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    OA06 - Early Stage Lung Cancer: Outcomes and Interventions

    • Type: Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Moderators:
      • Abstract

      Background
      Sex differences in non-small cell lung cancer (NSCLC) susceptibility, tumor biology and survival have been retrospectively reported. We conducted a prospective, case-series intergroup study (SWOG S0424) in 4 cohorts of females (F) and males (M), ever-smokers (ES) and never-smokers (NS) with newly-diagnosed stages I-III NSCLC. This is the first overall survival (OS) report. a9ded1e5ce5d75814730bb4caaf49419 Method
      Patients were accrued at US sites via SWOG/NCI-CTSU. A questionnaire of demographics and exposures (tobacco, environmental, reproductive, hormonal); stage and histology data; treatment; and OS were obtained. Tumor tissue was submitted for EGFR, RAS and p53 mutations. Nuclear and cytoplasmic estrogen receptor (ER) alpha and beta were measured (Cheng, JNCI 2017). Kaplan-Meier (KM) curves and OS modeled using Cox proportional hazards were examined. The NS cohorts remained open longer to maximize accrual. Patients were followed 5 years for OS or until death. 4c3880bb027f159e801041b1021e88e8 Result
      The accrual goal of 981 was achieved from 10/2005-3/2011. Evaluable cases were FES, n=337; MES, 383; FNS, 188; MNS, 49 (MNS under-accrued despite extension). The 4 cohorts differed significantly in demographics, tumor stage, histology, mutational profile (overall, by histology), ER expression, lifestyle factors and exposures. KM curves showed MNS/MES had overlapping OS and FNS/FES had significantly better OS. Five-year estimates were FNS, 73%; FES, 69%; MNS, 58%; MES, 52%. Markedly improved OS for females persisted after adjusting for other factors. Four multivariate OS models were constructed: all patients (model 1) and women only (model 2), each with mutations and ER expression added (models 3, 4). Model 1: better OS for females (HR 0.56, p <.001); higher BMI (continuous, HR 0.98, p=0.045); and adenocarcinoma, BAC, large cell (all vs squamous, HRs 0.84, 0.48, 0.57); worse OS for stages II and III (HRs 1.87, 3.76: each p<.001) and greater age. Model 2: worse OS if ES (HR 1.48, p=0.05), higher stages; histology and hormonal exposure variables were not significant. Model 3: better OS if EGFR mutation (HR 0.53, p=0.013), female, stage I, higher BMI or greater height; worse OS if p53 mutation, higher ER-alpha cytoplasmic or ER-beta nuclear H-scores. Model 4: worse OS if higher stage, p53 mutation or ER-alpha cytoplasmic H-score; EGFR mutation lost significance. 8eea62084ca7e541d918e823422bd82e Conclusion
      Sex, histology, mutations and exposures impacted OS, with dramatically better OS for females regardless of the analysis/model. Hormonal influences (persistent association of ER-expression with OS) were independently significant. Despite adjustments, favorable female survival could not be explained away. Randomized studies should stratify by sex and validation analyses should be conducted in targeted therapy and immunotherapy trials.

      SUPPORT: NIH/NCI grants R01CA106815, U10CA180888, U10CA180819 and UG1CA189974. 6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA06.02 - Video-Assisted Thoracoscopic Surgery vs. Thoracotomy for Non-Small Cell Lung Cancer: Oncologic Outcome of a Randomized Trial

      13:40 - 13:50  |  Presenting Author(s): Dongrong Situ  |  Author(s): Hao Long, Qunyou Tan, Qingquan Luo, Zheng Wang, Gening Jiang, Tie-Hua Rong

      • Abstract

      Background

      Video-assisted thoracoscopic surgery (VATS) has been widely used in the treatment of early-stage non–small cell lung cancer (NSCLC). However, there has not been a robust randomized control trial (RCT) to conclude VATS has similar oncologic efficacy to open surgery. Therefore, a large multicenter RCT in China was designed and initialed in order to verify the role of VATS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A non-inferiority phase 3 RCT was undertaken at five thoracic surgical centers in China. Patients aged 18-75 years who were diagnosed of clinically early-stage NSCLCs were randomized in a 1:1 ratio into VATS and thoracotomy groups. Radical lobectomy plus hilar and mediastinal lymph node dissection was the standard surgical intervention as per protocol. The long-term oncologic outcomes including 3-year locoregional recurrence rate, overall survival (OS) and disease-free survival (DFS) would be analyzed and reported here. This study is registered with the ClinicalTrials.gov, number NCT01102517.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 508 patients were recruited in the trial between January 2008 and March 2014. And 433 patients were eligible for final analysis (222 cases in VATS group and 211 cases in thoracotomy group). At 3 years, the locoregional recurrence rates were 4.5% in VATS group and 5.7% in thoracotomy group respectively (P=0.664). Patients who received VATS procedures had a similar DFS rate to those who underwent open surgery (66% versus 69%, P=0.925; Fig 1A). Again, the 3-year OS rates were of no significant difference between VATS and thoracotomy groups (74% versus 73%, P=0.382; Fig 1B).

      fig 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      VATS in the treatment of clinically early-stage NSCLCs was associated with equivalent oncologic efficacy when compared to open surgery.

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      OA06.03 - Sublobar Resection is Equivalent to Lobectomy for Screen Detected Lung Cancer

      13:50 - 14:00  |  Presenting Author(s): Brendon Stiles  |  Author(s): Mohamed K Hussein, Mohamed Rahouma, Benjamin Lee, Sebron Harrison, Jeffrey L. Port, Nasser Altorki

      • Abstract

      Background

      Despite the lack of survival data from modern, ongoing randomized clinical trials (CALGB 140503, JCOG 0802), sublobar resection (SLR) is increasingly offered to patients with small, peripheral lung cancers. In particular, SLR may be an attractive surgical strategy for screen detected lung cancers, some of which may be less biologically aggressive than cancers detected by other means. Utilizing prospective data collected from patients undergoing surgery in the National Lung Screening Trial (NLST), we sought to determine whether the extent of resection affected survival for patients with screen detected lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The NLST database was queried for patients who underwent surgical resection for confirmed lung cancer. Numerical variables were compared using Mann-Whitney U test. Categorical variables were compared using Chi-squared test. Propensity score matching analysis (lobectomy versus sublobar resection) controlling for age, gender, race, tumor size, and stage was performed (nearest neighbor, 1:1, matching with no replacement, caliper 0.2). Overall survival (OS) and cancer specific survival (CSS) were compared using log rank test in Kaplan Meier curves.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 1,029 patients who underwent resection for lung cancer, we identified 821 patients (80%) who had lobectomy and 166 patients (16%) who had SLR, among whom the majority (n=114, 69%) had wedge resection. Patients who underwent SLR were older (64 vs. 61, p=0.66), more likely to be female (53% vs. 41%, p=0.004), had smaller tumors (2 cm vs. 4.5 cm, p<0.001), and were more likely to be stage I (80% vs. 75%, p=0.001). At five years, for stage I patients undergoing SLR (n=129) there was no difference in OS (77% vs. 77%, p=0.889) or CSS (83% vs. 83%, p=0.959) compared to patients undergoing lobectomy (n=613). In order to more accurately compare surgical outcomes, we propensity matched 134 patients from each group undergoing SLR and lobectomy. Among these matched groups, there were no differences in age, gender, histology, or stage. Postoperatively, patients undergoing SLR had less total complications (22% vs. 32%, p=0.05) than those undergoing lobectomy (HR 0.59, CI 0.38-0.94). In matched patients at five years, there was no difference in OS (67% vs. 70%, p=0.629) or CSS (74% vs. 74%, p=0.980) for patients undergoing SLR compared to those undergoing lobectomy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      For patients with screen detected lung cancer, SLR confers equivalent survival to lobectomy. By decreasing perioperative complications and potentially preserving lung function, SLR may provide distinct advantages in a screen detected lung cancer patient cohort.

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      OA06.04 - Discussant - OA 06.01, OA 06.02, OA 06.03

      14:00 - 14:15  |  Presenting Author(s): Valerie W Rusch

      • Abstract

      Abstract not provided

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      OA06.05 - Do SBRT Planning and Delivery Factors Influence Local Control for Early Stage Non-Small Cell Lung Cancer (e-NSCLC)? 

