Background:
      Lung adenocarcinoma (LAC) patients (p) with EGFR mutations respond initially to EGFR tyrosine kinase inhibitors (TKIs) but invariably develop acquired EGFR TKI resistance. Prior studies identified the EGFR T790M mutation and activation of MET, NF-kB, PI3K, AXL, HER2 and the MAPK pathway as drivers of acquired EGFR TKI resistance. We hypothesized that tumor cell populations present pre-treatment harbor mechanisms of EGFR TKI resistance that are subsequently selected for by EGFR TKI therapy.

      Methods:
      We performed longitudinal comprehensive molecular tumor profiling on 10 p with metastatic EGFR-mutant LAC throughout the course of their disease. Exome sequencing to a mean depth of coverage of 100 X, was performed on FFPE or frozen patient tumor specimens as well as matched normal control specimens collected from patients prior to initiating standard erlotinib (erl) treatment, upon the development of erl resistance, and upon resistance to subsequent 2[nd] line therapy when available. One case of a patient with acquired resistance to the 3[rd] generation EGFR TKI Rociletinib was analyzed. We performed functional analysis of select mutations identified using established cellular models of EGFR-mutant LAC.

      Results:
      We constructed phylogenetic trees based on somatic mutations and copy number alterations identified by exome sequencing of longitudinally acquired patient specimens. Activating mutations (L858R or exon 19 deletion) were present in all tumor specimens analyzed, indicating that this is a ‘truncal’ event. We identified on-target mutation in EGFR (T790M) in ~ 50% of erl resistant specimens as expected. However, in three patients we identified concurrent low frequency oncogenic driver events pre-EGFR TKI treatment that subsequently increased in frequency upon erlotinib resistance. This included: 1) a BRAF V600E mutation that was detected pre-treatment at a low frequency that expanded in the erlotinib resistant tumor specimen; 2) a PIK3CA G106V mutation that was not present in a patient’s primary tumor, but developed in a lymph node metastasis at a low frequency and subsequently expanded in the erlotinib resistant tumor, and 3) a pre-treatment KRAS amplification that was found in a patient with de novo resistance to erlotinib. The functional significance of these mutations in driving tumor growth and EGFR TKI resistance will be discussed. We will also present exome sequencing analysis from multiple tumors (including a CNS and spinal metastasis) collected from the autopsy of a patient with initial response, but rapid development of acquired resistance to Rociletinib.

      Conclusion:
      These results indicate that EGFR-mutant LAC can harbor additional oncogenic driver mutations at low frequencies prior to therapy. EGFR TKI treatment can lead to expansion of these subclonal populations likely contributing to EGFR TKI resistance in patients with or without the EGFR T790M resistance mutation. These data demonstrate the utility of comprehensive molecular profiling of LAC p on targeted therapy beyond assessing EGFR T790M mutational status, and suggest that pre-treatment tumor analyses can in some cases predict mechanisms of EGFR TKI resistance before they become clinically significant.

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      MINI10.04 - Discussant for MINI10.01, MINI10.02, MINI10.03 (ID 3399)

      T. Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI10.05 - ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis (ID 2731)

      J.S.M. Mattsson, M.A. Svensson, B. Hallström, H. Koyi, E. Brandén, H. Brunnström, K. Edlund, S. Ekman, L. La Fleur, M. Grinberg, J. Rahnenführer, K. Jirström, F. Pontén, M.G. Karlsson, C. Karlsson, G. Helenius, M. Uhlén, J. Botling, P. Micke

      • Abstract
      • Presentation
      • Slides

      Background:
      Identification of EML4-ALK fusion proteins has revolutionized the treatment of a subgroup of non-small cell lung cancer (NSCLC) patients. Although the gene inversion is regarded as the relevant event for therapy response, the relation between gene rearrangement, mRNA and protein levels has not been evaluated in detail. Thus, the objective of this study was to comprehensively define the molecular relations induced by ALK rearrangements in a large representative Swedish NSCLC cohort incorporating genomic, gene expression and protein data, as well as corresponding clinical correlates.

      Methods:
      ALK protein analysis was performed on 860 NSCLC patients (551 adenocarcinoma, 224 squamous cell carcinomas, 85 large cell carcinomas/NOS) using immunohistochemistry (IHC) on tissue microarrays (TMAs), applying an established monoclonal ALK antibody (clone D5F3, Cell signaling). In parallel, ALK rearrangement was determined by fluorescent in situ hybridization (FISH, Abbott, Vysis ALK Break Apart FISH Probe Kit) on the same TMAs. A subgroup of patients was additionally analyzed utilizing gene expression microarrays (Affymetrix, n=194) or RNA-sequencing (n=202). The RNA sequencing data was also used to identify ALK gene fusions.

      Results:
      ALK protein expression was observed in 12/860 (1.4%). ALK rearrangement was detected in 11/860 samples (1.3%) by FISH analysis. Of 194 patients evaluated by microarray, six (3.1%) showed high ALK gene expression and of 202 patients analyzed by RNA-seq, nine (4.5%) demonstrated high ALK transcript levels. Of the 11 FISH rearranged patients, eight (73%) showed positive protein expression. High ALK gene expression was observed in all four ALK-FISH rearranged samples with matching microarray or RNA-seq data. Of five patients with positive protein expression, only three (83%) showed high gene expression levels according to gene expression microarray and RNA-seq data. RNA-seq revealed that 2/202 samples were ALK rearranged, both of which were detected by FISH and IHC. One sample that was not rearranged according to RNA-seq-data did, however, demonstrate rearrangement with FISH.

      Conclusion:
      The overall frequency of ALK rearrangements in this NSCLC cohort was lower than previously reported, with a significant but variable correlation on different molecular levels. It is possible that technical issues with regard to the use of TMAs, where only a fraction of the whole tumor is represented, may have hampered the results. Therefore, the FISH and IHC analysis will be complemented with assessments on whole tissue sections. The discordant results also stress the need for careful validation of these methods before they can be implemented in the clinical practice.

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      MINI10.06 - Incidence of ALK Gene Rearrangements in a Prospectively, Consecutively Collected Caucasian Population with Pulmonary Adenocarcinomas (ID 684)

      B.G. Skov, J.B. Soerensen, K.R. Larsen, P. Clementsen, A. Mellemgaard

      • Abstract
      • Presentation
      • Slides

      Background:
      EML4-ALK oncogene fusion in non- small cell lung cancer, identifies patients sensitive to ALK-targeted inhibitors. Estimates of the frequency of this fusion oncogene rearrangement are primarily available from selected patient cohorts. The true incidence in an unselected Caucasian population is unknown. This study assess the incidence of ALK rearrangement in a population based cohort, together with correlation to gender, age, smoking habits, as well as pathological and clinical.

      Methods:
      All patients in a well-defined catchment area of 1.7 million people in the capital region of Denmark diagnosed with pulmonary adenocarcinomas from April 1. 2013 to July 31. 2014 were prospectively included. The type and location of the diagnostic material, and data on smoking and clinical characteristics were registered. The rearrangement analyses were investigated by up-front analysis with immunohistochemistry (IHC) using clone 5A4 Novocastra and all IHC positive tests were also subsequently tested by FISH using Zytovision, spec. ALK Dual Color Break Apart.

      Results:
      Among 797 patients included in this study, 777 patients (97.5%) patients had sufficient material for mutation analysis. Fourteen patients (1.8%, 95% CI 1.1-3.0) were IHC positive, all with 3+ reaction. All but one of these were also FISH positive. Eight patients (57%) were women. Median age was 62.7 years. All tumors were strongly TTF1 positive with mucin present in the cytoplasm of the malignant cells without dominance of any subtype. Ten patients (71.4) were diagnosed in stage IIIa or higher. Nine patients (64.3%) were never smokers, 3 (21.4%) were light smokers (0.5-10 yrs), 2 (14.3 %) were heavy smokers (25-40 yrs). More than 1/3 (36%) of the analyses were done on cytological, cellblock material. Seven patients had localized or locally advanced disease and did not receive crizotinib. Among seven patients with advanced disease, six received crizotinib with one complete response in a light smoker (male) and three partial responses in two never and one light smoker (response rate 67%). One out of three females receiving crizotinib achieved a response while it was three out of three males. No heavy smokers received crizotinib despite an ALK translocation was identified. Median progression free survival for patients receiving crizotinib was 3.4 months (range 0-20 months).

      Conclusion:
      ALK rearrangement analysis was possible in 97.5% of all patients with pulmonary adenocarcinomas. 1.8% had a positive test. Rearrangements were primarily found in never/light smokers. No difference in gender regarding rearrangement status was observed. Response rate to crizotinib was 67% and was in this study more frequent in males than in females (not significant). Chance of response was equal in light and in never smokers.

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      MINI10.07 - Lung Adenocarcinomas Co-Expressing TTF-1, MUC5B and/or MUC5AC Show a High Incidence of ALK Rearrangement and a Poor Prognosis (ID 802)

      D. Lin, W. Sun

      • Abstract
      • Slides

      Background:
      The lung adenocarcinomas can be divided into terminal respiratory unit (TRU) and non-TRU types, as these tumors frequently show distinctive morphologic and gene expression characteristics. Tumors co-expressing thyroid transcription factor-1 (TTF-1) and mucins MUC5B and/or MUC5AC exhibit intermediate morphology between TRU-type and non-TRU-type adenocarcinomas. Few studies have focused on this type of adenocarcinoma.

      Methods:
      176 patients with lung adenocarcinoma were retrospectively reviewed. The tumors were divided into TRU type, non-TRU and the intermediate type by morphology and immunohistochemistry (TTF-1, MUC5B, MUC5AC). The expression of Napsin-A, CK20, epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement were also evaluated.

      Results:
      TTF-1, MUC5B, MUC5AC, Napsin-A and CK20 were detected in 157 (89.2%), 52 (29.5%), 10 (5.7%), 143 (81.3%), and 10 (5.7%) patients, respectively. EGFR mutation and ALK rearrangement were present in 56 (31.8%) and 13 (7.4%) patients, respectively. 99, 44 and 33 patients, respectively, were defined as TRU-type, intermediate-type, and non-TRU-type by morphology and immunohistochemistry (Fig 1). A cribriform pattern and extracellular mucus were present in 44 (25.0%) and 38 (21.6%) patients, and the intermediate type was associated with a cribriform pattern and extracellular mucus morphologically, a transitional phenotype in Napsin-A and EGFR mutations (Fig 2). ALK rearrangement tumors were significantly associated with the expression of MUC5B (P = 0.026). The intermediate type present a higher incidence of ALK rearrangement compared with the other types (P = 0.005), which ALK rearrangement were detected in 8 of 44(18.2%) cases. There was no significant difference in prognosis between the morphological TRU and non-TRU types (P = 0.076). However, when the tumors were classfied into 3 groups, TRU type showed better prognosis than the other types (P = 0.038). Figure 1 Figure 2





      Conclusion:
      Tumors co-expressed TTF-1, MUC5B, and/or MUC5AC had a high incidence of ALK rearrangement and exhibited distinctive features in comparison with TRU-type and non-TRU-type adenocarcinomas.

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      MINI10.08 - Discussant for MINI10.05, MINI10.06, MINI10.07 (ID 3400)

      B. Besse

      • Abstract
      • Presentation

      Abstract not provided

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      MINI10.09 - Comprehensive Genomic Profiling Identifies EGFR Exon 19 Deletions in NSCLC Not Identified by Standard of Care Testing (ID 3042)

      A.B. Schrock, S.M. Ali, D. Herndon, G.M. Frampton, J. Greenbowe, K. Wang, D. Lipson, R. Yelensky, Z. Chalmers, J. Chmielecki, J.A. Elvin, M. Wolner, R. Bordoni, F. Braiteh, A. Dvir, R. Erlich, M. Mohamed, J.S. Ross, P.J. Stephens, V. Miller

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell carcinoma (NSCLC) cases harboring deletions in exon 19 of EGFR typically respond to treatment with small molecule inhibitors of EGFR. Detection of EGFR deletions in routine clinical practice is performed using a large variety of assays and testing platforms, with varying performance characteristics that are often not readily available. Using a hybrid capture based comprehensive genomic profiling (CGP) assay we identified 250 consecutive NSCLC cases, obtained from a range of clinical institutions, harboring deletions in EGFR exon 19 and compared data from these cases with available prior EGFR testing results.

      Methods:
      DNA was extracted from 40 microns of FFPE sections and CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 678X for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA). Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials.

      Results:
      Of the 250 cases with exon 19 deletions excluding the C-Helix, consisting primarily of 746-750, 71 (28%) had previous EGFR testing results obtained through standard of care testing at multiple different institutions available for review. Of these 71 cases, 12 (17%) were negative for EGFR alterations, but were identified by CGP as harboring an exon 19 deletion. Of 14 cases with deletions affecting the C-Helix (753-761), 6 had previous EGFR testing results available for review, with 5 (83%) cases having a prior negative result. For select cases clinical histories were reviewed, and the clinical benefit from treatment with small molecule inhibitors of EGFR was observed, consistent with historic norms, including EGFR 746-750 deleted patients responding to erlotinib and afatinib, a patient with EGFR T751_I759>N responding to afatinib, and a patient with EGFR S752_I759del having an ongoing 18 month response to erlotinib.

      Conclusion:
      CGP in the course of clinical care can identify EGFR exon 19 deletions in NSCLC that may be missed by standard of care testing, including both the canonical 746-750 deletion as well as the less characterized C- Helix deletions. Tumors with either of these alterations that go undetected by standard testing but are identified by CGP can respond to anti-EGFR therapy. Given the proven improved extent and duration of tumor response and patient survival benefit conferred by anti-EGFR targeted therapy in patients whose NSCLC harbor EGFR exon 19 deletions, the 17% false negative rate in patients tested by standard hot spot assays is a concern. Further evaluation of the impact of the increased range and sensitivity of CGP to uncover EGFR alterations in NSCLC that have been missed by non-hybrid capture assays appears warranted.

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      MINI10.10 - A Multicenter Prospective Biomarker Study in Afatinib-Treated Patients with EGFR-Mutation Positive Non-Small Cell Lung Cancer (ID 472)

      K. Azuma, E. Iwama, K. Sakai, K. Nozaki, D. Harada, K. Hotta, F. Ohyanagi, T. Kurata, H. Akamatsu, K. Goto, T. Fukuhara, Y. Nakanishi, I. Okamoto, K. Nishio

      • Abstract
      • Presentation
      • Slides

      Background:
      Afatinib is an oral, irreversible ErbB family blocker and one of the key drugs for patients with EGFR mutation positive advanced non-small cell lung cancer (NSCLC). Although treatment with afatinib has a clinical benefit for these patients, such individuals inevitably develop drug resistance as with other TKIs. This is a multicenter prospective biomarker study to inform the usefulness of noninvasive liquid biopsy in the treatment of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and explore the molecular mechanism of acquired-resistance against afatinib.

      Methods:
      Eligible patients were EGFR-TKIs naïve and had histologically and cytologically confirmed stage IIIB/IV adenocarcinoma of the lung with activating EGFR mutations. Patients remained on afatinib treatment until disease progression or unacceptable toxicity. Tumor samples were collected upon before afatinib treatment and after disease progression. Plasma samples were collected upon before and during afatinib treatment (4 and 24 weeks after initiation) and after disease progression. DNA derived both from tumors and plasma was analyzed using Scorpion-ARMS (ARMS), digital PCR (dPCR) and next generation sequencing (NGS). We used a nanofluidic dPCR system (BioMark HD System; Fluidigm) with a digital chip to detect activating or resistance mutations of EGFR in a quantitative and highly sensitive manner. NGS on an Ion Torrent PGM device (Thermo Fisher Scientific) was applied to detect target molecules which contribute to the survival and growth of lung cancer cells. We compared the sensitivity of these methods in detection of EGFR activating mutations in plasma DNA.