      14:15 - 14:25  |  Presenting Author(s): Gregory M.M. Videtic  |  Author(s): Chandana A. Reddy, Aditya Juloori, Bindu Manyam, Neil M Woody, Kevin L Stephans

      • Abstract

      Background

      Stereotactic Body Radiation (SBRT) utilizes a variety of techniques to deliver very high-dose radiation to moving targets in the lung. We investigated the impact of dose-delivery factors on local failure (LF) by surveying our 12 year experience with e-NSCLC from our prospective database.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Curative SBRT was administered to 1,085 patients (pts) between 2005 and 2016 and planned with either pencil beam (PB) or collapsed cone convolution (CCC) dose calculation algorithms (DCA), using open (dynamic arcs) or modulated beams (IMRT or VMAT), immobilized by abdominal compression or automatic breathing control (ABC), and treated with/without available CBCT (aligned to external fiducials and KV x-rays to bone if no CBCT, PTV margins were not altered based on availability of CBCT). We limited our analysis to standard fractionation regimens, [60 Gy/3, 48 Gy/4, 50 Gy/5, & 30-34 Gy/1) chosen per the treating physician in a risk-adapted approach relative to tumor size and location. The intreaction of technical variables with known patient and tumor factors on LF was analyzed using Fine and Gray univariate regression, with significant predictors selected for a forward step-wise multivariate regression model.

      4c3880bb027f159e801041b1021e88e8 Result

      At mean follow-up time of 25.6 months the cumulative incidence of LF at 1, 2, & 5 years was 3.0, 8.3, and 9.8% respectively. Overall survival (1, 2, 5 years) was 83, 62, & 28%. Univariate correlates with LF were PB TPS (HR 2.87, p=0.0004), modulated beam (HR 2.3, p=0.005), lack of CBCT (HR 2.69, p=0.0004), SBRT dose relative to 60 Gy/3 (HR 5.2, p=0.0001 for 4-5 fx; HR 2.7, p=0.051 for 1 fx), tumor size (HR 1.2 per cm, p=0.0009), PET SUV (HR 1.04 per SUV, p=0.0039), and squamous histology (HR 1.8, p=0.0051). Immobilization with ABC (n=96) versus abdominal compression (n=989) did not correlate with LF (p=0.99). On multivariate analysis PET SUV, modulated beam, and use of CBCT were no longer significant correlates with LF, while TPS (HR 2.62, p=0.0019), SBRT dose (HR 4.1, p=0.0009 for 4-5 fx relative to 60 Gy/3) & HR 2.9, p=0.039 for 1 fx versus 60 Gy/3), tumor size (HR 1.2 per cm, p=0.042) and squamous histology (HR 1.7, p=0.027) remained statistically significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      While the use of PB versus CCC DCA was associated with higher rates of LF after SBRT, the use of abdominal compression vs ABC (univariate), open vs modulated beam, and CBCT vs bony alignment (multivariate) were not correlated with higher rates of LF after SBRT in e-NSCLC.

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      OA06.06 - MISSILE-NSCLC: A Phase II Trial Measuring the Integration of Stereotactic Radiotherapy Plus Surgery in Early-Stage Non-Small Cell Lung Cancer

      14:25 - 14:35  |  Presenting Author(s): David Palma  |  Author(s): Alexander Louie, Richard Malthaner, Dalilah Fortin, George Rodrigues, Brian Yaremko, Joanna M Laba, Keith Kwan, Stewart Gaede, Ting Lee, Aaron Ward, Andrew Warner, Richard Inculet

      • Abstract

      Background

      Stereotactic Ablative Radiotherapy (SABR) has emerged as a standard treatment option in patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), yet the pathologic complete response (pCR) rate after SABR is unknown. Neoadjuvant SABR in operable patients has been proposed as a mechanism of improving local control and inducing anti-tumor immune activity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This phase II study (NCT02136355) enrolled patients with biopsy-proven clinical T1-2N0M0 NSCLC who were candidates for surgical resection. Patients underwent neoadjuvant SABR using a risk-adapted fractionation of 54 Gy/3 fractions, 55 Gy/5 or 60 Gy/8. Surgical resection took place 10 weeks after SABR. Patients also underwent dynamic FDG-PET and dynamic contrast-enhanced CT prior to SABR and approximately 2 weeks prior to surgery. The primary endpoint was the pCR rate, and secondary endpoints included local, regional, and distant recurrence, quality of life using the FACT Trial Outcome Index (TOI), and toxicity.

      4c3880bb027f159e801041b1021e88e8 Result

      Accrual began in Sept 2014 and completed in August 2017 with 40 patients enrolled. Median age was 69 years (range 44–83 years), and 58% were female. Thirty-one patients (78%) had T1 tumors and 9 (23%) had T2 tumors; histology was adenocarcinoma (n=26; 65%), squamous cell (n=13; 33%) and NSCLC not otherwise specified (n=1; 3%). Baseline FEV1 was median 73% percent predicted (range 50%–117%). Nine patients (23%) received the 3-fraction regimen, 21 (53%) received 5 fractions and 10 (25%) received 8 fractions. Thirty-five patients underwent surgery and were evaluable for the primary endpoint. The pCR rate was 60% (95% CI 44%–76%). 30-day and 90-day post-surgical mortality rates were both 0%. Eighteen percent of patients had grade 3 or 4 toxicities, most commonly pulmonary in nature (Grade 4: atelectasis and respiratory failure [n=1]; Grade 3: pneumonia/pneumonitis [n=2]; bronchopleural fistula [n=1]). In the patients receiving surgery, 2-year outcomes were: overall survival 77%, local control 100%, regional control 53% and distant control 76%. There were no significant changes in FACT-TOI score within the first year of follow-up.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The pCR rate after SABR for T1 and T2 NSCLC was 60%. Toxicity of the combined approach appears favorable, compared to historical series of surgery alone, and there was no perioperative mortality. Larger studies are needed to determine the clinical role of this combined treatment approach.

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      OA06.07 - Predictors and Consequences of Refusing Surgery for Clinical Stage I NSCLC: A National Cancer Database Analysis

      14:35 - 14:45  |  Presenting Author(s): Brendon Stiles  |  Author(s): Mohamed Rahouma, Mohamed Kamel, Abu Nasar, Sebron Harrison, Benjamin Lee, Jeffrey L. Port, Nasser Altorki

      • Abstract

      Background

      Given perceived morbidity of lung cancer surgery, patients may instead pursue other treatment options, particularly in the current era of shared decision-making. We sought to determine predictors of refusal of surgery for clinical stage I non-small cell lung cancer (NSCLC) patients and to determine associated outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The NCDB (2004-2014) was queried for clinical stage I NSCLC patients who underwent or were recommended to undergo surgery. A unique field in the NCDB allows identification of those patients who were recommended to have surgery, but refused. We only included cases in which surgery was refused “by the patient, patient’s family member or guardian”. We excluded patients with multiple primary tumors, unknown treatment modality/sequence, those who did not undergo recommended surgery for unknown reasons, and those initially not recommended to have surgery. Survival was compared using log rank test in Kaplan Meier curves. Logistic regression was performed to identify predictors of refusing surgery.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 118,0217 patients undergoing surgery and 3,210 (2.6%) who were recommended, but refused surgery. By multivariate analysis older age (HR=1.09, CI=1.08-1.09), non-white race (HR=2.18, CI=1.97-2.42), low income (HR=1.28,CI=1.16-1.41), lack of insurance (HR=2.62,CI=1.89-3.62), squamous histology (HR=1.40,CI=1.29-1.53), and larger tumor size (HR=1.57,CI=1.42-1.73) predicted refusal of surgery.Patients refusing surgery were treated with chemoradiation (n=249, 7.8%), radiation or chemotherapy alone (n=1,568, 48.8%), or no treatment (n=1393, 43.4%). Median survival was worse for patients who refused any treatment versus those who received other treatment modalities (19.8 vs 42.2 months, P<0.001). Among those patients refusing surgery who were treated with radiation, we identified 758 patients (23.6%) who received stereotactic body radiation therapy (SBRT). The proportion of patients who refused surgery and received SBRT increased over time, from 3.8% in 2004-2006, to 17% in 2007-2009, to 31.1% in 2010-2012, and to 37.9% in 2013-2014. Patients receiving SBRT had improved survival compared to other patients refusing surgery (47.9 vs. 25.2 months, p<0.001), although survival in the SBRT group was inferior to patients undergoing surgery as recommended (47.9 vs. 82.8 months, p<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although patients may be reluctant to undergo surgery for early stage NSCLC, refusal of surgery when recommended comes at the expense of decreased survival. Socioeconomic factors may be associated with refusal of surgery. The use of SBRT is an effective and increasingly used alternative in these patients, which improves survival compared to no treatment but which is still not equivalent to surgery in this unmatched, retrospective cohort.

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      OA06.08 - Discussant - OA 06.05, OA 06.06, OA 06.07

      14:45 - 15:00  |  Presenting Author(s): Steven H Lin

      • Abstract

      Abstract not provided

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    PC02 - Debate on Local Therapies for Limited Small Cell Lung Cancer? Surgery PRO/CON and BID Radiation PRO/CON

    • Type: Pro-Con Session
    • Track: Small Cell Lung Cancer/NET
    • Moderators:
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      PC02.00 - Introduction with Poll Questions

      13:30 - 13:35  |  Presenting Author(s): Quincy Chu, Wilfried Eberhardt

      • Abstract

      Abstract not provided

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      PC02.01 - Surgery - PRO

      13:35 - 13:55  |  Presenting Author(s): Elliot Wakeam

      • Abstract

      Abstract

      Surgery in the treatment of small cell lung cancer (SCLC) was commonplace up until the mid-1970’s when the results of the medical research council (MRC) trial compared surgery to radiation and found no improvement with the addition of surgery. A later trial compared chemoradiation with adjuvant surgery to chemoradiation alone also failed to show an improvement with surgery. These two results have been used to justify nihilism amongst thoracic oncologists with respect to the use of surgery. However, modern screening, staging, minimally-invasive surgery and adjuvant therapy have changed the situation for the treatment of early SCLC. Modern evidence, albeit retrospective, supports a greater utility for surgery in the treatment of early SCLC than what may have been suggested by older randomized trials that are no longer applicable in the modern era. Surgery has much to offer in the treatment of early SCLC and this lecture will outline the potential utility of surgery - in particular anatomic resection and systematic lymph node dissection - as part of a multimodality treatment regimen.

      e353dbe42c8654f33588d4da0b517469

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      PC02.02 - Surgery - CON

      13:55 - 14:15  |  Presenting Author(s): Cecile Le Pechoux

      • Abstract

      Abstract not provided

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      PC02.02a - Poll Questions

      14:15 - 14:20  |  Presenting Author(s): Quincy Chu, Wilfried Eberhardt

      • Abstract

      Abstract not provided

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      PC02.03 - BID Radiation - CON

      14:20 - 14:40  |  Presenting Author(s): Ben Slotman

      • Abstract

      Abstract

      Thoracic radiotherapy for LS-SCLC: QD is just as good as BID ?!

      Most of the advances in outcome of small cell lung cancer (SCLC) in the past few decades can be attributed to improvements in radiotherapy, including better imaging and target selection, better treatment planning, better integration with chemotherapy, and use of prophylactic cranial irradiation.

      Thoracic radiotherapy plays an important role in the treatment of limited disease SCLC (LS-SCLC). Best results are obtained with twice daily (BID) radiotherapy, starting early and given concurrently with chemotherapy [1]. In addition, it was shown that a shorter time from start of chemotherapy to completion of radiotherapy was associated with longer survival [2]. Two meta-analyses demonstrated that use of thoracic radiotherapy led to improved local control and an absolute survival benefit at 3 years of 5% [3,4].

      Turrisi et al. [5] demonstrated in the Intergroup 0096 study that 45 Gy given BID in 30 fractions in 3 weeks was superior compared to the same dose delivered once-daily (QD) in 25 fractions over a 5 week period. Overall survival at 5 years was improved (26% vs 16%), but at the expense of more G3-4 oesophagitis (32 vs 16%). In spite of these results, BID radiotherapy is still used in a only a minority of SCLC patients [6,7]. In The Netherlands, early concurrent BID rasdiotherapy is given in about a quarter of the patients [7]. The radiotherapy dose in the QD arm of the Intergroup trial [5] was relatively low and some argued that a higher QD radiotherapy dose might be equivalent to or even better than the 45 Gy BID scheme. In the ongoing CALGB 30610 / RTOG 0538 study (NCT00632853) a dose of 70 Gy once-daily in 35 fractions in 7 weeks is compared with the 45Gy BD scheme. In this trial, radiotherapy starts with the first course of chemotherapy and includes elective nodal irradiation. Accrual is expected to continue for several years.

      In the recently published CONVERT trial (ISRCTN91927162), patients were randomized between 45 Gy BID in 3 weeks and 66 Gy QD in 33 fractions in 6.6 weeks starting with the second course of chemotherapy [8]. Treatment did not include elective nodal irradiation. The study was designed to investigate whether the higher QD regimen would lead to improved survival. Median overall survival was 30 months for the BID and 25 months for the QD arm. There were no statistically significant differences in the rates of local and metastatic progression. Survival in the control arm (BID) was 12% higher than expected when designing the study, possibly due to improvements in radiotherapy techniques. Based on the study, it can be concluded that a higher dose given QD does not lead to improved survival or better local control. There were no significant differences in acute toxicity, except for more G4 or higher neutropenia in the BID arm (49% vs 38%). The risk of Grade 3-4 oesophagitis was 19% with no significant differences between the two study arms.

      Based on the results of this trial, 45 Gy given BID in 3 weeks should remain the reference standard. This regimen leads to the best results in the shortest time with the fewest number of fractions. The CONVERT study also indicates that where delivery of a BED scheme is not feasible, a higher dose once-daily schedule does not compromise clinical outcomes. However, it Is surprising that the significantly higher biologically equivalent radiotherapy dose of the QD scheme in the CONVERT study did not translate into better outcome.Does the early distant dissemination of the disease preclude further improvements in local control and survival by local treatment? Or is the influence of the repopulation may greater than calculated in our radiobiological models?

      The possible benefit of shortened treatment time was evaluated in a phase II study from Norway in which 45 Gy BID in 3 weeks was compared with 42 Gy in 15 fractions in 3 weeks given QD. There was no significant difference in progression free survival at 1 year, the primary endpoint of this study in which 157 patients were enrolled (49% vs 45%). Although overall response rates were similar (88% and 92%), more complete responses were seen in the BID arm (33 vs 13%). In addition, although not statistically significant, overall survival was 25 months for the BID vs 19 months for the QD arm.

      In the BID scheme, treatment is completed in 3 weeks and a BED10 of 52 Gy is delivered, whereas the same BED10 is reached after about 22 fractions of 2 Gy delivered once-daily. The delivered BED during the last third of the QD treatment does not seem to contribute to outcome. This suggest that repopulation starts very early and that tumor doubling times may be much shorter than generally assumed and a shorter QD scheme may be preferable if treatmenti is not deliverded BID.. .

      References

      1. Fried DB. S J Clin Oncol 2004;22:4837–45.

      2. De Ruysscher D.et al., J Clin Oncol 2006;24:1057–63.

      3. Pignon JP, et al. N Engl J Med 1992;327:1618–24.

      4. Warde P, Payne D. J Clin Oncol 1992;10:890–5.

      5. Turrisi AT, ert al. et al. N Engl J Med 1999;340:265–71.

      6. Komaki R, et al. Int J Radiat Oncol Biol Phys 2013;85:1082-9.

      7. Damhuis R, et al. Clin Oncol 2018;30:17-22.

      8. Faivre-Finn C. et al. Lancet Oncol 2017;18:1116-25.

      9. Gronberg BH, Acta Oncol 2016;55:591-7.

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      PC02.04 - BID Radiation - PRO

      14:40 - 15:00  |  Presenting Author(s): Jeffrey Bogart

      • Abstract

      Abstract

      The optimal thoracic radiotherapy dose for treating limited stage small cell lung cancer remains to be defined. Given the radiosensitivity of small cell lung cancer cell lines in preclinical studies in the 1980's it was postulated that twice daily radiotherapy would result in improved efficacy. Subsequent clinical experience included the landmark Intergroup 0096 trial, which demonstrated improved overall survival for patients assigned to twice daily radiotherapy (45 Gy) compared with once daily radiotherapy to the same total dose. Despite being one of the few randomized trials showing that changing the radiotherapy regimen impacts overall survival, the twice-daily regimen was slow to be adopted in clinical practice and many NCI cooperative group studies continued to use once-daily radiotherapy. Reluctance to routinely use the twice-daily regimen likely relate to concerns with acute toxicity, logistic issues, and use of a modest radiotherapy dose of only 45 Gy on the standard arm. In addition, a contemporaneous study from NCCTG did not show an advantage to twice-daily radiotherapy, although a planned treatment break was included such that radiotherapy was not accelerated. Alternate strategies to improve the efficacy of thoracic radiotherapy have included the development of high dose once-daily regimens with a 70 Gy regimen utilized in several phase II trials from the Cancer and Leukemia Group B. These trials are somewhat difficult to interpret, as radiotherapy was not initiated until the 3rd cycle of chemotherapy and novel induction chemotherapy regimens were included. The RTOG has also studied a concomitant boost regimen, though overall survival was lower than expected in the phase II experience. Results from the CONVERT trial, comparing 45 Gy twice-daily and 66 Gy once-daily radiotherapy, were recently published. The trial was powered to show superiority of high dose daily radiotherapy and failed to do so, and thus the authors concluded that 45 Gy twice-daily remain the standard of care. The CALGB 30610 trial, which uses 70 Gy in the once-daily arm, is near completion and will provide further data regarding the therapeutic ratio of these regimens. For the time being it should be kept in mind that the long held assumption that increasing radiotherapy dose with conventional fractionation will result in improved outcomes may not be justified – particularly in the setting of concurrent chemotherapy. For example, increasing the radiotherapy dose from 50.4 Gy to 64.8 Gy, with cisplatin and 5-FU, did not improve outcomes for patients with esophageal cancer on the phase 3 Intergroup 0123 trial. Perhaps even more suprising are the results of RTOG 0617, where even in the era of advanced radiotherapy treatment planning raising the radiotherapy dose resulted in worse outcomes.