      Results:
      A total of 35 EGFR mutation positive NSCLC patients were enrolled. Twenty one patients harbored a deletion in exon 19 and fourteen patients had an L858R missense mutation in exon 21. Twenty seven (77.1%) patients had an objective response. In plasma DNA obtained before afatinib treatment, dPCR and NGS detected EGFR activating mutations more sensitively compared with ARMS (83.9% v 58.1%; p <0.005, 74.2% v 58.1%; p =0.059, respectively). Concordance of EGFR activating mutations detected by dPCR and NGS was 26/31 (84%) (kappa value: 0.52). All of the mutation type detected by NGS on plasma DNA completely corresponded to that found in matching tumor tissue by NGS. As of March 2015, serial plasma DNA was analyzed in 9 patients. The copy number of activating mutation was markedly decreased in 5 of 9 patients.

      Conclusion:
      EGFR activating mutations in plasma DNA were frequently detected by dPCR or NGS. We will present the detailed data for monitoring mutation load in plasma DNA during the afatinib treatment.

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      MINI10.11 - Classification of EGFR Gene Mutation Status Using Serum Proteomic Profiling Predicts Tumor Response in Patients with Stage IIIB or IV NSCLC (ID 874)

      L. Yang, C. Tang, B. Xu, W. Wang, J. Li, X. Li, H. Qin, H. Gao, K. He, S. Song, X. Liu

      • Abstract
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) gene mutations in tumors predict tumor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). However, obtaining tumor tissue for mutation analysis is challenging. Recently, peptide mass fingerprinting based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been widely used to detect diagnostic, prognostic, and predictive proteomic biomarkers. Here, we aimed to detect serum peptides/proteins associated with EGFR gene mutation status, and test whether a classification algorithm based on serum proteomic profiling could be developed to analyze EGFR gene mutation status to aid therapeutic decision-making.

      Methods:
      Serum collected from 223 stage IIIB or IV NSCLC patients with known EGFR gene mutation status in their tumors prior to therapy was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Differences in serum peptides/proteins between patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes were detected in a training group of 100 patients; based on this analysis, a serum proteomic classification algorithm was developed to classify EGFR gene mutation status and tested in an independent validation group of 123 patients. The correlation between EGFR gene mutation status, as identified with the serum proteomic classifier and response to EGFR-TKIs was analyzed.

      Results:
      Nine peptide/protein peaks were significantly different between NSCLC patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes in the training group. A genetic algorithm model consisting of five peptides/proteins (m/z 4092.4, 4585.05, 1365.1, 4643.49 and 4438.43) was developed from the training group to separate patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes. The classifier exhibited a sensitivity of 84.6% and a specificity of 77.5% in the validation group. In the 81 patients from the validation group treated with EGFR-TKIs, 28 (59.6%) of 47 patients whose matched samples were labeled as “mutant” by the classifier and 3 (8.8%) of 34 patients whose matched samples were labeled as “wild” achieved an objective response (p<0.0001). Patients whose matched samples were labeled as “mutant” by the classifier had a significantly longer progression-free survival (PFS) than patients whose matched samples were labeled as “wild” (p=0.001).

      Conclusion:
      Peptides/proteins related to EGFR gene mutation status were found in the serum. Classification of EGFR gene mutation status using the serum proteomic classifier established in the present study in patients with stage IIIB or IV NSCLC is feasible and may predict tumor response to EGFR-TKIs.

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      MINI10.12 - Preclinical Activity of AZD9291 in EGFR-Mutant NSCLC Brain Metastases (ID 410)

      P. Ballard, P. Yang, D. Cross, J. Yates, M.R.V. Finlay, M. Grist, M. Box, P. Johnström, K. Varnäs, J. Malmquist, C. Halldin, L. Farde, K. Thress

      • Abstract
      • Presentation
      • Slides

      Background:
      AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for the EGFR-TKI-sensitizing (EGFRm) and T790M resistance mutations. We examined how the level of AZD9291 brain penetration and activity compared to that of other EGFR-TKIs in preclinical models of EGFRm non-small cell lung cancer (NSCLC) brain metastases (BM).

      Methods:
      Brain exposure of AZD9291 and an active circulating metabolite of AZD9291 (AZ5104), CO-1686 (rociletinib), gefitinib, erlotinib, and afatinib were evaluated in mouse models. Brain distribution following intravenous administration of microdoses (<3 micrograms) of [[11]C]AZD9291 and [[11]C]CO-1686 were compared in healthy cynomolgus macaques using positron emission tomography (PET) imaging. In vivo efficacy of AZD9291 and CO-1686 were assessed in a mouse EGFRm (exon 19 deletion) BM xenograft (PC9) model. Human doses that could potentially deliver BM efficacy were predicted using a preclinical pharmacokinetic/pharmacodynamic (PK/PD) mathematical model, adapted to account for the differential exposure and binding of AZD9291 and AZ5104 in brain compared with plasma.

      Results:
      In preclinical studies, AZD9291 showed significant exposure in the brain with concentrations in mouse brain tissue approximately 2-fold higher than plasma, although the metabolite, AZ5104, did not show similar levels of exposure to parent. AZD9291 also showed higher brain exposure than other tested EGFR-TKIs. Furthermore, under microdosing conditions [[11]C]AZD9291 showed marked exposure in a cynomolgus macaques brain PET study in contrast to [[11]C]CO-1686. At clinically relevant doses, AZD9291 distribution to the mouse brain was approximately 10-fold higher than gefitinib. In the PC9 BM model, AZD9291 showed tumor growth inhibition at 5 mg/kg/day. Using an adapted preclinical PK/PD model, simulations with clinical AZD9291/AZ5104 PK data predicted that a human dose of 80 mg may be sufficient to target EGFRm BM.

      Conclusion:
      Preclinical studies indicate AZD9291 has significant exposure in the brain and activity against EGFRm BM, compared with the other EGFR-TKIs tested. In light of early clinical activity of AZD9291 observed in patients with EGFRm NSCLC BM, further investigation into the potential benefit of AZD9291 in patients with EGFRm NSCLC BM is warranted.

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      MINI10.13 - Prediction of Human Pharmacokinetics, Efficacious Dose and BBB Penetration of a Novel EGFR Inhibitor for Treating NSCLC with CNS Metastasis (ID 3282)

      K. Chen, P. Martin, S. Cohen-Rabbie, P. Johnstroem, Y. Wang, H. Jiang, Z. Yang, Z.(. Cheng

      • Abstract
      • Presentation
      • Slides

      Background:
      Increasing incidences of brain metastases (BM) and leptomeningeal metastases (LM) in lung cancer, especially in those patients with activating mutations of the epidermal growth factor receptor (EGFR) have been reported recently. However, there are currently no approved drugs available for the treatment of these diseases. AZD3759 is an oral EGFR TKI specifically designed to penetrate blood brain barrier (BBB) for the treatment of BM and LM.

      Methods:
      Efflux liability at BBB was assessed by using in vitro MDCKII-MDR1 and MDCKII-BCRP substrate assay, and central nervous system (CNS) penetration was evaluated in rats and mice and quantitatively measured by free brain to free blood ratio (K~p,uu,brain~) and CSF to free blood ratio (K~p,uu,CSF~). Brain uptake of [[11]C]-AZD3759 related radioactivity was also evaluated in two Cynomolgus monkeys by positron emission tomography (PET). Human clearance was predicted by different methods including In vitro In vivo extrapolation, liver blood flow method with fu correction and fu correction intercept method (FCIM). Human volume of distribution was projected from Oie-Tozer and PBPK methods. Human efficacious dose was predicted by achieving free brain concentration at steady state continuously covering the IC~50~ of pEGFR(Tyr1068) in PC-9(Exon19Del) cells.

      Results:
      AZD3759 has high passive permeability (29.5x10[-6] cm/sec) and is not a substrate of Pgp or BCRP. AZD3759 reached distribution equilibrium in rats and mice (K~puu,brain~ and K~puu,CSF~ > 0.5), suggesting good BBB penetration. The distribution of [[11]C]-AZD3759 related radioactivity to monkey brain was fast and homogenous. Estimated K~puu,brain~ in monkeys is greater than 0.5. In the animal model bearing EGFRm+ brain tumor, AZD3759 induced profound tumor regression and significantly improved animal survival. Predicted half-life in human PK is 13.3 hr and clinically observed t~1/2 ~ranges from 10 to 15 hr. Median K~puu,CSF ~value among six valuable BM patients is 1.2, suggesting good CNS penetration in human and consistent with the preclinical data. The predicted efficacious dose for AZD3759 in man is 100 mg bid. In an ongoing Phase I study, AZD3759 was well tolerated with no DLTs at 50 mg or 100 mg bid and some preliminary evidence of intracranial tumor shrinkage was observed.

      Conclusion:
      So far the preclinical predictions of CNS penetration of AZD3759 appear to be valid. Predicted and observed half-life of AZD3759 in human is consistent to date. Some preliminary evidence of intracranial tumor shrinkage was observed in clinical setting.

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      MINI10.14 - Brain Metastasis at Diagnosis and EGFR Mutational Status in Non-Small Cell Lung Cancer (ID 431)

      V.R. Bhatt, S.P. D`souza, L. Smith, A.M. Cushman-Vokoun, V. Noronha, V. Verma, A. Joshi, A. Chougule, N. Jambekar, A.K. Ganti, K. Prabhash

      • Abstract
      • Presentation
      • Slides

      Background:
      Prior studies have indicated higher epidermal growth factor receptor (EGFR) mutation rate in non-small cell lung cancer (NSCLC) patients (pts) with brain metastases; however, these studies did not adjust for the effects of potential confounding variables.

      Methods:
      This was a retrospective study of NSCLC pts diagnosed between 2007-2014 at the University of Nebraska Medical Center, USA and Tata Memorial Hospital, India. After excluding 87 pts due to missing data, a total of 1522 pts were included. Univariate analysis (Chi-square or Fisher’s exact tests) and multivariate logistic regression were used to determine any association between EGFR status and clinical factors.

      Results:
      EGFR mutations were more common in females than males (38% vs. 24%, p<.0001), Asians than Caucasians (31% vs. 13%, p<.0001), non-smokers than smokers (40% vs. 14%, p<.0001), alcohol non-consumers than consumers (32% vs. 15%, p<.0001), adenocarcinoma than other histologies (32% vs. 10%, p<.0001) and in pts with brain metastasis than extracranial metastases or no metastasis (39% vs. 29% vs. 15%, p<.0001). The type of EGFR mutation (exon 19 vs. 21) did not correlate with the presence of brain metastasis. Multivariate analysis demonstrated a higher likelihood of an EGFR mutation among Asians vs. Whites/other ethnic groups (odds ratio, OR 2.1, p=0.015), non-smokers vs. smokers (OR 2.8, p<0.0001), alcohol non-consumers vs. consumers (OR 1.6, p=0.022) and adenocarcinoma vs. other histologies (OR 3.1, p<0.0001). Pts with brain metastasis were 1.9 times more likely to have an EFGR mutation than pts with extracranial metastasis (p=0.0002). Pts with brain metastasis were 1.8 times more likely to have an EFGR mutation (p=0.0002) compared to those without. The distribution of EGFR mutations was similar between pts with brain metastasis vs. non-metastatic disease (p=0.86) and pts with extracranial metastasis vs. non-metastatic disease (p=0.44).

      Conclusion:
      Our study is the largest study to demonstrate almost two-fold higher likelihood of an EFGR mutation among newly diagnosed NSCLC pts with brain metastases vs. those without. Studies of prophylactic cranial irradiation in pts with earlier stages of EGFR mutation positive NSCLC may be warranted.

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      MINI10.15 - Discussant for MINI10.09, MINI10.10, MINI10.11, MINI10.12, MINI10.13, MINI10.14 (ID 3401)

      O. Arrieta Rodriguez

      • Abstract
      • Presentation

      Abstract not provided

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    MINI 11 - Tobacco Control and Prevention (ID 108)

    • Type: Mini Oral
    • Track: Prevention and Tobacco Control
    • Presentations: 12
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      MINI11.01 - The Upshot of Passive Smoke (ETS) Exposure on Pneumonia Risk in Children Under 7 Years in Nigeria (ID 517)

      B. Obiazi-Odiase

      • Abstract
      • Presentation
      • Slides

      Background:
      This study considers pneumonia risk on children under age 7 in Northern Nigeria exposed to ETS. The numerous adverse effects of Environmental Tobacco Smoke (ETS) on the non-smoking public have being evidenced through decades of research. This does not only affect adults but children. ETS effects on children have shown to be grave as it worsens asthma conditions, increases pneumonia cases and causes Sudden Infant Death Syndrome (SIDS).

      Methods:
      Most residents in all 44 Local Government Areas (LGAs) in Kano State of Northern Nigeria took part in a population-based large-scale cross-sectional survey in Kano state from 2007-2010. Demographic information coupled with socioeconomic status, smoking status and house environment of each household member, was collected from participants. Pneumonia case reported among children aged 7 years and below in each household in the previous 18 months were recorded based on parent’s/guardian's report.

      Results:
      Out of a total of 528, 800 people resident in 102,334 homes indentified in the survey areas and visible/present as at the time of the study, 52,888 (10%) were children aged 7 years and below. While the prevalence of ETS exposure on children was 81%, the prevalence of reported pneumonia cases was 3.5%. Multiple logistic regression analysis showed that exposure to ETS was independently associated with reports of pneumonia cases (adjusted odds ratio 1.55, 95% CI 1.25 to 1.92). The prevalence of tobacco smoking was higher among men than women (63.5% vs 44.1%). It is estimated that 32.7% of childhood pneumonia in the northern region of Nigeria is attributable to ETS.

      Conclusion:
      Attention should be given to reduction to children’s exposure to ETS not only in Nigeria but in all affected areas mostly all parts of the world. If nothing is done to protect children, there will be millions of avoidable deaths attributable to Pneumonia heightened by ETS exposure. This is a case of concern for any one involved in lung cancer/tobacco control.

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      MINI11.02 - Frizzled9 as a Predictor of Response to Iloprost Chemoprevention of Lung Cancer (ID 2397)

      M. Tennis, D.T. Merrick, L. Nield, R.L. Keith

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer remains the leading cause of cancer death in the United States and chemoprevention offers an appealing area of investigation in the face of limited therapeutic success. Improvement in endobronchial histology was recently demonstrated in former smokers after oral iloprost treatment. Of the 48 patients who received iloprost in the chemoprevention trial, 23 had regressive histology and 25 had stable or progressive histology. Identifying markers that predict which patients will respond to treatment will help refine target populations for future trials and clinical applications. In vitro studies of NSCLC indicate that iloprost, a prostacyclin analogue, acts through the G-protein coupled receptor Frizzled 9 (Fzd9) instead of the prostacyclin receptor. We hypothesize that Fzd9 expression status predicts response to iloprost chemoprevention and that current smokers may not respond to iloprost treatment due to carcinogen-induced decreases in Fzd9 expression. Prostacyclin may also induce expression of Fzd9, leading to increased anti-tumor signaling.

      Methods:
      Fzd9 expression was measured by quantitative real-time PCR in RNA extracted from mouse and human tissues, cultured dysplastic cell lines, and cultured human bronchial epithelial cells (HBEC). In the urethane model, FVB wild type and transgenic mice were exposed to a single dose of urethane and sacrificed after 20 weeks. In the smoking model, FVB wild type and transgenic mice were sacrificed after one week of cigarette smoke exposure. Human matched tumor and normal tissue and dysplastic cell lines were acquired from the University of Colorado SPORE in Lung Cancer Tissue Bank. HBEC were exposed to 5ug/ml cigarette smoke condensate and 10uM iloprost in culture media.

      Results:
      Human lung tumors demonstrated reduced Fzd9 mRNA expression compared to matched normal lung tissue. Fzd9 expression is also decreased in human primary dysplastic cell lines, suggesting that loss of Fzd9 expression occurs early in early lung lesions. In a urethane mouse model of lung cancer, Fzd9 mRNA expression is reduced in lung tumors compared to matched, uninvolved lung tissue. Tumors from urethane exposed prostacyclin synthase overexpressing (PGIStg) mice have higher Fzd9 expression compared to tumors from wild type mice. In a one-week smoking model, Fzd9 expression is decreased in lung from wild type smoked mice but higher in PGIStg smoked mice. In HBEC exposed to cigarette smoke, Fzd9 expression decreases and remains low with continued exposure from 1 to 28 weeks. After two weeks of exposure to iloprost alone, HBEC cells demonstrated increased Fzd9 expression.

      Conclusion:
      These initial studies suggest that Fzd9 expression is lost lung epithelial cells with early smoking-induced damage. Fzd9 expression will be measured in baseline and follow up biopsy tissues from the iloprost clinical trial. This study has the potential to improve iloprost lung cancer chemoprevention by allowing future trials to more effectively target high-risk patients and by providing a clinical biomarker for identification of chemoprevention candidates.

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      MINI11.04 - A New Preclinical Model of Airway Progenitor Cells to Identify Responders to Iloprost-Mediated Chemoprevention (ID 1698)

      J.B. Kwon, I. Nakachi, R.L. Keith, D.T. Merrick, M. Edwards, S. Leach, W.A. Franklin, Y.E. Miller, M. Ghosh

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer related deaths worldwide. The 5-year survival rate for this cancer is only 16%. Chemoprevention can improve prognosis in these patients. However, previous attempts at lung cancer chemoprevention that were soley based on epidemiological data were ineffective. Squamous cell lung cancer develops through a series of bronchial lesions or dysplasia. Persistent dysplasia harbors similar genetic changes as the tumor and has significantly higher chance of progression. Thus, bronchial dysplasia is a risk biomarker for SCC and improvement in dysplasia grade can be used as an outcome for chemoprevention trials. The long-acting prostacyclin analogue, iloprost is the only drug that has improved dysplasia in former smokers (p = 0.006). Despite this positive outcome we have little insight into the mechanisms of iloprost function. Understanding these mechanisms would be essential to identify people who have the highest chance to benefit from iloprost treatment. We propose that this endeavor will require a preclinical model that recapitulates the human disease and is amenable to mechanistic studies.

      Methods:
      Airway progenitor cells are critical for the maintenance of normal airways, because of their ability to self-renew (i.e. replicate) and differentiate into all cell-types of the airway (i.e. multipotentiality). Together these properties allow progenitors to return injured tissue to normal structure and function. In dysplasia, normal bronchial epithelium is changed into one that contains increased numbers of basal cells and lacks ciliated cells. These findings led to our hypothesis that ‘airway progenitors are malfunctioning in dysplasia’. Previously we showed that Keratin (K) 5/p63-expressing basal cells are the multipotential progenitors of the airway epithelium. During in vitro culture these cells form a unique 3-deimensional structure called the rim clone, which allows them to be distinguished from non-progenitors. To investigate a role of epithelial progenitors in dysplasia, we have collected bronchial biopsies from high-risk smokers and purified rim clone forming basal progenitor cells.

      Results:
      We demonstrate that both self-renewal and multipotentiality of progenitors is significantly (p < 0.001 for both) decreased in dysplasia. During differentiation in vitro at the air-liquid interface, progenitors from normal biopsies generated a normal epithelium. In contrast, progenitors from dysplasia made a squamous epithelium containing only basal cells and lacking ciliated cells. Mutational analyses of paired samples from epithelial brushings and biopsy-derived progenitors identified the same somatic mutations in p53, Notch 1, Notch 3, Survivin and FGFR1. Thus, epithelial progenitor culture reflects the histologic and genetic changes of dysplasia and therefore can be used as a personalized, preclinical model. A proof of concept study where dysplastic progenitor cells were treated with iloprost resulted in decreased dysplasia in 2 out of 3 cases.

      Conclusion:
      Thus our data indicate that progenitor cell cultures from a patient’s dysplasia may be used to identify responders versus non-responders to iloprost, as well as other chemopreventives. Future studies could focus on identifying downstream mechanisms via which iloprost exerts its beneficial effect.

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      MINI11.05 - Prevalence Use of Others Tobacco Products: Findings from the ITC Brazil Survey (ID 2769)

      C.D.A. Perez, T.M. Cavalcante, F.L. Mendes

      • Abstract
      • Presentation
      • Slides

      Background:
      Tobacco use is responsible for 5.4 million deaths every year worldwide and a leading cause of preventable death. Brazil is widely regarded as an international leader in tobacco control. The WHO FCTC aims to protect individuals from the consequences of tobacco use by providing a framework for tobacco control measures. Parties are obligated to implement measures to prevent and reduce all tobacco consumption and to monitor the magnitude and patterns of tobacco use. The ITC Brazil Survey includes several measures to assess smokers’ tobacco use behaviour, such as cigarette consumption and types of products used.

      Methods:
      The International Tobacco Control Policy Evaluation Survey (ITC) Brazil Survey is a longitudinal cohort survey and was conducted in Brazil with 1,200 adult smokers and 600 adult non-smokers living in three cities. Telephone-administered surveys were conducted using an area stratified random sampling strategy, yielding a representative sample of the four largest cities in Brazil (Rio de Janeiro, Porto Alegre, and Sao Paulo). The Wave 1 Survey (in 2009) and Wave 2 (2012-2013) included questions a variety of tobacco control measures, including use of tobacco products.

      Results:
      Brazilian smokers in the ITC Survey smoked mainly factory-made cigarettes and five percent reported that they regularly smoke a flavored brand (including menthol). In Wave 2, all respondents were asked about their use of other tobacco products, and the results show evidence of other tobacco product use even among non-cigarette smokers. Thirteen percent of the overall sample (smokers and non-smokers combined) have smoked clove cigarettes, 10% have smoked cigars, 8% smoked shisha, 5% smoked pipes, and 4% smoked bidis. The percentage of smokers and non-smokers in the sample who have tried various tobacco products, by city, shows a significantly higher use of shisha among smokers in São Paulo (18%) compared to Rio de Janeiro (5%) and Porto Alegre (8%), and non-smokers in São Paulo were significantly more likely to smoke cigars than in the other two cities. Despite the prohibition of electronic cigarettes (e-cigarettes) sale, importation, and advertising in Brazil since August 2009, in the ITC Brazil Wave 2 Survey, respondents were asked “Have you ever heard of electronic cigarettes or e-cigarettes?”. The results showed that 35% of smokers and 29% of non-smokers had heard of them. The highest level of awareness of the product was in Porto Alegre where 39% of smokers and 29% of non-smokers had heard of them. Among smokers who had heard of e-cigarettes, 38 smokers (12%) and one non-smoker reported trying these products.

      Conclusion:
      Daily consumption of cigarettes is relatively high in Brazil for both male and female daily smokers, based on a comparison of the average number of cigarettes smoked per day among 20 ITC countries and an average consumption of 17 cigarettes per day — twice the average consumption of smokers in Mexico, so its recommended to reinforce educational campaigns about the dangers of smoking, and the electronic cigarette use, increase its inspections and mainly reinforce educational campaigns about the dangers of shisha.

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      MINI11.06 - Comprehensive Tobacco Control Programs Reduce Tobacco Use and Secondhand Smoke Exposure: A Systematic Review (ID 3004)

      J.A. Reynolds, Y. Peng, N. Vaidya, C.G. Dumitru, D.P. Hopkins

      • Abstract
      • Presentation
      • Slides

      Background:
      Tobacco use is the single greatest cause of preventable disease, disability, and death in the U.S. Over the last few decades, several states have implemented comprehensive tobacco control programs (CTCP) to reduce tobacco use and secondhand smoke (SHS) exposure. This Community Guide (CG) systematic review was conducted to examine CTCP effectiveness in reducing tobacco use and tobacco-related diseases and deaths.

      Methods:
      A systematic search was conducted (search period Jan 2000-July 2014) to identify and abstract qualifying studies using standard CG systematic review methods. Studies published prior to 2000 were identified from a previous Community Guide review and added. Summary measures were calculated when possible and narrative results were provided when effect estimates could not be pooled. The review team worked under the guidance of the Community Preventive Services Task Force (CPSTF), a non-federal, independent, volunteer body of public health and prevention experts.

      Results:
      The review team identified 60 eligible studies; only results from the U.S. studies are reported here (55 studies). Most of the U.S. studies evaluated CTCP at the state level (48 studies from 10 states) with the remaining studies at the city (3 studies) and local or community level (4 studies). States with a CTCP reduced tobacco use prevalence among adults by a median of 2.8 percentage points (pct pts) [Interquartile interval (IQI): -3.5 to -2.4 pct pts; 12 studies]; reduced tobacco use prevalence among young people by a median of 4.5 pct pts (IQI: -6.0 to -0.7 pct pts; 9 studies); reduced cigarette pack sales by a median of 12.7% (IQI: -20.8% to -5.5%; 7 studies); and reduced daily tobacco product consumption by a median of 17.1% (IQI: -43.4% to -13.5%; 6 studies). Narrative results showed that states with a CTCP increased cessation (6 studies) and reduced SHS exposure (4 studies). States with a CTCP decreased tobacco-related diseases and deaths (6 studies), specifically in reduced lung cancer incidence (1 study), and reduced lung cancer (3 studies) and smoking-attributable cancer (1 study) mortality. Results indicated that increased program funding was associated with greater impact on the examined tobacco-related outcomes (16 studies). Stratified analysis showed CTCPs were effective across population groups with diverse racial and ethnic backgrounds (5 studies) and varied education or socioeconomic status (6 studies).

      Conclusion:
      Based on CG criteria, there is strong evidence that CTCPs are effective for reducing tobacco use prevalence among adults and young people, reducing tobacco product consumption, increasing quitting, reducing SHS exposure, and reducing tobacco-related diseases and deaths, especially lung cancer. These findings are broadly applicable to the U.S. settings and population groups at the state, city, and local levels.

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      MINI11.07 - The Relationship between Smoking Status and Prognostic Factors after Surgery in Lung Cancer Patients with Chronic Obstructive Pulmonary Disease (ID 1388)

      M. Yotsukura, T. Ohtsuka, Y. Sugiura, Y. Hayashi, I. Kamiyama, H. Asamura

      • Abstract
      • Slides

      Background:
      Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD), which frequently coexists with lung cancer. For non-small cell lung cancer (NSCLC) patients with COPD, the poor prognostic factors after curative surgery and their association with smoking status are unclear.

      Methods:
      We enrolled 858 patients who underwent curative surgical resection for pathological stage I or II NSCLC in our institute between January 2002 and December 2012. Of these patients, those with COPD, as determined by a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7, were evaluated (n = 302). Clinical and pathological characteristics of the patients were retrospectively analyzed using the Cox regression hazards model to determine those that serve as poor prognostic factors after surgery.

      Results:
      The mean follow-up time was 49.3 months (±30.8 months; range, 1 to 135 months). The five-year disease-free survival rate was 70.2%, and the overall survival rate was 81.5%. Of 302 COPD patients, 243 (80.5%) had a smoking habit, whereas 59 (19.5%) did not. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion, 143 patients (47.5%) were diagnosed with stage I COPD and 159 patients (52.6%) were diagnosed with stage II COPD. The presence of a smoking habit (p = 0.010, hazard ratio [HR] 3.340, 95% confidence interval [CI] 1.334-8.359), lymphatic permeation (p = 0.001, HR 2.352, 95% CI 1.450-3.814), pathological T2 or T3 disease (p = 0.005, HR 1.666, 95% CI 1.165-2.381), and a preoperative serum carcinoembryonic antigen (CEA) value > 0.5 ng/ml (p = 0.041, HR 1.637, 95% CI 1.021-2.625) were determined to be indicators of poor recurrence-free survival in multivariate analysis. For overall survival rates, a smoking habit (p = 0.048, HR 7.527, 95% CI 1.017-55.738), a preoperative serum CEA value > 0.5 ng/ml (p = 0.001, HR 2.782, 95% CI 1.495-5.175), a histology of squamous cell carcinoma (p = 0.014, HR 2.220, 95% CI 1.175-4.193), and pathological N1 disease (p = 0.031, HR 2.505, 95% CI 1.089-5.762) were determined to be poor prognostic indicators in multivariate analysis. The disease stage as determined by the GOLD criterion was associated with neither recurrence-free nor overall survival rates. With regard to smokers, the number of pack-years did not significantly influence prognosis.

      Conclusion:
      We identified poor prognostic indicators for resected NSCLC in COPD patients. It should be noted that COPD patients who did not smoke had a better prognosis after surgery than those who did. Neither the number of pack-years in smokers nor the stage of COPD was related to prognosis after surgery.

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      MINI11.08 - Smoking Cessation Results in a Clinical Lung Cancer Screening Program (ID 65)

      A.K. Borondy Kitts, A. McKee, S. Regis, B. McKee, S. Flacke

      • Abstract
      • Presentation
      • Slides

      Background:
      Published results, to date, on smoking cessation and lung cancer screening have been from lung cancer screening clinical trials and/or lung cancer screening studies. Most were done before publication of National Lung Screening Trail (NLST) results. To our knowledge, this is the first report on smoking cessation and smoking relapse rates in a clinical lung cancer screening program to assess the influence of initial screening results on smoking behavior.

      Methods:
      Self-reported smoking status for all individuals enrolled in a clinical CT lung screening program undergoing a follow-up CT lung screening exam between February 1, 2014 and July 31, 2014 was retrospectively reviewed and compared to self-reported smoking status using a standardized questionnaire at time of program entry. Point smoking cessation and relapse rates were calculated across the entire population and compared with exam results.

      Results:
      682 participants all of which met NCCN high-risk criteria for lung cancer were included in the study. 45% (309/682) were active smokers at program entry. The smoking cessation rate was 18.4%. Overall relapse rate was 9.9% with a relapse rate for former smokers quit for less than or equal to one year (24 of 64) of 37.5%, 14.8% for those quit for more than one year and up to two years (4 of 27), and 3.2% for those quit for more than two years (9 of 282). Initial screening exam results were not predictive of smoking status at the most recent scan (OR = 0.779, 95% CI = 0.415-1.460, p=0.435). In the group of smokers at the initial scan, screening results did not result in increased rates of smoking cessation (OR = 0.704, 95% CI = 0.308 – 1.610, p=0.405). In the group of former smokers at the initial scan, negative initial exam results did not result in increased smoking relapse rates (OR = 1.021, 95% CI = 0.364-2.860, p=0.969).

      Conclusion:
      Smoking cessation and relapse rates in a clinical CT lung screening program significantly exceed rates observed in the general population and do not correlate with exam results.

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      MINI11.09 - Trends in Lung Cancer Mortality Attributable to Smoking, Years of Potential Life Lost and Financial Cost, Puerto Rico 1983-2010 (ID 1719)

      J.C. Orengo, V. Green, H. Monsanto, C. Marques-Goyco, F. Arbelaez

      • Abstract
      • Presentation
      • Slides

      Background:
      During 1983, 2000 and 2004 the lung cancer deaths attributable to smoking (LCDAS) were 64.1% (>15 years old), 76% (> 35 years old) and 71% (34-65 years old), respectively. Objectives: a) LCDAS; b) Years of Potential Life Lost (YPLL) due LCDAS; c) cost associated with YPLL for the LCDAS.

      Methods:
      Mortality data of lung cancer (ICD-10, C33-C34) from the National Center for Health Statistics for Puerto Rico (2010) was analyzed. The prevalence of current, former and never smoking by gender was obtained from the Behavioral Risk Factor Surveillance System (2010) (CDC, US) and the Relative Risk of death dues to smoking by gender from the Cancer Prevention Study-II. The Smoke Attributable Fraction (SAF) was calculated as [p~0 ~+ p~cs ~* RR~cs ~+ p~fs ~* RR~fs ~] – 1 / [p~0 ~+ p~cs ~* RR~cs ~+ p~fs ~* RR~fs ~], where p~0 ~= prevalence of never smoker, p~cs ~= prevalence current smoker, p~fs~ = prevalence of former smoker, RR~cs, ~= Relative Risk of current smoker and RR~fs~ = Relative Risk of former smoker. The LCDAS (D~as~) were calculated as D~o~*SAF, where D~o~ = deaths observed of lung cancer 2010. To compare the data of 1983, 2000 and 2010, SAF was calculated by sex for the total population (not by age groups), with correspondent same death-risk LCDAS. YPLL used life expectancy (women=82.56 years old; men=74.85 years old). The method of willingness to pay, using three times the GDP per capita in 2010 (US$82,353), a discount rate of 3% and an annual increase of 1%, to calculate the economic cost.