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    MA08 - Clinical Trials in Brain Metastases

    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Moderators:
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      MA08.01 - Phase 3 Trial of Whole Brain Radiotherapy with Concurrent Erlotinib Versus WBRT Alone for NSCLC with Brain Metastases (ENTER)

      15:15 - 15:20  |  Presenting Author(s): ZhenZhou Yang  |  Author(s): Yan Zhang, RongQing Li, Abulimiti Yisikandaer, BiYong Ren, JianGuo Sun, JianJun Li, Long Chen, Ren Zhao, JuYing Zhang

      • Abstract

      Background

      Brain metastasis (BM) is a leading cause of death for non-small cell lung cancer (NSCLC). Whole Brain Radiotherapy (WBRT) is a standard-of-care treatment for NSCLC patients with multiple brain metastases. Elevated EGFR expression and activity are important causes of tumor resistance to radiotherapy. This phase 3 trial sought to determine if concurrent erlotinib with WBRT will benefit patients with multiple BM compared with WBRT alone.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this open-label, randomised, multicenter phase 3 study in China (NCT01887795), we enrolled NSCLC patients with at least two metastatic brain lesions who were naive to brain radiation and free from any EGFR-TKI for at least 4 weeks. Participants were randomly assigned (1:1) to receive either WBRT (2.0 Gy per day, 5 days per week, to 40 Gy) or WBRT plus concurrent oral erlotinib 150 mg daily (Erlotinib was given for 6 days then concurrently with WBRT). Subsequent treatments were maintenance therapy of erlotinib for EGFR-positive patients or standard chemotherapy for EGFR-negative patients until unacceptable adverse events or disease progression. The primary endpoint was intracranial progression-free survival (iPFS), defined as time from randomisation to either intracranial disease progression or death for any cause.

      4c3880bb027f159e801041b1021e88e8 Result

      Between August 7, 2013 and November 25, 2016, in total 222 patients from 11 centers across China were randomized to treatments: 115 with WBRT alone and 107 with WBRT and concurrent erlotinib. Median follow-up was 11.2 months (IQR 4.6-18.2). Median iPFS was 11.2 months (95% CI: 7.2-13.7) with WBRT and concurrent erlotinib versus 9.2 months (95% CI: 6.7-10.9) with WBRT alone (HR 0.926; 95% CI: 0.695-1.234; P=0.601). In the subgroup of 109 patients who were positive for the EGFR mutation, iPFS was not significantly longer among those who received WBRT with concurrent erlotinib than WBRT with sequential erlotinib (14.6 [95% CI 11.8-17.7] vs 12.8 [7.9-14.9] months; HR 0.743; 95% CI: 0.489-1.129; P=0.164). Median PFS of concurrent erlotinib arm was 5.3 months versus 4.0 of WBRT alone (HR 0.969; 95% CI: 0.735-1.277; P=0.825) and median overall survival (OS) was 12.9 versus 10.0 months (HR 0.913; 95% CI: 0.680-1.226; P=0.545).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This multi-institutional study demonstrated WBRT with concurrent erlotinib improved neither iPFS significantly than WBRT alone in the intention-to-treat population and the EGFR-positive subgroup, nor improved PFS or OS in intention-to-treat population, indicating that erlotinib played limited role when concurrently used with WBRT and for EGFR-positive NSCLC patients, WBRT with concurrent erlotinib was not significantly superior to WBRT with sequential erlotinib.

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      MA08.02 - Prophylactic Cranial Irradiation Reduces the Risk of Brain Metastases in High-Risk Lung Cancer Patients: EGFR and ALK Mutations

      15:20 - 15:25  |  Presenting Author(s): Oscar Arrieta  |  Author(s): Federico Maldonado, Laura-Alejandra Ramírez-Tirado, Feliciano Barron, Yelitza Esmeralda Campos-Salgado, Monica Blake, Andrés F. Cardona, Jaime G De La Garza

      • Abstract

      Background

      Prophylactic Cranial Irradiation (PCI) is considered standard-of-care for small-cell lung cancer, due to consistent findings of a reduced risk of developing brain metastases (BM) and a survival benefit. The role of PCI for patients with Non-small cell lung cancer (NSCLC) is less well established, since a clear survival benefit has not been identified, although high-risk subgroups have been identified, including patients with driver mutations and with elevated carcinoembryonic antigen (CEA) levels.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We assessed the use of PCI compared to observation in patients with stage IV NSCLC (NCT01603849). PCI dose was set 25 Gy/10 f. An amendment to the original record was requested so that patients who received PCI after January 2016 had hippocampal sparing. Primary end point was Intracranial Progression-Free survival (IPFS), secondary was overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      84 patients were included, 43 were randomized to observation and 41 to PCI. 83.3% had a driver mutation (DM). Baseline characteristics were well balanced among groups. Median IPFS was 21.0 months (95%CI 16.2-25.9). Factors which were independently, positively associated with IPFS included ECOG (p=0.012) and therapeutic arm (p=0.006). PCI was associated with lower odds of progression to CNS (OR:0.16 (0.04–0.53), p=0.006).Cumulative incidence of BM at 1-yr was higher among patients without PCI (22% vs. 3%, p<0.001). Relative risk for IPFS in patients with DM was 0.29 (0.10-0.82, p=0.01), HR for OS was 0.48 (0.20-1.16, p=0.098). Median OS was higher in the PCI group compared to control [42.8 (95%CI: 28.1–57.6) vs. 25.9 (95%CI: 17.7 – 34.2)] months. Last, PCI was associated with lower hazards of death, 0.47 (0.24–0.95), p=0.035.rt-prof figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      PCI significantly increases IPFS and decreases risk of death in patients with advanced NSCLC, without neurocognitive impairment or decreased QoL. This intervention appears to be particularly useful for patients with good performance status and driver mutations. PCI increased IPFS without neurocognitive impairment or decreased QoL.

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      MA08.03 - EGFR-TKI Plus Brain Radiotherapy Versus EGFR-TKI Alone in the Management of EGFR Mutated NSCLC Patients with Brain Metastases: A Meta-Analysis

      15:25 - 15:30  |  Presenting Author(s): Wenhua Liang  |  Author(s): Xiaojun Xia, Minzhang Guo, Jianxing He

      • Abstract

      Background

      It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) presented better efficacy than brain radiotherapy (brain RT) in the treatment of brain metastasis (BM) in EGFR mutated NSCLC patients. However, whether the combination of EGFR-TKI and brain RT is better than EGFR-TKI alone remains unclear. We aim to compare the benefit of adding brain RT to EGFR-TKI by a meta-analysis of currently available data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A systematic search for relevant articles was conducted in six databases (PubMed, EMBASE, Cochrane database, Medline, Web of Science, Google scholar). The primary outcome was overall survival (OS) between groups, and the secondary outcome was intra-cranial progression-free survival (icPFS), both being measured as hazard ratios (HRs). The data was synthesized by random-effects model using STATA 13.0.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of four retrospective studies involving 507 EGFR mutated patients with BM at the first diagnosis were included, 209 patients received brain RT (predominantly whole brain RT). Combined therapy of EGFR-TKI and brain RT reduced 19% risk of deaths (OS HR=0.81, 95% CI 0.53-1.26; P=0.36) and 16% risk of intracranial progression (icPFS HR=0.84, 95% CI 0.55-1.27; P=0.40) compared with EGFR-TKI alone, however, no statistically significance was observed. Further subgroup analyses suggested that patients with 21 exon L858R mutation were more inclined to have greater icPFS benefit under combination therapy (HR 0.67, 95% CI 0.19-2.40) in contrast to 19 exon deletion patients (HR 1.35, 95% CI 0.88-2.09). In addition, patients older than 65 (HR 0.74, 95% CI 0.37-1.48) might benefit more from combination than those younger than 65 (HR 4.47, 95%CI 0.29-70.13).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This meta-analysis suggested that the combination of EGFR-TKIs and brain radiotherapy showed similar but potentially better OS and intracrnial control in EGFR-mutated NSCLC patients when compared to EGFR-TKI alone, especially for those with L858R mutations or older than 65. The current results underscore the importance of future randomized control trials and provide information for study design.

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      MA08.04 - Discussant - MA 08.01, MA 08.02, MA 08.03

      15:30 - 15:45  |  Presenting Author(s): Nasser Hanna

      • Abstract

      Abstract not provided

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      MA08.05 - Brain Penetration of Lorlatinib and Cumulative Incidence Rates for CNS and Non CNS Progression from a Phase 1/2 Study

      15:45 - 15:50  |  Presenting Author(s): Todd M. Bauer  |  Author(s): Alice T. Shaw, Melissa L. Johnson, Alejandro Navarro, Justin F Gainor, Holger Thurm, Yazdi K. Pithavala, Antonello Abbattista, Enriqueta Felip

      • Abstract

      Background

      The potent, selective, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib was designed to penetrate the blood-brain barrier (BBB). In a phase 1/2 study, lorlatinib showed robust clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), most of whom had CNS metastases and failed ≥1 ALK TKI. In preclinical studies, lorlatinib demonstrated high BBB permeability with rapid brain uptake in vivo and significant activity against ALK-positive intracranial tumor models.1,2 To assess brain penetration of lorlatinib in a clinical setting, we report exploratory analyses from a phase 1/2 study (NCT01970865), evaluating CSF-to-plasma concentration ratios from a small sample of patients and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and deaths for pretreated patients with ALK-positive NSCLC ± baseline CNS metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Across the ongoing phase 1/2 study, 5 patients at lorlatinib 100 mg QD starting dose underwent CSF sampling. Patients with ALK-positive NSCLC with ≥1 prior ALK TKI were analysed for progressive disease, categorized as either CNS or non-CNS progression, based on independent central review. CIRs for patients in expansion cohorts EXP2–5 from the phase 2 portion of the phase 1/2 study (N=198) were calculated using competing risks methodology.

      4c3880bb027f159e801041b1021e88e8 Result

      In patients (n=5), mean CSF-to-plasma concentration ratio was 0.73 (SD 0.14). The table shows CIRs at 6 and 12 months.

      Months Cumulative Incidence Probability
      Patients with ≥1 prior ALK TKIa CNS Progression

      Non-CNS

      Progression

      Death
      All patients (n=198)

      6 mos

      12 mos

      0.13

      0.18

      0.25

      0.37

      0.05

      NE
      Patients with baseline CNS metastases (n=131)

      6 mos

      12 mos

      0.14

      0.22

      0.21

      0.31

      NE

      NE
      Patients with no baseline CNS metastases (n=67)

      6 mos

      12 mos

      NE

      NE

      0.32

      0.49

      0.05

      NE

      aPatients in expansion cohorts EXP2–5 from the phase 2 study

      NE, not evaluable
      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib showed high BBB permeability as evidenced by a high mean CSF-to-plasma concentration ratio, in line with preclinical rat studies showing CNS penetration. This translated into high activity against CNS metastases as suggested by the numerically higher probability of the first progression event being extracranial rather than intracranial, including in patients with a history of CNS metastases.

      References

      1. Collier, et al. Mol Imaging 2017;16:1–3.

      2. Zou, et al. Cancer Cell 2015;28:70–81.

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      MA08.07 - Real World Data of Osimertinib in Patients with Central Nervous System (CNS) Metastasis in ASTRIS Korean Subset.

      15:50 - 15:55  |  Presenting Author(s): Jin-Hyoung Kang  |  Author(s): Byoung Chul Cho, Dong-Wan Kim, Keunchil Park, Jong-Seok Lee, Seung soo Yoo, Sung Yong Lee, Cheol Hyeon Kim, Seung Hun Jang, Young-Chul Kim, Hyoung-Kyu Yoon, Sang-We Kim

      • Abstract

      Background

      More than 40% of non-small cell lung cancer (NSCLC) patients develop CNS metastasis in their lifetime. Osimertinib is a third-generation EGFR-TKI which selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations. Clinical studies have shown superior efficacy of osimertinib in CNS compared to platinum chemotherapy. Treatment efficacy in patients with or without CNS metastasis were observed within the second interim analysis of ASTRIS (NCT02474355). Data cut-off (DCO) was 20 October 2017.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In ASTRIS, advanced NSCLC patients with a locally confirmed T790M mutation, WHO performance status 0-2, prior EGFR-TKI therapy were enrolled. Patients with stable CNS metastases were allowed. The primary endpoint was overall survival (OS); other endpoints included investigator-assessed response rate (RR), progression-free survival (PFS), time to treatment discontinuation (TTD) and safety. These endpoints were also analyzed according to presence of CNS metastasis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 466 patients received at least one dose of osimertinib 80mg from 31 Korean sites. CNS metastasis was evaluated in 310 patients and was present in 211 (68.1%) patients (CNS-met); 181 brain only, 1 leptomeningeal only, 29 both. 99 (31.9%) patients did not have CNS metastasis (CNS-no), and 155 patients were not evaluated (CNS-ne). At DCO, 236 patients (50.6%) were ongoing and median duration of exposure was 11.2 (0–19) months. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, RR was 71.0% (320/451; 95% CI, 66.5–75.1): Patients with (N=211), without (N=99), and not-evaluated CNS metastasis (N=155) had RR of 68% (134/197; 95% CI, 61.0-74.5), 79.6% (78/98; 95% CI, 70.3-87.1), and 69.7% (108/155; 95% CI, 61.8-76.8), respectively. Median PFS was 12.4 months (95% CI, 11.1-13.6 months); 10.8 months (95% CI, 9.5-11.5) in CNS-met,11.0 months (95% CI, 9.2-14.5) in CNS-no, and 15.1 months (95% CI, 13.6-18.2) in CNS-ne. Median TTD was 16.5 months (95% CI, 14.1-NC); 11.2 months (95% CI, 9.4-14.8) in CNS-met, 14.7 months (95% CI, 12.2-NC) in CNS-no, and NC (95% CI, 15.5-NC) in CNS-ne. OS was not reached (data maturity: 19.7%). Serious adverse event (AE) regardless of causality were reported in 116 patients (24.9%) and AEs leading to death in 13 patients (2.8%). ILD/pneumonitis-like events were reported in 8 patients (1.7%), and QTc prolongation in 7 patients (1.5%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In ASTRIS Korean subset, patients with or without CNS metastasis had comparable efficacy outcome. This data continues to support osimertinib’s clinical benefit on EGFRm T790M NSCLC patients with CNS metastasis.

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      MA08.08 - Discussant - MA 08.05, MA 08.07

      15:55 - 16:10  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract

      Abstract not provided

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      MA08.09 - Impact of Brain Metastases in Immune Checkpoint Inhibitors (ICI) Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

      16:10 - 16:15  |  Presenting Author(s): Lizza Hendriks  |  Author(s): Clémence Henon, Eduard Auclin, Laura Mezquita, Roberto Ferrara, Clarisse Audigier-Valette, Julien Mazieres, Corentin Lefebvre, Sylvestre le Moulec, Sophie Cousin, Boris Duchemann, Cecile Le Pechoux, Angela Botticella, Samy Ammari, Anas Gazzah, Caroline Caramella, Julien Adam, David Planchard, Dirk De Ruysscher, Anne-Marie C. Dingemans, Benjamin Besse

      • Abstract

      Background

      Brain metastases (BM) are frequent in NSCLC. Unfortunately, patients with (untreated) BM are often excluded from ICI trials so that their outcome on ICI is largely unknown..

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective data collection of all consecutive advanced ICI treated NSCLC patients in 6 centers (5 French, 1 Dutch) (nov 2012 – march 2018). Active BM was defined as non-irradiated new and/or growing lesions on brain imaging < 6 weeks before ICI start. Progression free survival (PFS), overall survival (OS) and site of progression on ICI was collected.

      4c3880bb027f159e801041b1021e88e8 Result

      945 patients included: 63% male, 83% WHO PS 0-1, median age 64 years, 73% non-squamous, 4% targetable driver mutations, 33% known PD-L1 (65% ≥1% expression). ICI treatment was median 2nd line (range 1-12), 94% had monotherapy PD-(L)1 inhibition. 241 patients (26%) had BM, 68% had previous cranial irradiation, 40% had active BM. BM patients were significantly younger than others (61 vs 66 years), had more adenocarcinoma (78 vs 62%), more organs involved (median 3 vs 2), a poorer PS (0-1: 76 vs 85%) and more steroids at baseline (26 vs 9%). Median follow-up: 15 months. Median (95% CI) PFS and OS without and with BM were 2 (2-3) vs 2 (1-2) months and 13 (9-16) vs 9 (7-13) months, respectively. In multivariate analysis, > 2 metastatic sites, PS ≥2 and steroids use were associated with worse PFS and OS, BM were not (table 1). In univariate analysis of BM patients, active BM were not associated with worse outcome compared to stable BM (HR PFS 0.98 (p=0.66), HR OS 0.93 (p=0.92)). Progressing BM patients had more often brain PD and a dissociated response (not specifically brain dissociated) on ICI (40 vs 12% and 13 vs 7%, respectively).