      Results:
      In 2010, 50.3% deaths by lung cancer in women were LCDAS, men 83.7% , in 1983 women and men were 65.9% and 91.2% respectively and in 2000, 58.9% and 84.4% women and men respectively; percentage of all LCDAS (2010) was 73.3% (by sex and group of five). Total population, 2010, not by age groups 75.8%, 2000, 76.3% and1983, 82.5%. In 2010, SAF higher in women was in the age group=45-49 (smoker=13%, SAF=0.66); men was in the age group of 50-54 years (SAF=0.86) (smoker= 17.5%). In women, 1% point decreased (1983-2010) in the prevalence of smoking representing 1.5% point of decreasing LCDAS; men 1% point representing 0.3% point. Lung cancer YPLL in >35 years old represented in 2010 a total of 4,597 years [3,239 years (70.5%) were LCDAS], men accounted 2,383 years [2,014 (84.5%) years LCDAS] and women accounted 2,214 years [1,225 (55.4%) years LCDAS]. In 2010 the cost (willingness to pay) associated for men was $166 million [$139 million (84%) LCDAS], and for women was S146 million [$82 million (56%) LCDAS]. The Average Years Life Lost LCDAS for men was 10.6 years and for women 14.2 years.

      Conclusion:
      LCDAS have been decreasing in Puerto Rico, as demonstrated in the reduction of SAF. LCDAS occur at an earlier age in women than in men. Notwithstanding , the financial cost of LCDAS is greater in men than in women. Total financial cost for LCDAS represented 0.3% of the Puerto Rico GDP in 2010.

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      MINI11.10 - Quality of Lung Cancer Treatment in Two Neighbouring Regions of Germany and Denmark (ID 374)

      H.H. Storm, G. Engholm, R. Pritzkuleit, A.M.T. Kejs, A. Katalinic, J. Dunst, N.H. Holländer

      • Abstract
      • Presentation
      • Slides

      Background:
      A comparison of lung cancer incidence, mortality, prevalence and survival in two neighbouring regions of Germany, Schleswig-Holstein, and Denmark, Region Zealand, separated by the Fehmarn Belt, was planned based on data recorded as part of routine monitoring with a view to joint research and sharing of patients and treatment facilities

      Methods:
      Altogether 14,080 lung cancer patients were recorded in 2004-2010 in Schleswig-Holstein and 5,009 in Region Zealand. Excluding cases of age 90+ years or only known from death certificates, 1- and 4-year relative survival by stage and sex for the periods 2004-2006 and 2007-2009 (1-year survival only) were calculated.

      Results:
      A very high proportion (19%) of cases in Schleswig-Holstein was only known from death certificates contrary to Region Zealand (0%). The incidence of both, age-standardised and age-specific lung cancer, was much higher in Region Zealand versus Schleswig-Holstein (men 73/100,000 versus 68/100,000, women 58/100,000 versus 32/100,000), also reflected in the mortality figures. Lung cancer incidence was increasing among women during the observation period, more so in Schleswig-Holstein (3% estimated annual change) compared to Zealand (1%). Overall relative survival was lower in Zealand than in Schleswig-Holstein for 1-year survival in 2007-2009 (DK: 33% in men and 39% in women, versus G: 43% in men and 49% in women) and 4-year relative survival for 2004-2006 (DK: 9-13% versus G: 16-21%). Stage, sex and period specific relative survival was rather similar between countries. When restricting the analysis to patients with recorded treatment, stage-specific relative survival differences in 2007-2009 nearly disappeared.

      Conclusion:
      Improved data quality and comparability are needed, especially by lowering the proportion of cases only reported via death certificates in Germany. This would diminish the survival differences as a high proportion of such cases leads to an over-estimation of survival. Smoking is a strong risk factor for lung cancer and smoking prevalence 10 years before our study was high, specifically 37% in men and 22% in women in Germany and 45% in men and 38% in women in Denmark respectively. Smoking prevalence dropped to 24% in men and 21% in women in Denmark 2010, but only to 31% in men and 24% in women respectively in Germany. Such dramatic changes over a short period of time in Denmark are over time expected to be reflected in the overall incidence, mortality and even survival. International benchmarking studies are needed to understand lung cancer trends and to improve prevention and treatment of this serious cancer disease. Research presented here was partly funded by EU INTERREG 4a Fehmarn Belt 2011-2014.

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      MINI11.11 - Lung Cancer and Smoking in Nepal (ID 2395)

      S.C. Acharya, M.K. Piya

      • Abstract
      • Presentation
      • Slides

      Background:
      Smoking and Tobacco kills 15,000 people in Nepal every year. The combined prevalence of smoking and tobacco use is 56.5% in men and 19.5% in women, of whom 32.5% of men and 15.2% of women smoked cigarettes. The estimated incidence of lung cancer is 8000 per year, making it the first commonest cancer in both sexes. Lung cancer accounts for 15.4% of total cancer as per the hospital based cancer registry for both genders in Nepal.

      Methods:
      This prospective observational study was conducted at National Hospital and Cancer Research Centre, Nepal. Following informed consent, patients with lung cancer attending the hospital for appointments completed pre-set questionnaires about smoking only, and their stage of cancer and histological type were obtained from case notes.

      Results:
      A total of 116 patients completed the questionnaire between March 2012 and February 2015. 59% of the respondents were male and 41% were female. The mean age was 64 years with ranging from 31 to 81 years. The proportion of patients presenting in the different stages of lung cancer were IB (3%), IIA (2%), IIB (4%), IIIA (30%), IIIB (41%), and IV (23%). The histological type of cancer showed that 53% were Squamous Cell Carcinoma, followed by Adenocarcinoma 28%, Small cell lung Cancer 13% and Neuroendocrine tumors 4%. 85% were smokers. Of the smokers, 14% started smoking before the age of 10, 53% when they were between 11-20 years of age, 13% when they were 21-30 years and only 5% started when they were 40 years or older. Only 4% smoked more than 30 cigarettes per day, 13% smoked 21-30 per day, 32% smoked 10-20 per day and 36% patient smoked less than 10 per day. 68% used local cigarettes, 7% foreign and 10% used both. Further analysis showed that 27% used cigarettes without filters, 50% filtered and 8% used both. 28% were relighting the butt ends, 5% did this occasionally and 52% did not practice this. 13% of patients were still smoking after their diagnosis, 24% quit less than a month later, 11% quit less than a year later, 19% had already quit smoking 5 years before the diagnosis of cancer, 12% had quit 10 years before and 8% had quit 20 years before. Out of 28% of relighting, 48% patient developed cancer in compare to 52% who never relight the butt end.

      Conclusion:
      The results shows that majority of patients are presenting at stage III and IV. NSCLC is still on the rise in Nepal. This late presentation suggests a lack of education in the community as well as a delayed diagnosis and referral to the specialist. Focus should be given to make the population in Nepal aware about smoking and tobacco use and its link to cancer, as well as the high prevalence of lung cancer in both genders in Nepal. Focus should also be given to educating the population and non-specialist health care professionals about the symptoms of lung cancer and the importance of early presentation to improve prognosis.

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      MINI11.12 - Is There Any Role for Residential Radon in Patients with Non Small Cell Lung Cancer (NSCLC) Harbouring Molecular Alterations? Preliminary Results (ID 993)

      L. Mezquita, M.E. Olmedo, A. Ruano-Ravina, J.M. Fraile, A. Benito, A. Santon, S. Mayoralas, L. Gorospe, A. Cortes, S.P. Cortez, J. Munoz, A. Gomez, E. Roberts, A. Carrato, P. Garrido

      • Abstract
      • Presentation
      • Slides

      Background:
      World Health Organization (WHO) recommends radon concentration lower than 100 Bq/m3. Previous studies have demonstrated the correlation between high level of residential radon exposure and lung cancer especially in non-smokers patients (p.). Similarly, most of the advances in personalized therapy in NSCLC p. also occurred in non-smoker. We hypothesized that residential radon could be associated to some specific molecular alterations in NSCLC p.

      Methods:
      A detector alpha-track was delivered to each p. to measure radon concentration in residence for 3 months and a questionnarie to fill out. The elegible population were NSCLC p. harbouring molecular alterations (EGFR, KRAS or BRAF mutations (m)), ALK or ROS1 rearrangements (r)) and non-smoker p. treated in the Medical Oncology Department, at Hospital Universitario Ramon y Cajal, Madrid. Incident cases and prevalent cases collected from lung cancer patients database have been included from September 2014 to March 2015. We collected demographic information, smoking history, environmental exposure and clinicopathological characteristics including histology, molecular profile, stage, treatment and survival. The radon concentration was analysed using optical microscopy with radosys system 2000. EGFR, KRAS, BRAF mutation (m) were analysed using quantitative real-time polymerase chain reaction (PCR) and ALK and ROS1 rearrangements by fluorescence in situ hybridization (FISH). Statistical analysis was performed using IBM SPSS.

      Results:
      So far now, 48 NSCLC adenocarcinoma p. have been enrolled although only 31 have already completed radon measurement. Median age 59 years (range 33- 82); 58,1% female; 77% ECOG 0; 74,4% stage IV; 90,3% living in Madrid. Smoking habits: non-smokers 58% (9p. EGFRm, 7p. ALKr, 2p. BRAFm), light smokers 6,45% (1p. EGFRm, 1p. ALKr) and heavy smokers 35,4% (6p. EGFRm, 5p. KRASm). Median pack-years: light smokers 2,5 (2-3), heavy smokers 44 (20-80). Non-smoker p. reported 27,8% passive-smoking exposure and 44,4% childhood exposure. Radon measurement characteristics: type of building 83.9% flat; building material: 87.1% bricks. Median time of permanence in the same house: 25 years (2-55). Median height of house 3 floors (0-6). Most of measurement at bedroom (93,5%). Median of radon concentration: 103 Bq/m3 (42- 852); 51.6% over WHO recommendation. By molecular alteration: EGFRm median 91 Bq/m3 (42-164), ALKr median 128 Bq/m3 (64-852), BRAFm median 125 Bq/m3, KRASm median 80 Bq/m3 (44-149). ALKr demonstrated association with levels higher than WHO recommendation (p=0.045 Fisher's exact test).

      Conclusion:
      Our preliminary results show that radon concentrations in NSCLC harbouring molecular alterations are higher than WHO recommendation, particularly in patients with ALK rearrangement. Final results will help to confirm this possible association.

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      MINI11.13 - Q&A (ID 3530)

      • Abstract

      Abstract not provided

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    MINI 12 - Biomarkers and Lung Nodule Management (ID 109)

    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 15
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      MINI12.01 - A Novel Serum 4-MicroRNA Signature for Lung Cancer Detection (ID 585)

      E. Nadal, A. Truini, A. Nakata, J. Lin, R. Reddy, A.C. Chang, N. Ramnath, N. Gotoh, G. Chen, D. Beer

      • Abstract
      • Presentation
      • Slides

      Background:
      Early detection of lung cancer using low-dose CT led to a 20% reduction in mortality. However, this strategy has several limitations including high false-positive rates, potential over-diagnosis, and the potential harm associated with radiation exposure. The aim of this study was to identify differentially-expressed miRNAs in the serum of non-small cell lung cancer (NSCLC) patients that might be a clinically-useful tool for lung cancer early detection.

      Methods:
      We performed miRNA expression profile analysis using TaqMan OpenArray Human panel in a discovery set of 70 serum samples obtained at lung tumor resection including lung adenocarcinoma (AD) and lung squamous carcinoma (SCC) and 22 non-cancer subjects (NC). To construct the diagnostic signature, the miRNA candidates were selected based upon the following criteria: miRNAs significantly up-regulated (adjusted t-test p < 0.001) in the NSCLC tissue and serum as compared to normal lung tissue and NC serum respectively, not overexpressed in circulating blood cells and with Area Under the Curve (AUC) > 0.840 for discriminating stage I LC from NC in the receiver-operating characteristic (ROC) plots. Selected serum miRNAs were then validated by quantitative PCR using an independent validation set of serum samples from LC patients (n=84) and NC (n=23).

      Results:
      Sixty miRNAs were significantly up-regulated and 31 were down-regulated in the serum from NSCLC patients versus NC (adjusted p<0.001). Four miRNAs (miR-193b, miR-301, miR-141 and miR-200b) were selected for validating their diagnostic value in an independent cohort. A diagnostic signature was obtained by logistic regression based upon the expression values of these 4 serum miRNAs in the discovery set. This miRNA signature generated an AUC of 0.985 (95% CI 0.961 – 1.000, p < 0.001) for detecting NSCLC (all stages) and of 0.989 (95% CI 0.967 – 1.000, p < 0.001) for detecting stage I NSCLC in the discovery set. In the test set, the diagnostic utility of this miRNA signature was validated and exhibited an AUC of 0.993 (95% CI 0.979 – 1.000, p < 0.001).

      Conclusion:
      We identified a serum 4-miRNA signature that discriminated with high accuracy lung cancer patients from NC. Further prospective validation of this miRNA signature is warranted using an independent cohort of serum samples from patients who participated in a lung cancer screening program.

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      MINI12.02 - Clinical Utility of Chromosomal Aneusomy in High Risk Individuals (ID 1299)

      A.E. Barón, S. Kako, W.J. Feser, D.T. Merrick, K. Garg, S. Malkoski, S. Pretzel, T. Byers, J.M. Siegfried, W.A. Franklin, Y.E. Miller, H.J. Wolf, M. Varella-Garcia

      • Abstract
      • Presentation
      • Slides

      Background:
      In the context of CT screening in current and former smokers at high risk for lung cancer, the false positive rate is high (26% at first NLST screening; 13% with Lung-RADS criteria applied to NLST) and indeterminate nodules are frequently discovered. Noninvasive biomarkers are urgently needed to reduce false positives with screening CT and to improve risk stratification in those with indeterminate nodules. The Colorado (CO) Lung SPORE program performed a retrospective longitudinal evaluation (Pepe Phase 3 validation) to assess the potential of chromosomal aneusomy detected in sputum via fluorescence in situ hybridization (CA-FISH) as a biomarker for early detection in four nested case-control studies. Two of the cohorts (ACRIN/NLST and PLuSS) enrolled current and former smokers to investigate use of low dose CT to diagnose lung cancer. The other two were Colorado cohorts in which pulmonary clinic patients (mostly current and former smokers) were enrolled to investigate biomarkers to predict lung cancer. One of these cohorts (CO High Risk) was a COPD population and the other, still in the accrual phase, comprises patients referred for care of indeterminate lung nodules (CO Nodule).

      Methods:
      The cohorts were grouped into a Screening cohort (ACRIN/NLST (49 cases, 96 controls) and PLuSS (48 cases, 89 controls)) and a High Risk cohort (CO High Risk (55 cases, 59 controls) and CO Nodule (13 cases, 10 controls)). The CA-FISH assay was a 4-target panel including genomic sequences encompassing the EGFR and MYC genes, and the 5p15 and centromere 6 regions or the FGFR1 and PIK3CA genes. At the subject level, the assay was scored on a 4-category scale representing normal, probably normal, probably abnormal and abnormal. Operating characteristics (with 95% CI) of the assay were estimated for each group of cohorts overall and separately for COPD patients: sensitivity, specificity, likelihood ratio+ (LR+) and likelihood ratio- (LR-).

      Results:
      Using the cutoff of abnormal vs. not abnormal for CA-FISH, sensitivity and specificity for Screening subjects are 0.20 (0.13, 0.30) and 0.84 (0.78, 0.89), respectively; and for High Risk subjects are 0.67 (0.55, 0.78) and 0.94 (0.85, 0.98), respectively. Likelihood ratios for Screening subjects are LR+: 1.36 (0.81, 2.28) and LR-: 0.93 (0.83, 1.05), and for High Risk subjects are LR+: 11.66 (4.44, 30.63), and LR-: 0.34 (0.24, 0.48). Similar results were observed when only COPD subjects were analyzed.

      Conclusion:
      The high LR+ of sputum CA-FISH indicates that this noninvasive biomarker could be a clinically useful adjunct to CT among patients in high risk settings. Whether this same high level of LR+ will be reproducible in patients at high risk because of their indeterminate nodules remains to be seen. If so, a hypothetical patient with indeterminate nodules and a pre-test (CA-FISH) lung cancer risk of 20% would have a post-test probability of lung cancer of 78% if the CA-FISH test were positive. In the screening setting, however, the low LR+ of CA-FISH limits its clinical utility. Prospective assessment of sputum CA-FISH is ongoing in the Nodule Cohort of the CO Lung SPORE.

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      MINI12.03 - Comprehensive Analysis of MicroRNA Expression Patterns in Lung Adenocacinoma Presenting with GGNs and Non-Tumorous Tissues (ID 701)

      Y. He, C. Zhou, S. Ren

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80% of primary lung cancer cases and approximately two thirds of them are diagnosed at an advanced stage . The poor prognosis of this disease is partially due to the lack of an effective means of early diagnosis. Discovery of an effective and reliable tool for early diagnosis of lung cancer would play a pivotal role in improving the prognosis of patients with lung cancer. Pulmonary ground-glass nodules (GGNs) are increasingly detected in clinical practice. GGNs are related to lung cancer, especially lung adnocacinoma . The subject of how to manage the pulmonary GGNs remains controversial. It is necessary to identify biological markers that can be used to screen high-risk patients in order to allow better lung adenocacinoma presenting with GGNs detection, earlier intervention and increase the likelihood of successful treatment. MicroRNAs are small non-coding RNAs of 18–24 nucleotides, typically excised from 60–110 nucleotide foldback RNA precursor structures . MicroRNAs have drawn significant attention in cancer research after it was linked to oncogenesis and tumor metastasis. Abnormal expression of microRNAs has been found in both haematopoietic and solid tumours by various genome-wide techniques. There is no report about the relationship between microRNA and pulmonary GGNs. It is necessary to identify biological markers that can be used to screen high-risk patients presenting GGNs in order to allow early lung adenocacinoma detection. Our study investigated microRNA expression with the intention to identify a panel of microRNAs for the diagnosis of lung adenocarcinoma presenting with GGNs.

      Methods:
      73 pairs of samples (tumorous and non-tumorous) were surgically resected from lung adnocacinoma patients presenting with GGNs from Shanghai Pulmonary Hospital between May 2012 and June 2014. After obtaining the approval of the patient consent, fresh tissues samples were taken during surgical resection, snap-frozen on dry ice and stored at−80◦C. MicroRNA expression of tumor and non-tumorous tissues was investigated in 3 participants by the next generation sequencing. Then, we analyzed the difference expression microRNA profiles which were identified by second generation sequencing in 73 pairs of lung adenocacinoma presenting with GGNs and adjacent non-tumorous tissues using a quantitative reverse-transcriptase polymerase chain reaction assay (qRT-PCR).

      Results:
      When we compared microRNA expression among lung cancer tissues versus corresponding noncancerous lung tissues via next-generation sequencing, 23 microRNAs had statistical differences in expression between groups. Five microRNAs (hsa−miR−548ar−5p, chr10_7330_star, chr17_10932_star, hsa−miR−148a−3p, hsa−miR−210−3p) exhibited higher expression in the adnocacinoma samples than that in the non-tumorous samples, eighteen microRNAs (hsa−miR−548x−5p, hsa−miR−144−3p, hsa-miR-106a-5p, hsa−miR−548ay−5p, hsa−miR−199a−3p, hsa−miR−378d, hsa−miR−4732−3p, hsa−miR−486−3p, chr7_5517, hsa−miR−1307−5p, chr17_10880, hsa−miR−127−3p, hsa−miR−411−5p, chr1_1402, chr16_10269, hsa−miR−138−5p, hsa−miR−212−3p, hsa−miR−33b−5p) demonstrated lower expression in adnocacinoma samples than that in the non-tumorous samples (P<0.05). Further validated by qRT-PCR, six microRNAs (chr17_10932_star, hsa−miR−148a−3p, hsa−miR−210−3p, chr1_1402, hsa−miR−378d, hsa−miR−138−5p) were statistically differentially expressed in tumorous compared with non-tumorous tissues.

      Conclusion:
      We found a microRNA panel that has considerable clinical value in diagnosing lung adenocacinoma presenting with GGNs. Thus, patients who would have otherwise missed the curative treatment window can benefit from optimal therapy.

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      MINI12.04 - Blinded Evaluation of the LuCED test to Detect Early Stage Lung Cancer (ID 869)

      M. Meyer, C. Presley, D. Wilbur, R. Katdare, J. Hayenga, T. Bell, J. Liang, A. Nelson

      • Abstract
      • Presentation
      • Slides

      Background:
      A previous, non-blinded study presented at the American Society of Cytopathology demonstrated performance of the LuCED[®] test for early detection of lung cancer and showed a sensitivity to cancer of 93.6% with 100% specificity based on 94 patients. Sensitivity was consistent across tumor histology, stage, size and location. Here, LuCED performance is presented where the pathologist was blinded to the case diagnosis. Data for this evaluation was produced as part of the CLIA validation of LuCED for use in the VisionGate Biosignatures Laboratory.

      Methods:
      Sputum from 42 patients was processed by LuCED: 23 patients had biopsy-confirmed lung cancer and 19 patients were normal. Sputum was collected from three spontaneous morning coughs, fixed and stained with hematoxylin, and enriched for epithelial cells using fluorescence activated cell sorting. Each enriched specimen was analyzed using the Cell-CT® platform that computes 3D digital images of single cells through tomographic reconstruction with isometric, sub-micron resolution. 3D morphometric biosignatures were automatically measured to produce a probabilistic score that identified abnormal cell candidates while a second score identified normal bronchial epithelial cells to determine specimen adequacy. Specimen adequacy was achieved when either abnormal cells were detected or 800 normal bronchial epithelial cells were enumerated by the classifier, whichever came first. Data was randomized by case and cell images of abnormal candidates were viewed using a CellGazer® workstation for blinded, cytopathologist confirmation. Cases were run until one of the following conditions was met: an abnormal cell was discovered, the specimen was exhausted, the criterion for specimen adequacy was reached. Example images of positive cells are shown in Figure 1. Figure 1



      Results:
      For cancer cases, lung cancer histology included adenocarcinoma (10 cases), squamous cancer (7), small cell lung cancer (3) and undifferentiated cancer (3); representing TNM stages I (5), II (10), IV (5), and unknown (3). Abnormal cells were found in all 23 cancer cases for 100% case sensitivity (lower 95% CI bound: 85.1%). Non-cancer lung diseases may produce reparative changes whose morphology can mimic cancer cell features. To stress test LuCED, patients with COPD, bronchitis, etc., were included in the normal group. 100,645 cells were processed from the 19 normal cases with 0.47% identified by the classifier for review using CellGazer. No abnormal cells were found. Case specificity is 100% (lower 95% CI bound: 82.4%).

      Conclusion:
      This interim blinded study of LuCED performance demonstrates highly sensitive (100%) and specific (100%) early lung cancer detection suggesting utility as a non-invasive screening test.

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      MINI12.05 - Discussant for MINI12.01, MINI12.02, MINI12.03, MINI12.04 (ID 3418)

      L. Montuenga

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI12.06 - Bioconductance Compared to 18FDG-PET in Evaluating CT-Detected Lung Lesions (ID 647)

      R. Yung, J. O'Driscoll, M. Garff, M.Y. Zeng

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer (LC) is the leading cause of cancer mortality. Computed tomographic (CT) screening detects LC at earlier stages but also results in finding many more smaller, benign nodules. Positron-Emission-Tomography (PET) is commonly used to evaluate suspicious lesions prior to invasive biopsies. However, PET accuracy is confounded by various factors including size, inflammation and tumor metabolic activity. Another potential biomarker of cancerous tissue is a non-invasive measure of transcutaneous bioconductance. This study compares Electro Pulmonary Nodule (EPN), a tissue bioconductance scan, to 18FDG-PET in evaluating CT detected suspicious lung lesions.

      Methods:
      Cohort- 27 patients with suspicious nodules evaluated with both PET and EPN scanning (IRB approved protocol) prior to biopsy or long-term radiologic follow-up. An EPN Scan measuring bioconductance was performed on bilateral anatomic skin sites and results were scored as either positive or negative dependent on a defined cut-off point. The PET results were interpreted as positive, negative or indeterminate.

      Results:
      There were 18 LCs (16 non-small cell LC, 2 small cell LC) and 9 benign lesions. PET results yielded 7 indeterminate readings. Excluding these 7, PET had 100% sensitivity (14/14 true positives) and 67% specificity (4/6 true negatives). EPN Scan evaluation of these 20 determinate PET cases had 86% sensitivity (12/14 true positives) with 83% specificity (5/6 true negatives). When evaluating the entire cohort of 27, the EPN results improved sensitivity and specificity to 89% (16/18 true positives) and 89%(8/9 true negatives), respectively. Table 1 describes the 7 lesions 18FDG-PET indeterminate lesions compared to EPN Scanning. Figure 1 In these 7 cases, the EPN Scan correctly classified all cases for 100% accuracy. Of note, 2 of the 4 cancers classified by PET as “indeterminate” were < 1 cm and were correctly categorized by the EPN Scan.



      Conclusion:
      While 18FDG-PET is often used as a clinical adjunct in the evaluation of suspicious CT detected pulmonary lesions, it has recognized limitations. In this feasibility study of measuring transcutaneous bioconductance as a pre-biopsy assessment, EPN Scan performed favorably versus PET, especially in evaluating smaller or PET-indeterminate lesions.

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      MINI12.07 - Exhaled Breath Analysis in Lung Cancer - One Stop Shop for Diagnosis, Staging and EGFR Analysis (ID 2431)

      N. Peled, O. Liran, M. Abud-Hawa, M. Ilouze, N. Gai-Mor, D. Shlomi, A. Ben-Nun, A. Onn, J. Bar, H. Haick

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer (LC) is the leading cause of cancer death in the United States with more than 158,000 estimated deaths in 2015. Early detection of LC has been well established as a significant key point in patients' survival and prognosis, yet unfortunately, the vast majority of new LC patients are being diagnosed at advanced disease stages. Exhaled breath analysis can serve as a non-invasive method in early detection of LC. The tumor's micro-environment releases various compounds to blood, some of which are then exhaled at breath as Volatile Organic Compounds (VOCs). This study evaluates the potential of exhaled breath analysis in LC detection and to further diagnose histology, EGFR mutational status and to discriminate early from advanced disease in a multinational study.

      Methods:
      Breath samples were taken from untreated LC patients and matching controls. Patients were enrolled in a large tertiary referral hospital in Israel. Analysis was performed by gold nanoparticle-based Artificial Olfactory System (NaNose®) and Pattern recognition methods were used to analyze the results obtained from the NaNose®. Histology, EGFR mutation status and staging was taken from patient's files.

      Results:
      A total of 174 patients participated in this study, and Inter-group analysis of 80 LC patients (64 advanced stage) and 31 matched controls showed a significant discrimination between disease and control. Among all patients, 83 were adenocarcinoma and 11 were squamous. EGFR mutations were detected in 24 patients. The comparisons resulted in: early LC versus control: p < 0.0001; accuracy 85.11%, advanced LC versus control: p < 0.0001; accuracy 82.11%, early LC versus advanced LC: p < 0.0001; accuracy 78.75%. Histology (Adenocarcinoma vs. Squamous cell carcinoma) and EGFR status was also significantly determined by the volatile signature.

      Conclusion:
      Breath analysis may support early detection of cancer as well as histological diagnoses, staging and mutational testing in lung cancer. This innovative method may pose as an important non-invasive tool for lung cancer early detection, thus promoting better prognosis and therapeutic possibilities for patients.

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      MINI12.08 - Validation of Autoantibody Panel for Early Detection of Lung Cancer in Chinese Population (ID 2529)

      S. Ren, S. Zhang, Z. Ma, H. Cai, X. Xu, J. Zhou, X. Liu, X. Hu, C. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Autoantibodies is an attractive diagnostic approach for early detection of malignant tumors. Our previous studies found a panel of 7 TAAs(p53, GAGE7, PGP9.5, CAGE, MAGE A1, SOX2, GBU4-5) was associated with lung cancer. We performed this large-scale, multi-center clinical trial to validate their ability to aid early diagnosis of lung cancer in Chinese population. Autoantibodies is an attractive diagnostic approach for early detection of malignant tumors. Our previous studies found a panel of 7 TAAs(p53, GAGE7, PGP9.5, CAGE, MAGE A1, SOX2, GBU4-5) was associated with lung cancer. We performed this large-scale, multi-center clinical trial to validate their ability to aid early diagnosis of lung cancer in Chinese population.

      Methods:
      The 7 TAAs were selected from 43 candidate TAAs from our previous studies, which were detected by ELISA in 1915 participants from 5 clinical centers in China. These samples including lung cancer (n = 818), benign lung diseases (n = 386), healthy volunteers (n = 415) and interference group (n = 296). The sensitivity and specificity from 7 TAAs and the traditional cancer biomarkers CEA, NSE and CYFRA21-1 were compared.

      Results:
      The sensitivity and specificity of autoantibody assay were 61% and 90% respectively, which were similar in different subgroups such as age, gender, smoker status and histological type. As for the enrolled patients with lung cancer, the sensitivities were 60% for patients with stage I/II, which were significantly higher than 27% ( p < 0.01)when using the combination of CEA, NSE and CYFRA21-1 to detect patients with lung cancer. While in patients with stage III/IV lung cancer, sensitivities were similar (63% vs. 56%, p > 0.05) and specificity was significantly improved (90% vs 71%, p < 0.01). The specificity was consistent in benign lung diseases and autoimmune diseases(interference group) and were 90% and 94% respectively and a concentration decrease of 7 TAAs were also observed after tumor resection.

      Conclusion:
      This study suggest that the 7 TAAs autoantibody panel can be used to aid diagnosis of lung cancer, and show a significantly improving sensitivity in patients with early stage lung cancer when comparing with the combination of CEA, NSE and CYFRA21-1.

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      MINI12.09 - Progress with an RCT of the Detection of Autoantibodies to Tumour Antigens in Lung Cancer Using the Early CDT-Lung Test in Scotland (ECLS) (ID 48)

      F. Sullivan, S. Schembri

      • Abstract
      • Presentation
      • Slides

      Background:
      Since the majority of lung cancer cases are detected at a late stage the prognosis remains poor at present. The National Lung Screening Trial (NLST) reported 20% reductions in lung cancer mortality in 2011, however as a primary screening modality CT is expensive and may lead to significant morbidity in individuals whose tests are false positives. The EarlyCDT-lung test detects autoantibodies to proteins in the earliest stages of the disease with a specificity of 93%. Research question Does using the EarlyCDT-Lung test reduce the incidence of patients with late-stage lung cancer (3 & 4) or unclassified presentation (U) at diagnosis, compared with standard practice?

      Methods:
      We are conducting an RCT of 12 000 participants in areas of Scotland within the most deprived quintile of the population whose mortality from lung cancer is high by international standards. Adults aged 50 to 75 who are at 1.2% risk over the next 2 years are eligible to participate. They should also be healthy enough to undergo curative interventions. We will undertake a comparison of the EarlyCDT-lung test and follow-up imaging at six monthly intervals for 2 years with standard clinical practice. The primary outcome is the difference, after 24 months, between the rates of patients with stage 3, 4 or unclassified lung cancer at diagnosis. Participants who develop lung cancer will be followed-up via electronic record-linkage to assess both time to diagnosis and stage of disease at diagnosis. The secondary outcomes are cost-effectiveness, and a range of psychological measurements. There is a nested qualitative study of the psychological effects test of results on participants.