      Factor PFS HR (95% CI) p-value OS HR (95% CI) p-value
      Age > 65 vs ≤ 65 1.02 (0.87-1.20) 0.79 1.11 (0.92-1.34) 0.29
      Smoking yes vs no 0.53 (0.41-0.69) <0.001 0.81 (0.59-1.12) 0.20
      Histology squamous vs adeno 1.07 (0.89-1.28) 0.78 1.24 (0.99-1.55) 0.12
      Nr of organs with metastases > 2 vs ≤ 2 1.28 (1.09-1.50) 0.003 1.48 (1.22-1.80) <0.001
      Immuno line > 2 vs ≤ 2 1.11 (0.94-1.30) 0.22 1.10 (0.91-1.33) 0.34
      WHO PS 0-1 vs ≥2 2.14 (1.75-2.62) <0.001 3.48 (2.78-4.36) <0.001
      Use of corticosteroids yes vs no 1.36 (1.10-1.69) 0.005 1.31 (1.03-1.68) 0.03
      BM yes vs no 1.05 (0.88-1.26) 0.58 0.96 (0.77-1.19) 0.70

      8eea62084ca7e541d918e823422bd82e Conclusion

      BM, treated or active, do not negatively impact outcome on ICI although BM failure is more common in these patients.

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      MA08.10 - Real-Life Intracerebral Efficacy of Nivolumab in Non-Small Cell Lung Cancer Patients with Brain Metastases

      16:15 - 16:20  |  Presenting Author(s): Margaux Geier  |  Author(s): Renaud Descourt, Romain Corre, Guillaume Léveiller, Regine Lamy, Eric Goarant, Jean-Louis Bizec, Cyril Bernier, Gilles Quéré, Francis Couturaud, Gilles Robinet

      • Abstract

      Background

      Data regarding intracerebral efficacy of nivolumab in advanced non-small cell lung cancer (NSCLC) are lacking because of routinely exclusion of patients with active brain metastases (BMs) from clinical trials. We aimed at assessing intracranial activity of nivolumab in patients with BMs in a real-life setting and determining the potential role of prior radiotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between 01/09/2015 and 30/09/2016, all consecutive advanced NSCLC patients treated with nivolumab after failure of at least one line of chemotherapy were included. Nivolumab was administered at a dose of 3 mg/kg q2w until progression or unacceptable toxicity. Primary endpoint was intracerebral objective response rate (IORR) assessed by brain magnetic resonance imaging or brain computed-tomography scans. Secondary endpoints were overall response rate (ORR) and median duration of intracerebral response.

      4c3880bb027f159e801041b1021e88e8 Result

      259 patients were treated with nivolumab in 9 centers. Among them, 77 patients who presented BMs before nivolumab initiation were enrolled: 53 (20.5%) at diagnosis and 24 (9.3%) during the course of treatments. Median age at diagnosis was 57 years [29-78]. Most patients were males (72.7%) with smoking history (90.9%) and had adenocarcinoma (72.7%). 23 patients harbored a KRAS mutation. PD-L1 status was unknown. The median of prior lines was 1 [1-6]. BMs were pretreated in 48 (62.3%) patients: 16 received prior SBRT, 32 WBRT. Median time between prior radiotherapy and nivolumab initiation was 4 months [1-;27]. IORR and ORR were 10.4% and 20.8%, respectively. Among the 8 patients with intracerebral response, 5 (6.5%) had pretreated BMs, 3 (3.9%) had radiotherapy-naïve BMs. Median duration of intracerebral response was 11.5 months. No neurological adverse events occurred during nivolumab treatment. Among 259 patients, 36 (13.8%) developed BMs during nivolumab treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab intracerebral response achieved 10.4% in real-life with a satisfactory neurological safety profile. If prior radiotherapy improves IORR must be determined by further investigations.

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      MA08.11 - Early Safety Data of a Phase I/II Combining Nivolumab and Stereotactic Brain Radiosurgery for Treatment of Brain Metastases in Patients with NSCLC

      16:20 - 16:25  |  Presenting Author(s): Raafat Alameddine  |  Author(s): Philip Wong, Laura Masucci, David Roberge, Cynthia Menard, Bertrand Routy, Mustapha Tehfe, Normand Blais, Marie Florescu

      • Abstract

      Background

      Radiotherapy can stimulate the immune system through various means. Highly cytotoxic stereotactic radiosurgery (SRS) doses (>10Gy per fraction) may synergize with anti-PD1 to reduce intracranial disease progression or recurrence.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Within a phase I/II trial evaluating the combination of nivolumab with SRS in the treatment of brain metastases from NSCLC and RCC (NCT02978404), 8 patients were enrolled (1 RCC and 7 NSCLC) in the first trial cohort. Herein, only the NSCLC cases are reviewed. Patients were eligible if their KPS ≥70, were minimally symptomatic (RTOG neurological function <2), and had ≤10cc of untreated brain metastases. Prophylactic corticosteroids were not given. Nivolumab (240mg IV q2 weeks) was started 2 weeks prior to SRS, and administered until RECIST progression. SRS (15-20Gy in 1 fraction) was given to each brain metastasis. The aim of the first patient cohort is to estimate the tolerability of the combined treatment strategy.

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up of the three male and four female patients was 2 months. Median age was 63 years (55-84 years). Five NSCLC patients completed ≥1 cycle of nivolumab and SRS, and were evaluated for tolerability of the combination. One patient elected to withdraw before the first nivolumab dose and 1 patient died prior to SRS. Median baseline brain edema and total brain metastases volumes were 0.5cc (0-46.97cc) and 1.25 cc (0.1-3.46cc), respectively. To date, the median number of nivolumab cycles administered is 4.5 (1-15). Intracranial adverse effects were limited to apraxia and paresthesias in the patient who had the largest volume of peri-tumoral brain edema at baseline (46.97cc). Nivolumab was held and dexamethasone was given for 74 days at doses >1mg/day until neurological symptoms resolved. Systemic adverse events included one patient with grade 2 arthritis necessitating a 6-week treatment delay and 51 days of prednisone ≥10mg. At last follow-up, three patients had died of extracranial disease progression, including the two patients who did not receive protocol SRS. Among the three patients evaluable for intracranial response, there was one partial response and two stable diseases. All three patients had stable extracranial disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combining SRS and immunotherapy is safe in regards to acute toxicity with a manageable side effect profile. Close monitoring may be required for patients with significant baseline brain edema. Evaluation for efficacy awaits further follow-up and completion of recruitment in the phase 2 component of the trial.

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      MA08.12 - Discussant - MA 08.09, MA 08.10, MA 08.11

      16:25 - 16:40  |  Presenting Author(s): Arjun Sahgal

      • Abstract

      Abstract not provided

    • +

      MA08.12a - Q&A

      16:40 - 16:45

      • Abstract

      Abstract not provided

  • +

    MA09 - Lung Cancer Surgical and Molecular Pathology

    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Moderators:
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      MA09.01 - Correlation of Pre-Operative Cancer Imaging Techniques with Post-Operative Macro and Microscopic Lung Pathology Images  

      15:15 - 15:20  |  Presenting Author(s): Stephen James Harrow  |  Author(s): Gabriel Reines-March, Craig Dick, Xiangyang Ju, Stephen Marshall

      • Abstract

      Background

      This research project aims to investigate the performance of several PET radiotracers in lung cancer by aligning PET-CT and pathology imagery acquired from the same patients at different points in time. The discrimination of tumour substructures is of great importance in therapy planning, as a given treatment may be better adapted depending on the local characteristics of the carcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Due to the high deformability of lung tissue, several intermediate steps must be used for merging pathology and pre-operative PET-CT in a coherent manner. Firstly, the tumour volume is reconstructed from the macroscopic images taken during dissection. For this purpose, an enhanced dissection protocol is used, where the lung specimen is placed in a bespoke slicing rig and embedded in agar to hold it in place. Using a threaded plunger, the specimen is pushed upwards in 5mm steps, sliced and photographed. This procedure allows us to obtain slices of uniform thickness. Secondly, microscopic digital slides of the cancerous tissue are merged with the macroscopic 3D model. Finally, the whole volume is fused with the pre-operative PET-CT scan, using a non-linear deformable model.

      4c3880bb027f159e801041b1021e88e8 Result

      Preliminary results obtained with a synthetic phantom allowed us to analyse the accuracy of the tumour 3D reconstruction algorithm from planar macroscopic slices. Using these findings, we could optimise the interpolation and segmentation routines for building an accurate 3D model of the tumour mass. During our first trial with lung tissue (on-going work), each cross-sectional slice was photographed, the tumour boundary was delineated in each image by a pathologist (CD), and from these contours a high-resolution 3D tumour model was built. Next, the corresponding microscopic digitised slices were merged. To date, ten patients have been identified and consented, therefore allowing us to test our algorithm on different cases and assess its performance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrate a novel set of methods for co-registration of pre-operative PET-CT to macro and microscopically defined lung tumours. This proof of principle now allows interrogation of the raw data from PET-CTs using a range of tracers and the development of algorithms that identify substructure detail within a tumour mass, which could lead to tailored radiotherapy for individual tumours based on tracer patterns and uptake.