      Results:
      In the first 14 months of recruitment 8 848 patients have been recruited and 9.0% of those tested have had a positive blood test with eight early cancers and 13 abnormalities undergoing further investigation detected to date in those who tested positive. Six of the eight cancers have been staged and four of these are early cancers. Provisional data reported to the trial team on those tested negative include three cancers. No data are currently available for the main trial comparison. From prior observational studies the test performance is expected to be: 40% sensitivity and 90% specificity these early data. Based on the study so far the current Positive Predictive Value of the test is 2.0%.

      Conclusion:
      The study will determine the EarlyCDT-Lung test’s clinical and cost effectiveness. It will also assess potential morbidity arising from the test and potential harms and benefits of a negative EarlyCDT-Lung test result. Early results in the test only arm of the trial are encouraging.

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      MINI12.10 - Discussant for MINI12.06, MINI12.07, MINI12.08, MINI12.09 (ID 3419)

      H.I. Pass

      • Abstract
      • Presentation

      Abstract not provided

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      MINI12.11 - Screening for Lung Cancer with the Early CDT-Lung and Computed Tomography (ID 204)

      J.R. Jett, D. Dyer, J. Kern, D. Rollins, M. Phillips

      • Abstract
      • Presentation
      • Slides

      Background:
      Early CDT-Lung, a serum based biomarker consisting of a panel of seven autoantibodies that develop in response to tumor associated antigens, has been shown to detect lung cancer in all stages of disease. We hypothesized that this biomarker when used in combination with a low-dose CT (LDCT) in screening of a high-risk population would increase the detection of early stage lung cancer.

      Methods:
      A prospective study of 1,600 subjects at high risk for lung cancer was designed. Eligibility criteria included persons 50-75 years of age, current or former smokers of ≥ 20 pack years and < 10 years since quit smoking. Those with a history of lung cancer in first degree relative(s) and any history of smoking were included. Exclusion criteria ware any history of cancer within 10 years (except skin cancer), any use of oxygen, and life expectancy of < 5 years. A direct mail campaign was conducted with study announcements sent to the homes of potentially high-risk individuals, who then contacted us for consideration of participating in this screening study. Those fitting inclusion criteria received the Early CDT-Lung blood test and a LDCT. A nodule of ≥ 3mm was considered as a positive scan. The Early CDT-Lung test was considered positive if any one of the seven autoantibodies was positive. All participants are to have yearly telephone follow-up for two years.

      Results:
      From May 2012 through November 2014, 815 individuals were enrolled and 814 completed the initial blood and LDCT screening tests. The cohort median age was 59 years with 55% female and 45% male gender distribution. The mean smoking history was 44 pack-years. Fifty-four per cent were current smokers while 46% were former smokers. Forty-six per cent of the LDCTs were negative for any lung nodule while 38% were positive. Incidental non-lung cancer findings were identified in 15% of the study group. The Early CDT-Lung biomarker was positive in 60 (7%) of participants, 23 males and 37 females. In those with a positive LDCT (n=313), the biomarker was positive in 25 (8%). As of January 30, 2015, there have been six confirmed lung cancers: two limited stage small cell, two Stage IB adenocarcinoma (ACA), and two Stage IA (one ACA and one squamous cell). The Early CDT-Lung blood test was positive in two of the four Stage IA/B lung cancers and negative in the two small cell cancers.There are 35 Early CDT-Lung biomarker positive individuals whose LDCT had no nodule. These individuals are being followed with yearly LDCT for two years. The study is continuing to accrue with a goal of 1,600. (NCT01700257)

      Conclusion:
      The Early CDT-Lung biomarker was positive in 7% of our high-risk population. The biomarker was positive in two of six lung cancers, specifically in two of four Stage I lung cancers. Accrual to the study and follow-up of 35 biomarker positive but LDCT negative participants continues.

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      MINI12.12 - Validation of Blood-Based Biomarker for Classification of Patients with Indeterminate Pulmonary Nodules (ID 559)

      J.L. Tomic, R.L. Lagier, H.I. Pass, W.N. Rom, T.R. Pollard, C.E. Birse

      • Abstract
      • Presentation
      • Slides

      Background:
      The United States Preventive Services Task Force recommends annual CT-screening for lung cancer in high risk adults but also acknowledges that one disadvantage of CT-screening is the large number of false positive results. Circulating biomarkers may provide a noninvasive, cost-effective means of addressing this disadvantage by assisting with classification of patients with indeterminate pulmonary nodules. Here, we describe the development and testing of a blood-based 5-analyte panel to classify these patients.

      Methods:
      A 5-analyte panel was developed in a training study comprising stage I NSCLC patients (n=95) and healthy smoker controls (n=186). The ability of the biomarker to resolve patients with benign nodules from those with malignant lesions was investigated in two validation studies: (1) Prostate, Lung, Colorectal, Ovarian (PLCO), a CXR-based screening trial, cases n=56, controls n=56; (2) Conversant Bio (CB), cases n=22, controls n=22.

      Results:
      In the training study, the 5-marker classifier (TFPI, OPN, CEA, CYFRA, SCC) resolved malignant cases with 72% sensitivity and 90% specificity (AUC=0.90). In the PLCO validation study, the biomarker distinguished pre-diagnostic cases with an AUC=0.65. In the CB study, a clinical model developed integrating nodule size, nodule location and gender, classified subjects with an AUC=0.79. When added to the clinical model, the biomarker significantly improved overall accuracy (P=0.016; AUC=0.86).

      Conclusion:
      A blood-based biomarker has been developed that accurately classifies patients with indeterminate nodules. Adding this biomarker to currently employed clinical and imaging-based evaluations of pulmonary nodules, may prove valuable in assessing malignant risk.

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      MINI12.13 - Early Detection of Lung Cancer Using DNA Methylation in Plasma and Sputum (ID 1691)

      A. Hulbert, A. Stark, C. Chen, I. Jusue-Torres, K. Rodgers, B. Lee, C. Griffin, A. Yang, K. Sugimoto, Z. Lu, J. Wrangle, P.B. Illei, R. Battafarano, D. Molena, S. Yang, P. Huang, T. Wang, S. Baylin, R. Brown, M. Brock, J. Herman

      • Abstract
      • Slides

      Background:
      Lung cancer is the worldwide leading cause of cancer-related mortality. Almost 85% of lung cancer cases are diagnosed at late stages with a five-year-survival probability at the time of diagnosis of 16.8%. The National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality using low-dose computed tomography (CT) screening, but there was also a 96.4% false positive rate. Lung cancer screening might be improved through cancer specific biomarkers detected in body fluids such as plasma or sputum. Previous studies using DNA methylation failed to achieve adequate sensitivity because of use of infrequently methylated genes and detection techniques unable to detect the small amounts of DNA yielded from blood and sputum. We sought to improve the diagnostic accuracy using gene promoter methylation in blood and sputum through the use of Methylation On Beads (MOB) and a highly lung-cancer specific panel of genes for detection of lung cancer.

      Methods:
      We conducted a prospective case-control study obtaining cases and controls from the Lung Cancer Spore. Cases had pathological confirmation of Non-Small Cell Lung Cancer (NSCLC) lesion stage IA or IB. Controls were defined as patients with pathological confirmation of non-cancerous lesion in the surgical specimens. Plasma, sputum and CT scans were obtained pre-operatively. We quantified methylation levels and the amplification cycle threshold from sputum and plasma samples by using MOB and quantitative methylation specific real-time PCR lung cancer-related genes previously identified from The Cancer Genome Atlas (TCGA). This panel of genes include: CDO1, TAC1, HOXA7, HOXA9, SOX17 and ZFP42.

      Results:
      A total of 210 subjects fulfilled inclusion criteria, including 150 patients with NSCLC and 60 patients with non-cancerous lesions. All six genes were methylated in significantly more people with cancer than without cancer in both plasma and sputum (p<0.001) with the exception of HOXA9 in sputum, which was methylated in more than 90% of people with cancer and more than 90% of people without cancer. After adjusting by age and pack·year, the methylated genes that were significantly associated with risk of lung cancer stage IA & IB from blood samples were: CDO1 (p=0.009), TAC1 (<0.001), HOXA9 (p=0.005), SOX17 (<0.001) & ZFP42 (p=0.003) and from sputum samples were: CDO1 (p=0.066), TAC1 (p=0.007), ZFP42 (p=0.009). Sensitivity and specificity for lung cancer diagnosis using the 3 best genes in plasma was 91% and 68% respectively and for sputum 91% and 88%. Area under the curve for 3 best genes in plasma was 0.78 95% confidence interval (CI) (0.69-0.87) (p<0.001) and for the best 3 genes in sputum 0.88 95% CI (0.77-0.99) (p<0.001).

      Conclusion:
      This study shows that its is possible to obtain high diagnostic accuracy for Lung Cancer in early stages using a panel of methylated promoter genes in Plasma and Sputum, by using Methylation-on-beads. These epigenetic biomarkers could potentially be used to identify patients with high risk of lung cancer development. reducing unnecessary tests and increasing the chance to diagnose lung cancer at earlier stages

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      MINI12.14 - Exhaled microRNAs as Potential Biomarkers of Lung Cancer Case versus Control Status (ID 2948)

      M. Shi, W. Han, J. Lin, S.D. Spivack

      • Abstract
      • Presentation
      • Slides

      Background:
      There is a need for non-invasive airway-based biomarkers in lung carcinogenesis for both risk assessment of the ex-smoker, and earlier diagnosis. Exhaled breath condensate (EBC) contains airway molecules, presumably in part from bronchial and alveolar epithelial cellular origins. Our previous study showed microRNAs could qualitatively be detected in EBC. Here both qualitative and quantitative multivariate analysis were applied to look for microRNA candidates in EBC from a new sample of lung cancer patients and controls.

      Methods:
      MicroRNA expression profiling using RNA-specific RT-qPCR was performed in EBC from 41 patients and 41 contols with clinical and microRNA expression data. The panel of microRNAs was assembled based on literature-derived reports of blood or lung microRNAs which segregate with case-control status, combined with our own lung tissue-based discovery effort using microRNA-seq on lung tumor-non-tumor pairs. The assembled panel for this effort included n=19 tumor-non-tumor differentiating microRNAs (miR-9, 18a, 20a, 31, 130b, 142, 146, 182, 183, 196a, 200a, 200c, 205, 210, 212, 221, 224, 330 and 708) chosen from the literature and our own lung tissue-based discovery data. Small nuclear RNA U1 was a housekeeping gene in the study based on its universality. Qualitative and quantitative (miRNA qPCR data normalized to internal reference U1 small ncRNA) analyses were considered. Multivariate analyses considered clinical information, including age, smoking status, underlying lung disease (COPD or not).

      Results:
      By univariate analyses, between cases (all histologies) and controls, qualitative/binary data showed miR-221 (p=0.030; OR=3.11) and miR-708 (p=0.016; OR=3.04) were significantly different. The case-adenocarcinoma subgroup (n=13) also differed from the controls in miR 708 frequency (p=0.034, OR=4.71). Examples of multivariate analyses (qualitative/binary data, case – all histologies) are shown in the Table: ontrols.

      miRNA Odds Ratio lower bound of CI upper bound of CI p-value
      miR.221 3.339 0.994 12.482 0.059
      age 1.084 1.026 1.158 0.008
      smoking 1vs0 1.467 0.304 8.372 0.642
      smoking 2vs0 2.211 0.411 14.436 0.371
      Underlying lung dz (COPD vs no COPD) 3.400 1.184 10.349 0.026
      miR.708 5.041 1.651 17.603 0.007
      age 1.093 1.031 1.172 0.006
      smoking former vs never 1.378 0.273 8.145 0.704
      smoking current vs never 2.144 0.386 14.269 0.397
      Underlying lung dz (COPD vs no COPD) 4.437 1.448 15.047 0.012
      Similar multivariate models were obtained for miR 221 and miR708 in the cancer-adenocarcinoma subgroup. No clear case-control discriminant exhaled microRNAs were found in the analogous quantitative data (delta CT) analyses, by univariate or multivariate analyses.

      Conclusion:
      From the qualitative analysis, two possible miRNA biomarkers of case status (miR-221 and miR-708) were obtained. Previous work had suggested miR 221 as a discriminant microRNA in lung cancer case versus control setting. Quantitative data was not informative. We are working on expanding and refining the miR panel, and larger sample size to partition covariates such age, underlying lung disease, and other factors. Our goal is to test this non-invasive biomarker approach to lung cancer risk assessment.

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      MINI12.15 - Discussant for MINI12.11, MINI12.12, MINI12.13, MINI12.14 (ID 3478)

      A. Spira

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 13 - Immunotherapy Biomarkers (ID 104)

    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 8
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      ORAL13.01 - PD-L1 Expression in Lung Adenocarcinomas Correlates with KRAS Mutations and Th1/Cytotoxic T Lymphocyte Microenvironment (ID 2496)

      T. Huynh, V. Morales-Oyarvide, H. Uruga, E. Bozkurtlar, J.F. Gainor, A. Hata, E. Mark, M. Lanuti, J.A. Engelman, M. Mino-Kenudson

      • Abstract
      • Presentation
      • Slides

      Background:
      The interaction of PD-1, with its ligand, PD-L1 induces apoptosis of T cells and inhibits cytokine production, allowing tumor cells to bypass immune surveillance. PD-L1 expression on tumor cells can be upregulated via interferon gamma that is secreted by CD8+ cytotoxic T lymphocytes (CTLs) and/or Th1 pathway activation, counterbalancing the Th1/CTL microenvironment. Blockade of the PD-1/PD-L1 immune checkpoint in solid tumors has resulted in durable responses in early phase clinical trials. Moreover, protein expression of PD-L1 by immunohistochemistry (IHC) reportedly predicts patient response to anti-PD-1/PD-L1 therapies. Multiple studies have reported associations of PD-L1 expression with clinicopathological variables in lung adenocarcinomas (ADC), but such studies have produced conflicting results, possibly due to use of different antibody clones and cutoffs and possibly different ethnicities of the cohort. Thus, we correlated PD-L1 expression with clinicopathological and molecular profiles including subtypes of tumor infiltrating lymphocytes (TILs) in a large lung ADC cohort using a cut-off commonly used in clinical trials.

      Methods:
      PD-L1 (E1L3N, 1:200, CST), CD8 (4B11, RTU, Leica Bond), T-bet (Th1 transcription factor, D6N8B, 1:100, CST), and GATA3 (Th2 transcription factor, L50-823, 1:250, Biocare) IHC were performed on tissue microarrays constructed of 242 resected lung ADC. All cases underwent detailed histological analysis and a subset (n=128) of cases underwent clinical molecular testing. Membranous expression (regardless of intensity) in 5% or more tumor cells was deemed positive for PD-L1 expression. CD8+, T-bet+ and GATA3+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3).

      Results:
      Our study cohort consisted of 242 patients with a pathologic stage of 0 in 1 case, I in 188, II in 37, III in 9, and IV in 7. Among those, 38 (15.7%) exhibited PD-L1 expression which was significantly associated with smoking history (p=0.008), large tumor size (p=0.007), solid predominant pattern (p<0.001), high nuclear grade (grade 3, p<0.001), vascular invasion (p=0.012), increased T-bet+ TILs (grade 2, p<0.001) and CD8+ TILs (grade 2, p<0.001), and KRAS mutations (p=0.001). High nuclear grade (p=0.011), KRAS mutations (p=0.004), and increased CD8+ TILs (p=0.005) remained significant predictors of PD-L1 expression in multivariate analysis, while advanced stage (II or higher vs. I, p=0.056) showed a trend towards PD-L1 expression. There was no difference in the 5-year progression free survival (PFS) between the PD-L1 positive and negative patients. In contrast, increased CD8+ TILs showed a borderline significance with favorable outcome (p=0.082), with the 5-year PFS being 87% for the CD8 positive group and 68% for the CD8 negative group, but neither PD-L1 nor CD8+ TILs was a significant predictor of survival by the cox proportional-hazards regression model.

      Conclusion:
      PD-L1 expression in ADC significantly correlates with KRAS mutations and several clinicopathological signatures of KRAS-mutants, including significant smoking history. The latter may have resulted in development of multiple passenger mutations that serve as neoantigens promoting the Th1/CTL microenvironment. These results suggest that blockade of the PD-1/PD-L1 axis may be a promising treatment strategy to reinstitute the Th1/CTL microenvironment for patients with KRAS-mutated ADC, in which there are currently no available treatment options.

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      ORAL13.02 - Characterization of PD-L1 Expression Related to Unique Genes in NSCLC Tissue Samples (ID 2173)

      E.B. Garon, R. McKenna, J. Dering, B. Wolf, S. Pitts, N. Kamranpour, H. Chen, A. Lisberg, R.B. Cameron, J.M. Lee, S.M. Dubinett, D.J. Slamon

      • Abstract
      • Presentation
      • Slides

      Background:
      Programmed cell death protein 1 (PD-1) receptors are members of the B7:CD28 family that interact with PD-1 ligands PD-L1 and PD-L2 to regulate cytotoxic T cell (CTL) tolerance (Freeman, J Exp Med. 2000; Latchman, Nat Immunol. 2001). Successful evasion of transformed cells from host defense is a feature of cancer (Hanahan, Cell 2011). Immune evasion can occur via the engagement of PD-1 with PD-L1 or PD-L2 (Dong, Nature Med 2002). In metastatic non-small cell lung cancer (NSCLC), PD-L1 expression has been associated with increased response to inhibitors of PD-1 (Garon, NEJM 2015). Current adjuvant cytotoxic approaches are associated with a real but small survival increases and significant toxicity. Characterization of PD-L1 expression in resected tumors could guide development of immune checkpoint based adjuvant trials.

      Methods:
      Microarray analyses were performed to assess gene expression for 320 NSCLC and 15 normal lung resection specimens profiled on the Agilent Whole Human Genome 4x44K 2-color platform. The reference sample used in the experiments was an equal mixture of 258 of the 320 NSCLC samples included in the study. Microarray data was imported into Rosetta Resolver for analysis. The Rosetta Similarity Tool (ROAST) was utilized to find genes correlated to PD-L1 expression. Both PD-L1 and the target gene had to be differentially expressed for sample to be included in computation of correlation. Cosine correlation was used as the similarity metric. Functional genomic analysis on the list of PD-L1 correlated genes was performed using tools available with the DAVID Bioinformatics resources (david.abcc.ncifcrf.gov) Survival analyses based on PD-L1 expression were performed using the Kaplan-Meier method and compared using the log-rank test. Samples with PD-L1 log(ratio) > 0 and p-value < 0.01 were classified as upregulated, samples with p-value>0.01 were classified as unchanged, and sample with log(ratio) < 0 and p-value <0.01 were classified as downregulated.

      Results:
      The reference level of PD-L1 expression among the subset of normal lung and NSCLC tissue samples was higher compared to levels seen in 503 breast cancer and 149 endometrial cancer tissue samples. Within the 320 NSCLC tissue samples, 174 unique genes are highly correlated with PD-L1 expression (r range= 0.692-0.904). 80 tissue samples (25%) had a PD-L1 log ratio > 0, and 63 tissue samples had large sets of highly correlated genes, a similar prevalence to membranous staining in half the cells in metastatic NSCLC (Garon, NEJM 2015). Functional analyses revealed that the genes significantly correlated with PD-L1 expression were involved in immune and inflammatory response. No significant difference in overall survival was noted (p=.661), but increased PD-L1 expression was clearly not associated with better outcomes.

      Conclusion:
      Within the NSCLC cohort, there is a group of patients with high expression for PD-L1 and related genes. This group does not have a better prognosis in comparison to those with typical or decreased PD-L1 expression. Due to the relationship between PD-L1 expression and response to anti-PD-1 therapy in metastatic NSCLC, this data and its correlation with other clinical characteristics of the patients can guide the design of adjuvant approaches based on immune checkpoint inhibitors.

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      ORAL13.03 - Spatiotemporal Effects on Programmed Death Ligand 1 (PD-L1) Expression and Immunophenotype of Non-Small Cell Lung Cancer (NSCLC) (ID 1609)

      M. Kowanetz, H. Koeppen, M. Boe, J.E. Chaft, C.M. Rudin, W. Zou, D. Nickles, R. Desai, R. Nakamura, A. Sandler, L. Amler, P. Hegde, N.A. Rizvi, M.D. Hellmann

      • Abstract
      • Slides

      Background:
      PD-L1 is one of the immune-checkpoint molecules that regulates Th1 immune responses and mediates cancer immune evasion. PD-L1 can be expressed on tumor cells (TC) or tumor-infiltrating immune cells (IC) and expression in both cell types can negatively regulate T-cell function in the tumor microenvironment. The goal of this study was to evaluate the intra-patient heterogeneity and temporal changes in PD-L1 expression and overall immune phenotype in NSCLC using paired synchronous and metachronous tumor specimens.

      Methods:
      Thirty-nine patients (pts) with NSCLC treated at Memorial Sloan Kettering Cancer Center were evaluated as part of an IRB approved project. Most were former/current smokers (n=30, 77%) and had adenocarcinoma histology (n=36, 92%). 17 pts were KRAS mutant (45%), and 5 were EGFR mutant (13%). Paired synchronous samples were collected from 17 pts with stage IIIA-N2 resected primary lung and metastatic lymph node (met LN) tissue. Paired metachronous samples were collected from 23 pts (including one patient also with synchronous tissue) with at least two metachronous primary/metastatic (n=14) or metastatic/metastatic tissues (n=9). In pts with metachronous samples, 14 (61%) had systemic intercurrent anti-cancer therapy and 9 (39%) had none. PD-L1 expression was assessed by IHC (clone SP142) on TC and IC. CD8 expression was evaluated by IHC using the C8/144 clone. In addition, expression of ~600 immune genes was analyzed by iChip.

      Results:
      Twenty-five out of 39 tissue pairs were evaluable by PD-L1 IHC (14/17 synchronous, 11/23 metachronous). Among pts with synchronous samples, in the primary tumor, PD-L1 was expressed in <1% of TC or IC in 6 pts, in 1-4% of cells in 5 pts, and in ≥5% of cells in 3 pts. Among those with metachronous samples, in the first collected sample, the PD-L1 expression in <1% of TC or IC was detected in 6 pts, in 1-4% of cells in 2 pts, and in ≥5% of cells in 3 pts. PD-L1 expression was similar across all paired tissues. PD-L1 status at the TC or IC 5% cut-off remained unchanged in all evaluable paired specimens and at the TC or IC 1% cut-off remained unchanged in 80% (11/14 synchronous and 9/11 metachronous) pairs. In both synchronous and metachronous samples, CD8 expression was also similar across paired specimens. The median inter-sample difference in CD8+ T-cell infiltration was 0.5% (95% CI: -0.6% - 3.4%) in synchronous pairs; three pts had a difference >5%. In metachronous pairs, the median difference was -0.4% (95% CI: -1.4% - 0.1%); one pt had a >5% change in CD8+ T-cell infiltration.

      Conclusion:
      In this study, there was a high agreement in PD-L1 expression and CD8+ T-cell infiltration in both paired synchronous and metachronous NSCLC specimens. The low intra-patient heterogeneity of PD-L1 and CD8 expression in this study suggests any available tissue (e.g. primary or met) may be reliable to assess these markers in NSCLC. Overall immune characterization by gene expression analysis in paired tumor specimens will be presented.

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      ORAL13.04 - Discussant for ORAL13.01, ORAL13.02, ORAL13.03 (ID 3403)

      S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ORAL13.05 - Predictive Biomarker Testing for Programmed Cell Death 1 Inhibition in Non-Small Cell Lung Cancer (ID 1081)

      B.S. Sheffield, G. Geller, E. Pleasance, S. Zachara-Szczakowski, K. Milne, S.E. Kalloger, E. Zhao, S. Bidnur, M. Jones, B.H. Nelson, S. Yip, M.A. Marra, J. Laskin, C. Ho, D. Ionescu

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the largest cause of cancer-related mortality in the developed world. Advances in molecular targeted therapies have led to improved survival in a subset of non-small cell lung cancer (NSCLC) patients. Recently, inhibitors of the programmed cell death receptor 1 (PD1) have proven clinical efficacy in NSCLC. Only a subset of patients respond to PD1 inhibitors, likely reflecting variation in tumor-expression of the PD1 ligand (PD-L1). Many clinical trials have evaluated PD-L1 as a possible predictive biomarker for immune therapy; however several parallel and uncoordinated efforts have led to a high amount of heterogeneity, uncertainty, and ambiguity in the literature around PD-L1 and its use as a biomarker. We aim to investigate the feasibility of PD-L1 biomarker testing in NSCLC using immunohistochemistry (IHC).

      Methods:
      Cases of stage II, surgically resected NSCLC, adenocarcinoma were identified retrospectively from the archives of the British Columbia Cancer Agency. A tissue microarray (TMA) was constructed with matched primary and metastatic lung tumors. IHC directed towards PD-L1 was performed with 3 different primary antibody clones: E1L3N (Cell Signaling Technology), SP142 (Spring Bioscience), and 28-8 (Dako), each stain was prepared using a unique protocol. Additional cases of NSCLC with available whole-genome sequence were also stained. Staining results were reviewed and scored by intensity of staining and the percentage of positive tumor cells. Cases with positive staining of any intensity in greater than 1% of tumor cells were considered positive (H score > 1). Clinical, pathological, and genomic features of PD-L1 positive cases were reviewed.

      Results:
      Eighty cases of NSCLC were identified and used in TMA construction. 78 cases had matched lymph node metastases included in the TMA. 29 cases (36%) were positive by the SP142 clone, 19 (24%) by E1L3N, and 27 (34%) by the 28-8 clone. The 3 clones showed concordant results in 61 (76%) of cases, 15 (19%) discordant cases showed low level staining with SP142/28-8 and no staining with E1L3N, 2 (2.5%) cases showed no staining by 28-8 with moderate staining by SP142/E1L3N. Lymph node metastases showed a concordant PD-L1 score in 65 (83%) cases, with no detectable trend in the discordance. Comparison of primary antibodies showed a high rate of concordance (κ=0.68). Exploratory analysis of 6 additional cases with whole-genome and transcriptome data showed no statistical correlation between PD-L1 IHC and tobacco-induced hypermutation signature (p=0.22), or PD-L1 mRNA expression (R[2] = 0.35) by linear regression.

      Conclusion:
      PD-L1 IHC is reproducible in the setting of an academic reference laboratory. There are small, but potentially clinically relevant, differences between commercially available PD-L1 diagnostic antibodies. Primary tumor PD-L1 status is generally reflective of metastatic tumor PD-L1 status. Molecular correlates of PD-L1 positive cases remain to be elucidated and warrant further investigation.

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      ORAL13.06 - Programmed Death Ligand-1 (PDL-1) Expression in Non-Small Cell Lung Cancer (NSCLC): Analysis of a Large Early Stage Cohort; and Concordance of Expression in Paired Primary-Nodal and Primary-Metastasis Tumour Samples (ID 3226)

      P. Mitchell, C. Murone, K. Asadi, C. Harbison, S. Knight, T. John

      • Abstract
      • Presentation
      • Slides

      Background:
      PDL-1 expression in NSCLC is frequently associated with response to PD-1 pathway inhibitor therapy. However, it is unclear whether PDL-1 expression status is maintained in nodes and distant metastases and further information is needed on the relationship between expression and patient and tumour characteristics and prognosis

      Methods:
      TMAs were constructed using 1mm cores (triplicate) of FFPE primary tumour from patients undergoing surgery with curative intent, from N2 nodal tumour (triplicate) and from metastatic NSCLC tumour (duplicate cores or single small sections). PDL-1 protein expression was measured using a validated, automated immuno-histochemical assay using the 28-8 monoclonal antibody (Dako, Carpinteria, CA), with samples categorised as positive when tumour cell membranes were stained to any intensity in 5% of assessable tumour in any core.

      Results:
      57 paired primary–metastasis cases were analysed: median age 64 years (33-56); 30 male (53%); adenocarcinoma 27 (47%) and squamous cell 15 (26%). Metastatic sites were: brain 27; trachea/bronchus/lung/pleura 17; chest wall/skin 5; lymph nodes 6. Seven cases were synchronous (6 brain) while the median interval between primary and metastasis for other cases was 1.3 years (range 0.2-8.5). Primary and metastatic tumour samples were PDL1 positive for 13 (23%) and 14 (25%) cases respectively and for 44 cases (77%) expression was concordant. Discordance with negative primary and positive metastasis was seen in 7 cases (12%), while 6 cases (11%) were positive in primary and negative in metastasis. Using assay cut offs of 1% and 50%, concordance was 63% and 89% respectively. Eight cases had more than one metastasis analysed and the primary and all metastases were concordant for 6 cases while 2 cases were positive in primary but negative in one of the metastases. TMAs from 518 primary cases were also analysed and data on 123 cases are currently available. Histology was adenocarcinoma 58 (47%) and squamous 38 (31%). Thirty seven cases (30%) were PDL1+. Of the 13 never or light (≤10 PY) smokers, only 2 (9%) were positive. Further data on all cases and matched primary-nodes will be presented.

      Conclusion:
      PDL1 expression in ≥5% tumour cell was seen in 30% of cases. Concordance of expression in matched primary and metastasis was seen in 77% of cases. These data suggest that if PDL-1 expression status is critical in the decision to treat metastatic NSCLC with a PD-1 pathway inhibitor, then re-biopsy of a metastasis may be warranted.

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      ORAL13.07 - EMT Is Associated with an Inflammatory Tumor Microenvironment with Elevation of Immune Checkpoints and Suppressive Cytokines in Lung Cancer (ID 2134)

      Y. Lou, L. Diao, E.R.P. Cuentas, W. Denning, L. Chen, Y. Fan, J. Rodriguez, L. Byers, J. Wang, V. Papadimitrakopoulou, C. Behrens, I.I. Wistuba, P. Hwu, J.V. Heymach, D.L. Gibbons

      • Abstract
      • Presentation
      • Slides

      Background:
      Promising results in the treatment of NSCLC have been seen with immunomodulatory agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents. Epithelial-mesenchymal transition (EMT) is a key process driving metastasis and drug resistance. Previously we have developed a robust EMT gene signature, highlighting differential patterns of drug responsiveness for epithelial and mesenchymal tumor cells.

      Methods:
      We conducted an integrated analysis of gene expression profiling from three independent large datasets, including The Cancer Genome Atlas (TCGA) of lung and two large datasets from MD Anderson Cancer Center, Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse phase protein array (RPPA), immunohistochemistry, in vivo mouse models and correlation with clinical data were performed.

      Results:
      EMT is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation co-existent with elevation of immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, BTLA and CTLA-4, along with increases in tumor infiltration by CD4+Foxp3+ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Similarly, IL-6 and indoleamine 2, 3-dioxygenase (IDO) were elevated in these tumors. We demonstrate that in murine models of lung adenocarcinoma, many of these changes are recapitulated by modulation of the miR-200/ZEB1 axis, a known regulator of EMT. Furthermore, B7-H3 is found to negatively correlate with overall survival and recurrence free survival, indicating a potential new therapeutic target in lung adenocarcinoma in the future.

      Conclusion:
      EMT, commonly related to cancer metastasis and drug resistance, is highly associated with an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoints and that is regulated at least in part by the miR-200/ZEB1 axis. These findings suggest that EMT may have potential utility as a biomarker selecting patients more likely to benefit from immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers.