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      MA09.02 - Tumor Size and Frozen Section Should Be Considered Jointly to Predict the Final Pathology for Lung Adenocarcinoma

      15:20 - 15:25  |  Presenting Author(s): Erjia Zhu  |  Author(s): Chang Chen

      • Abstract

      Background

      Invasive adenocarcinoma intraoperatively misdiagnosed as adenocarcinoma in situ or minimally invasive adenocarcinoma is more likely to undergo potentially insufficient resection. The purpose of our study was to evaluate the diagnostic accuracy of frozen section.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed 1,111 lung adenocarcinomas to evaluate the diagnostic performance of frozen section. A derivation cohort consisting of 436 cases of AIS or MIA diagnosed by frozen section in the same period were analyzed to find predictive factors for invasive adenocarcinoma as the final diagnosis. Validation cohorts were included to confirm the results.

      4c3880bb027f159e801041b1021e88e8 Result

      Intraoperatively measured tumor size was the only independent factor for invasive adenocarcinoma as the final diagnosis (P = 0.001) in the derivation cohort, and was confirmed by validation cohorts. Fifty-nine misdiagnosed invasive adenocarcinomas in the three cohorts consisted of 54 lepidic predominant type, 1 papillary and 4 acinar predominant type. There were no positive N1, N2 node, pleural, lymphatic and vascular invasion cases found. Thirty-seven (37/59, 63%) cases of misdiagnosis were attributed to sampling error, which was the main reason.figure1.jpgfigure3.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Adenocarcinoma in situ or minimally invasive adenocarcinoma ≥ 1 cm by frozen section were more likely to be invasive adenocarcinoma because of sampling error.

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      MA09.03 - Multiple Pathological Variables Predict Efficacy of Adjuvant Chemotherapy in Primary Lung Adenocarcinoma

      15:25 - 15:30  |  Presenting Author(s): John Le Quesne  |  Author(s): Marco Sereno, Claire Smith, Madhumita Das, Robert Hastings, Grace Rake, David Moore

      • Abstract

      Background

      Adjuvant chemotherapy has become established as a vital complement to surgery over the last decade, and improves survival by targeting micrometastatic disease which is clinically inaparrent at the time of surgery. However, in comparison to other common malignancies, the guidelines for the administration of adjuvant chemotherapy in lung cancer are rudimentary, being based solely upon clinical stage II and above at the time of surgery. We set out to discover pathological factors with the potential to better identify patients who are likely to benefit from this vital therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      662 cases of primary lung adenocarcinoma treated with surgery with curative intent were identified from 2005-2014; 109 received adjuvant chemotherapy. Comprehensive survival/recurrence data, pathological data, and treatment history data were collected. Detailed histopathological data (growth pattern, vascular invasion, pleural stage) were collected by review of scanned histopathological images.

      Multivariate Cox regression survival models were used to identify interactions between clinicopathological variables and adjuvant chemotherapy. A propensity score matching approasch was used to reduce selection biases in the data.

      4c3880bb027f159e801041b1021e88e8 Result

      The existing stage criteria for the recommendation of adjuvant chemotherapy are stage pN1/2 and size>40mm; only nodal invasion interacts with chemotherapy in an OS model (interaction term HR=0.67 P=0.017). However, signficant interactions are seen with predominant growth pattern (HR=0.47 P=0.001 ), pleural stage (HR=0.62 P=0.002 ), and vascular invasion (HR=0.56 P=0.033).

      We reduced selection bias by balancing treated and untreated groups by propensity matching for all prognostic variables. In the matched dataset, patients with predominantly in situ tumours experience no benefit of chemotherapy (HR=1.81 P=0.18), while higher-grade cases show substantial benefit (HR=0.53 P=0.01). Similar benefits were seen for patients with increasing pleural stage and vascular invasion.

      In a multivariate model designed to identify which variable(s) had the most ability to predict treatment efficacy, only tumour growth pattern showed a significant interaction with chemotherapy treatment (HR=0.51 P=0.01 ).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We find that the existing stage-based criteria for adjuvant chemotherapy can be much improved. Low-grade cases experienced only negative effects of chemotherapy, while higher-grade cases showed a benefit. Pleural stage and vascular invasion were also significantly predictive. We suggest that the current criteria may be leading to substantial over- and under-treatment. A nuanced algorithm for the identification of patients likely to benefit from chemotherapy, which includes these additional pathoogical measures, may significantly improve patient outcomes. This would be especially impactful to the majority of surgical patients for whom no personalised therapy is as yet available.

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      MA09.04 - Discussant - MA 09.01, MA 09.02, MA 09.03

      15:30 - 15:45  |  Presenting Author(s): Natasha Rekhtman

      • Abstract

      Abstract not provided

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      MA09.05 - Can We Predict Radiosensitivity in Non-Small Cell Lung Cancer?

      15:45 - 15:50  |  Presenting Author(s): Juvenal Baena  |  Author(s): Christopher Talbot, John Le Quesne

      • Abstract

      Background

      Patients with lung cancer receive different treatments depending on their detailed clinical-pathological context. However, over 70% of patients are treated with radiotherapy, which is of varying efficacy. Rather surprisingly, no biomarkers are currently used to predict tumour response and to aid with radiotherapy dosing or regimen. The aim of this study is to identify histopathological features which may predict tumour radiosensitivity in patients with NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have identified a set of 67 NSCLC cases with a history of radiotherapy for which pre-treatment archival tissue and CT imaging follow-up is available from the period 2009 to 2014. Digital images of archival diagnostic tissue sections were examined to derive morphological measures with the potential to predict radiosensitivity. Quantitative radiological measures of response up to 6 months after radiotherapy were derived. Since radiographic measurements were taken at variable time-points, we standardised by inferring the fractional maximum diameter of the tumour 100 days after radiotherapy (FRT100)

      4c3880bb027f159e801041b1021e88e8 Result

      The density of multipolar mitoses seen microscopically is related to radiosensitivity (regression against FRT100: R2 = 0.14, p=0.005*) and a trend toward a negative relationship with neuroendocrine differentiation (R2 =0.06, p=0.058). The presence of multipolar mitoses was further associated with poor overall survival ( Univariate Cox p= 0.02*). Patients with radiological evidence of good response (ie low FRT100) showed a time-dependent survival benefit (p=0.02*), while after 2 years tendency of both groups was similar. Patients showing squamous differentiation had a poor prognosis, with no overall survival after 4 years, while 21.8% of the ACA were still alive after 4 years (p= 0.04*)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Multipolar mitoses and neuroendocrine differentiation may be predictive histological markers of radiosensitivity in NSCLC. More samples are being gathered, and immhunohistochemical and DNA sequence biomarkers of radiosensitvity are currently being assessed.

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      MA09.06 - The Newly Recognized Filigree Pattern of Micropapillary (MIP) Lung Adenocarcinoma (LADC) is as Clinically Important as the Classical Pattern

      15:50 - 15:55  |  Presenting Author(s): Katsura Emoto  |  Author(s): Takashi Eguchi, Raj G. Vaghjiani, Yusuke Takahashi, Natasha Rekhtman, Prasad S. Adusumilli, William D Travis

      • Abstract

      Background

      Filigree pattern is a newly recognized addition to the morphological spectrum of the poor prognostic category of micropapillary (MIP) LADC. However, its morphologic features and clinical importance are not well understood. The aim of this study was to investigate the morphologic spectrum and clinical significance of filigree MIP pattern.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Filigree pattern was defined as tumor cells growing in delicate lace-like narrow stacks of cells (at least 3 piled-up nuclei) without fibrovascular cores, with frequently visible attachments to alveolar walls. This differs from the 2015 WHO description of classical MIP pattern as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores. In order to assess for filigree vs classical MIP, we documented the frequency and extent of both patterns in 1325 Stage I LADC. These were correlated with recurrence free probability (RFP) and lung cancer-specific survival (LCSS) using Kaplan-Meier analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      In addition to 87 MIP predominant ADC previously diagnosed, we identified 57 more cases of MIP predominant LADC due to the new criteria of MIP filigree pattern. Of these 57 cases, 37, 16, and 4 cases were reclassified from papillary, acinar, and solid predominant LADCs, respectively. Survival curves of previously diagnosed MIP and newly diagnosed MIP for RFP showed a similar worse prognosis compared to other LADC histologic subtypes (previously diagnosed MIP vs newly diagnosed MIP, 5-year RFP 66% vs 68% [Figure]) as well as LCSS (previously diagnosed MIP vs newly diagnosed MIP, 5-year LCSS 82% vs 85%). When the MIP cases were divided into filigree or classical predominant MIP, no significant prognostic differences were observed between the two groups.

      figure filigree.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The lack of significant prognostic difference between filigree vs classical predominant MIP LADC supports our proposal that the filigree pattern is an important addition to the morphologic spectrum of the MIP subtype.