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      ORAL13.08 - Discussant for ORAL13.05, ORAL13.06, ORAL13.07 (ID 3404)

      D. Rimm

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      Abstract not provided

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    ORAL 14 - Biology 2 (ID 112)

    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 8
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      ORAL14.01 - Early Contrast Enhancement as a Non-Invasive Objective Biomarker of Pleural Malignancy (ID 1687)

      S. Tsim, D.B. Stobo, G.W. Cowell, R. Woodward, J.E. Foster, K.G. Blyth

      • Abstract
      • Presentation
      • Slides

      Background:
      Despite imaging advances, differentiating pleural malignancy (PM) from benign pleural disease (BPD) remains challenging, particularly early-stage Malignant Pleural Mesothelioma (MPM), which can look similar to benign asbestos-related pleural effusion (BAPE). We report the diagnostic performance of a novel Magnetic Resonance Imaging (MRI) biomarker of PM - Early Contrast Enhancement (ECE).

      Methods:
      24 patients with suspected PM were recruited prospectively (January 2013-November 2014). All underwent contrast-enhanced Computed Tomography (CT) scanning and Thoracoscopy. 3-T Pleural MRI was performed prior to Thoracoscopy (median 4 (IQR 4–8) days). Imaging methodology was developed using patients 1-6. In 18 patients, T1-weighted 3D-spoiled-gradient-echo sequences were acquired coronally at baseline, 40 and 80 seconds and 4.5, 9 and 13.5 minutes after intravenous Gadobutrol contrast. Mean signal intensity (SI) of parietal pleura at each time-point was derived from 15 regions of interest placed by two respiratory physicians. ECE on the resulting SI/time curve was defined objectively as an early peak (at/before 4.5 minutes) and/or late fall in mean SI (Figure 1). CT and MRI scans were assessed for morphological features of PM by two thoracic radiologists. All analyses were blinded. Diagnostic performance was assessed using contingency tables. Inter- and intra-observer agreement was assessed using Cohen’s kappa statistic. Figure 1



      Results:
      Median patient age was 73 (IQR 70–80) years. 75% (n=18) were asbestos-exposed. ECE was present in 10/11 patients with PM (MPM (10); lung cancer (1)). The false negative case had MPM. 1 MPM case was initially diagnosed with BAPE but reclassified as MPM after developing progressive PM, consistent with their initial MRI result (ECE present). ECE was absent in 6/7 patients with BPD (BAPE (4), fibrothorax (2), TB (1)). The false positive case had TB. Table 1 summarises diagnostic performance.

      Table 1: Diagnostic performance and reproducibility of ECE, CT morphology and MRI morphology in pleural malignancy
      Sensitivity (%) Specificity (%) Negative Predictive Value (%) Positive Predictive Value (%) Inter-observer agreement Intra-observer agreement
      CT Morphology 90 50 80 69 0.753 Not done
      MRI Morphology 91 71 83 83 0.727 Not done
      MRI Early Contrast Enhancement 91 86 86 91 0.766 1.000


      Conclusion:
      ECE appears a sensitive and specific objective biomarker of PM, out-performing subjectively-defined CT and MR morphology. SI/time curves for ECE assessment can be generated reproducibly in patients with minimal pleural thickening, suggesting potential utility as a non-invasive biomarker for the early detection of MPM or low-volume metastatic PM.

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      ORAL14.02 - Clinical Significance of Soluble CD26 in Malignant Pleural Mesothelioma (ID 354)

      N. Fujimoto, K. Ohnuma, K. Aoe, O. Hosono, T. Yamada, T. Kishimoto, C. Morimoto

      • Abstract
      • Presentation
      • Slides

      Background:
      There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM.

      Methods:
      The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. To make a comparative review of the usefulness of sCD26, we determined serum and pleural fluid soluble mesothelin-related peptides (SMRP). SMRP was measured by the chemiluminescent enzyme immunoassay (CLEIA) based on 2-step sandwich method.

      Results:
      Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P=0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P=0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P=0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P=0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P=0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P=0.028). Median values of serum and pleural fluid SMRP in MPM patients were 0.43 and 15.37 mmol/l, respectively. Median value of pleural fluid SMRP in epithelioid MPM was 17.28 mmol/l. Median values of serum SMRP in SPE and pleural fluid SMRP in OPD were 0.90 and 0.43 mmol/l, respectively. Pleural fluid SMRP in MPM was significantly higher than in OPD (P=0.000) and serum SMRP in MPM was significantly higher than in SPE (P=0.000).

      Conclusion:
      Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.

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      ORAL14.03 - Integrin Linked Kinase Pathway: A Potential Driver of Tumorigenesis of Malignant Pleural Mesothelioma (ID 2135)

      A. De Rienzo, M.A. Archer, B.Y. Yeap, N. Dao, D. Sciaranghella, A.C. Sideris, A.G. Holman, Y.E. Wang, L. Croft, W.G. Richards, R. Bueno

      • Abstract
      • Slides

      Background:
      Identifying driver mutations assists with understanding molecular aspects of cancer and development of novel drugs. The genetics of malignant pleural mesothelioma (MPM) has primarily been to date described in terms of deletions of specific chromosomal regions with CDKN2A and NF2 most commonly mutated, and more recently, evidence for a role of BAP1. The current work suggests that activation of the Integrin Linked Kinase (ILK) pathway may be oncogenic in a subset of MPM.

      Methods:
      Whole-genome sequencing was accomplished for 10 tumor and matched normal genomic DNA samples using a Complete Genomics platform. Tumor and normal genomes were sequenced to at least 30-fold haploid coverage, with corresponding diploid coverage of at least 99.5%. Selected candidates single nucleotide variations (SNVs) were further characterized using PCR and Sanger sequencing to identify tumor-specific single nucleotide mutations. Potential driver genes were investigated in 147 additional MPM cases by targeted resequencing. Levels of transcripts were examined in an available expression data set (Affymetrix® Human Gene 1.1 ST Array). Association of mutation status and gene expression to clinicopathologic variables was explored statistically.

      Results:
      Among 146 single nucleotide variants (SNVs) mapping in amino acid coding regions of annotated exons and generating non-synonymous amino acid changes, 85 were confirmed to be tumor specific. Functional enrichments of genes affected by point mutations were performed utilizing Ingenuity Pathway Analysis to identify clusters of genes annotated in pathways potentially relevant to the biology of MPM. Mutations affecting genes involved in the Integrin Linked Kinase (ILK) pathway were the most significantly (p = 4.9e-5) enriched. Specifically, 5 of 10 sequenced MPM samples showed point mutations in at least one of 6 genes of this pathway (MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A). Re-sequencing analysis of 147 MPM tumors identified 40 SNVs in these genes among 31 MPM samples (21%). Thirty-five (88%) SNVs were present in both tumor and matching normal DNA samples. In 4 samples, tumor specific mutations were identified, 3 in MYH9 (1.4%) and 2 in RHOA (1.4%) both recently proposed as genes involved in tumorigenesis. Non-epithelioid tumors expressed significantly higher levels of MYH9 (p<0.001), RHOA (p<0.001), and MYH10 (p=0.001) compared to epithelioid tumors. RHOA was more highly expressed in men than women (p=0.001). The highest quartile of MYH9 and of RHOA expression was associated with higher gender-adjusted risk of death (HR=2.23 and HR=1.95, respectively) compared to the lower three quartiles (p<0.001) by multivariate analysis.

      Conclusion:
      Tumor specific mutations in MYH9 or RHOA were found in six of 157 (3.8%) MPM patients. Interestingly, both MYH9 (22q13.1) and RHOA (3p21.3) reside in two chromosomal regions frequently deleted in MPM. Additional analysis is in progress to investigate the role of ILK pathway activation in MPM. These observations suggest that a sub-class of MPM may respond to therapy targeting the ILK pathway.

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      ORAL14.04 - Discussant for ORAL14.01, ORAL14.02, ORAL14.03 (ID 3332)

      D.S. Schrump

      • Abstract
      • Presentation

      Abstract not provided

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      ORAL14.05 - Intracavitary Cisplatin-Fibrin After Resection of Malignant Pleural Mesothelioma (ID 1165)

      I. Opitz, A. Kostron, O. Lauk, M. Meerang, M. Friess, G. Wuilleret, C. Bommeli, A. Jetter, B. Aeschlimann, D. Günther, R. Stahel, W. Weder

      • Abstract
      • Slides

      Background:
      Local tumor recurrence is very frequent after resection of malignant pleural mesothelioma (MPM). Intracavitary chemotherapy has been shown to be a promising approach to improve local tumor control. Here, we present the results of a phase-I-dose-escalation trial with intracavitary application of cisplatin-fibrin after surgical tumor resection.

      Methods:
      Altogether 12 patients (75% IMIG stage III-IV) were treated with 4 different dose levels of cisplatin (11, 22, 33 and 44mg/m[2] body surface area (BSA)). Eight patients of 22, 33 and 44mg/m[2] groups received previous induction treatment with intravenous cisplatin/pemetrexed. Cisplatin-fibrin was sprayed on the surface of chest wall, diaphragm, mediastinum and lung after pleurectomy/decortication (P/D). Blood was taken before surgery and at several time points after the treatment. Tissue sampling was conducted before and at 90 minutes after the administration. Cisplatin levels were measured by inductively coupled plasma sector field mass spectrometry.

      Results:
      Serum cisplatin kinetics and AUC0-120 are depicted in figure 1. Induction intravenous chemotherapy contributed to >50% of total serum cisplatin levels compared to cisplatin-fibrin (figure 1B). The median AUC0-24 of the 3 patients in the highest dose level (44mg/m[2]BSA) including predoses from induction chemotherapy reached 23h*µg/g, which is still below the suggested renal toxicity risk level, 25h*µg/g (Royer 2008). Our serum cisplatin AUC levels stayed far below levels reported after intrapleural perfusion (approx. 89h*µg/g (Ried 2013)). Local cisplatin concentration in tissues varied from 12-133 (median: 36.5µg/g) and did not seem to be dose dependent. No dose limiting toxicity due to cisplatin was observed. Major morbidity was observed in 4 patients (33%). 30day- and 90day-mortality was 0%. The median follow up after surgery was 11 months (range: 5-28 months). In 8 patients receiving 11, 22, 33 mg/m[2]BSA, relapse was detected after a median freedom from recurrence (FFR) of 8 months (95% confidence interval (CI): 1-14 months). In three patients with early IMIG stage (I and II), no sign of relapse was observed at 28, 8 and 6 months after the treatment (11, 44, 44 mg/m[2]BSA, respectively). The last patient (44mg/m[2]BSA) with IMIG stage III tumor currently shows no sign of recurrence at 5 months after surgery. Figure 1



      Conclusion:
      The administration of intracavitary cisplatin-fibrin as high as 44mg/m[2]BSA is safe after P/D, also in combination with induction chemotherapy. Tissue cisplatin concentration was high whereas no dose limiting toxicity due to systemic distribution was detected. A confirmation of the safety and efficacy of the highest dosage, 44 mg/m[2]BSA, in a phase II trial is warranted.

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      ORAL14.06 - MesobanK - an International Mesothelioma Tissue Bioresource - Now Open for Tissue Requests (ID 988)

      R.C. Rintoul, D.M. Rassl, J. Gittins, J. Edwards, D.A. Fennell, N. Maskell, R. Booton, V. Hughes, A. Chauhan, S. Marciniak

      • Abstract
      • Presentation
      • Slides

      Background:
      Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures (SOPs) to facilitate basic and translational research is very limited. MesobanK, funded by the British Lung Foundation and the Mick Knighton Mesothelioma Research Fund, is a UK based bioresource to collect fresh tissue, blood, pleural fluid and anonymised linked clinical data to strict SOPs from patients with malignant pleural mesothelioma.

      Methods:
      1) To construct a tissue microarray (TMA) from 1000 cases of formalin fixed paraffin embedded pleural mesothelioma tissue linked to a clinical data set. Each case will have several cores taken to allow for tumour heterogeneity. 2) To collect 300 cases of fresh pleural mesothelioma tissue (5 samples per case), blood (whole blood, serum, plasma and buffy coat) and pleural fluid (supernatant and cell pellet) linked to a clinical data set. Longer term follow up and survival data will be provided by the UK National Cancer Registration Service. 3) To develop at least 20 new fully characterised and annotated mesothelioma cell lines. Governance MesobanK abides by all relevant UK and EU legislation regarding the collection of tissue and data. Mesobank is a member of the UK Confederation of Cancer Biobanks. Prioritisation for access to samples will be based solely on scientific merit. The project is managed by a dedicated project manager and overseen by a Steering Committee; an independent Scientific Advisory Board reviews anonymised applications for samples.

      Results:
      All required ethical permissions have been obtained. A secure, web-based multi-user database has been constructed for data collection. As of April 2015, 730 of the 1000 cases for the TMA have been acquired from UK pathology departments and the first part of the TMA construction is underway at the Cancer Research UK Cambridge Institute. In the first year of operation, 100 prospective cases have been banked and quality control to assess tumour percentage and necrosis in each sample is underway. Figure 1 shows weight of sample versus tumour percentage from the QC of the first 144 samples. Twenty six new cell lines have been developed and are currently being characterised. Figure 1



      Conclusion:
      Procurement of formalin fixed tissue for the TMA and fresh biospecimens is progressing well and MesobanK is now open for investigators to apply for tissue samples. Enquiries about tissue availability should be directed to mesobankadmin@papworth.nhs.uk. An application form is available at www.mesobank.com. A cost contribution model has been developed to support on-going funding of MesobanK.

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      ORAL14.07 - Preclinical Investigation of the Therapeutic Potential of Nintedanib in Malignant Pleural Mesothelioma (ID 2655)

      V. Laszlo, J. Ozsvar, M.A. Hoda, T. Klikovits, D. Lakatos, T. Garay, W. Berger, M. Grusch, W. Klepetko, F. Hilberg, B. Dome, B. Hegedus

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is a devastating malignancy with still rising incidence worldwide. Its aggressive biological behavior and therapy resistance result in a median overall survival (OS) of 9 to 17 months only. Currently, platinum-based chemotherapy in combination with antifolate agents is the standard front-line therapy for MPM and to date no molecularly targeted therapeutic approaches have been approved in the clinics. Nintedanib is an indolinone derivative that has been demonstrated to efficiently inhibit the activity of VEGFR, PDGFR and FGFR tyrosine kinase isoforms and thus to be capable to suppress angiogenesis and tumor growth. Here, we report the antitumor activity of nintedanib in MPM.

      Methods:
      21 MPM cell lines were treated with nintedanib and SRB assays were performed to determine the IC50 values for each cell line. 4 sensitive cell models were selected for further in vitro analysis: BrdU, TUNEL and clonogenic assays were performed to investigate the impact of the drug on the proliferation, apoptosis and colony formation capacity of MPM cells, respectively. The migratory activity of MPM cells was analyzed with 2D videomicroscopy. The downstream signaling of the target receptors was investigated by Western blot analysis. Drug interactions with cisplatin were assessed in the p31 MPM cell line and in its cisplatin-resistant subline (p31cis) by using the CalcuSyn software. The in vivo anti-MPM activity of nintedanib was studied in an orthotopic human MPM xenograft model in SCID mice. Tumor-bearing animals were treated with 50 mg/kg nintedanib daily, per os (PO) or intraperitoneally (IP) and followed for survival.

      Results:
      Nintedanib exerted a growth inhibitory effect on MPM cell lines in both short- and long-term viability assays. The inhibition of proliferation was observed in all MPM cell models analyzed, whereas significant apoptosis induction was only found in half of them. Migratory activity strongly decreased upon nintedanib treatment. Down-regulation of Erk1/2 phosphorylation was evident within 10 min of treatment and was present even after 24h. Nintedanib, however, had no inhibitory effect on the activation of Akt or S6. Additive, but no synergistic effect on cell viability was detected in the p31 and p31cis MPM cells when nintedanib was combined with cisplatin. In vivo, survival of PO-treated animals showed favorable trend (vs. PO control, log-rank test, p=0.059). Nintedanib significantly prolonged the survival of mice when it was administered IP (vs. IP control, log-rank test, p=0.0008).

      Conclusion:
      Our data suggest that nintedanib exerts antitumor activity in MPM both in vitro and in vivo and thus may represent a promising novel therapeutic option in this malignancy.

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      ORAL14.08 - Discussant for ORAL14.05, ORAL14.06, ORAL14.07 (ID 3331)

      H.L. Kindler

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      Abstract not provided

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