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      MA09.07 - Developing a Pathological Grading System in Predicting Prognosis for Invasive Mucinous Adenocarcinomas

      15:55 - 16:00  |  Presenting Author(s): Wei-Chin Chang  |  Author(s): Yu Zhi Zhang, Eric Lim, Andrew G Nicholson

      • Abstract

      Background

      Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma with a predominance of mucinous type neoplastic epithelial cells, often showing aerogenous spreading and multifocality. The correlation between histopathological features and prognosis has not been well studied due to its relatively rare incidence compared to non-mucinous adenocarcinoma. Our study aims to evaluate the significance of histopathological features in relation to clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed a series of 101 cases of IMAs resected between 2000 to 2012, comprised of stage I~IV tumours. Five pathological features were scored for each tumour: predominant histological pattern (lepidic: 1, acinar/papillary: 2, solid/micropapillary/cribriform: 3), nuclear atypia (mild:1, moderate: 2, severe: 3), mitotic activity per 2mm2 (<4: 0, ≥4: 1), necrosis (absent: 0, present: 1), lymphovascular invasion (absent: 0, present: 1), and pleural invasion (PL0: 0, PL1: 1, PL2: 2, PL3: 3). Each pathological feature was correlated with disease-free (DFS) and overall survival (OS). Cases were then divided into three grades based on the total pathological score (grade I: 2-4, grade II: 5-7, grade III: 8-11) and correlated with outcome.

      4c3880bb027f159e801041b1021e88e8 Result

      Nuclear atypia, mitotic activity, lymphovascular invasion, and pleural invasion showed significant correlation with OS (p < 0.05). Histological pattern and necrosis showed no significant correlation in relation to OS (p = 0.09). Pleural invasion and lymphovascular invasion were significantly correlated with DFS (p < 0.05), while a trend was noted for nuclear atypia (p = 0.086). No correlation with DFS was seen for histological pattern (p = 0.499), necrosis (p = 0.464), and mitotic activity (p = 0.931). There was an inverse correlation between OS and grade, with grade III tumours showing a significantly worse prognosis (p = 0.001). There was no significant difference in DFS between the three groups (p = 0.201).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our pathological scoring system was able to stratify IMAs into three separate groups with statistically significant differences in overall survival between grade III and grades I/II tumours.

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      MA09.08 - Discussant - MA 09.05, MA 09.06, MA 09.07

      16:00 - 16:15  |  Presenting Author(s): Lucian R Chirieac

      • Abstract

      Abstract not provided

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      MA09.09 - EBUS-TBNA in Assessing PD-L1 Expression in NSCLC

      16:15 - 16:20  |  Presenting Author(s): Jason S Agulnik  |  Author(s): Goulnar Kasymjanova, Hangjun Wang, Lama Sakr, David Small, Victor Cohen, Alan Spatz

      • Abstract

      Background


      Pembrolizumab is the only immunotherapy approved as a first line agent for metastatic NSCLC in patients with high programmed death‐ligand 1 (PD‐L1) expression. The standard samples for PD-L1 testing are considered surgical or core biopsies. In this study, our primary objective is to identify the adequacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) tumor samples in detecting PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between July 2016 and April 2017 a total of 1352 consecutive cases of non-small cell lung cancer (NSCLC) were identified. 29 specimens were deemed inadequate (less than 100 viable tumor cells) and were excluded. 1323 specimens analyzed included surgical samples (N=238), small biopsy (N=744) and cytology cell blocks (N=341). Cytology cell blocks were from EBUS-TBNA (N=190), fine needle aspiration (FNA) (N=61) and pleural/pericardial fluid (N=90). PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1-49% and ≥ 50% tumor cells.

      4c3880bb027f159e801041b1021e88e8 Result

      Most of the 1323 specimens (84%) were non-squamous carcinomas. Overall yield for TPS > 50% was 36%. Rate of PD-L1 positivity was no different in non-squamous (37%) compared to squamous (32%). Diagnostic yield of PD-L1 for different sample types varied substantially (Table 1). The EBUS-TBNA samples had the highest yield for TPS ≥ 50% (p=0.025).

      TPS Surgical resection Small biopsy EBUS-TBNA FNA Fluid cytology Total
      Adequacy 100% 99% 98% 96% 92% 98%
      ≥ 50% 69 (29) 269 (36) 84 (44) 21 (34) 38 (42) 481
      1-49% 87 (37) 274 (37) 57 (30) 22 (36) 22 (24) 462
      <1% 82 (35) 201 (27) 49 (26) 18 (30) 30 (33) 380
      Total 238 744 190 61 90 1323
      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that cytology cell blocks could be considered as a valuable resource for PD-L1 testing in advanced NSCLC. Future studies are warranted to explore clinical correlation of PD-L1 on EBUS-TBNA samples and immunotherapy outcome.

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      MA09.10 - Molecular Profiling and PD-L1 Status in 900 Cases of Surgically Resected Non-Small Cell Lung Cancer with Clinical and Pathological Correlation

      16:20 - 16:25  |  Presenting Author(s): Zhaolin Xu  |  Author(s): Mathieu Castonguay, Wenda Greer, Akram Alwithenani, Drew Bethune, Arik Drucker, Gordon Flowerdew, Marika Forsythe, Daniel French, Harry Henteleff, Michael Johnston, Mary Macneil, Wojciech Morzycki, Madelaine Plourde, Stephanie Snow, Alexi Surette

      • Abstract

      Background

      Precision medicine provides efficient treatment options for lung cancer patients as it targets the individual tumor’s genetic makeup. Recent development of immune therapy based on immune checkpoint inhibitor also provides hope for patients. Currently lung cancer mutational data available in the literature are mainly from advanced stage non-small cell lung cancer. There is insufficient information from early stage lung cancer patients. PD-L1 status in relation to clinical and pathological characteristics is also unclear. This study tried to address these issues from 900 cases of surgically resected lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiplexed molecular profiling in 900 surgically resected lung cancer specimens. A panel of gene including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK was tested. PD-L1 was also evaluated by immunohistochemistry using pharmDx22C3. Tumor proportional score (TPS) in a 10% increment was measured. Mutational status and PD-L1 TPS in each cancer subtype in relation to cancer pathological characteristics were investigated. Correlations between gene mutation, PD-L1 status and cancer staging were performed. Gene mutation and PD-L1 status with patients’ demographic information such as gender, age, smoking history, as well as survival data after surgery were also analysed.

      4c3880bb027f159e801041b1021e88e8 Result

      This cohort includes adenocarcinoma (65%), squamous cell carcinoma (24%), large cell carcinoma (6%), other subtypes (5%). Stage I accounts for 56%, stage II, 26%, stage III, 16%, stage IV, <2% with a mean age of 66 years. In adenocarcinoma, KRAS accounts for 36%, EGFR 10%, BRAF 1%, PIK3CA 1%, ALK 0.2%, no mutations 52%. Only 5% squamous cells carcinoma showed mutations.

      PD-L1 TPS <1% accounts for (37%), TPS 1-9% (18%), TPS 10-19% (7%), TPS 20-29% (5%), TPS 30-39% (5%), TPS 40-49% (1%), TPS 50-59% (5%), TPS 60-69% (4%), TPS 70-79% (4%), TPS 80-89% (5%), TPS 90-99% (7%) and unsuccessful (2%). EGFR mutations were significantly associated with female (p<0.001) and never smokers (p<0.001), with well differentiated adenocarcinoma (p<0.001), and with absence of vascular invasion (p<0.01). KRAS mutations were more prevalent in younger age group (p=0.003). Poorly differentiated cancer histology was associated with absence of KRAS or EGFR mutations. There was no significant association between PD-L1 expression and age, sex, pathological stage and smoking status. PD-L1 expression was significantly associated with vascular invasion (p=0.035). EGFR mutations were significant associated with absence of PD-L1 expression (p=0.02), but no association between KRAS mutations and PD-L1 expression (p=0.10).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study provides comprehensive information enhancing our knowledge in depth about driver gene mutations and immune checkpoint PD-L1 status in non-small cell lung cancer patients.

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      MA09.11 - Genomic Landscape and its Correlation with TMB, CD8 TILs and PD-L1 Expression in Chinese Lung Squamous Cell Carcinoma

      16:25 - 16:30  |  Presenting Author(s): Tao Jiang  |  Author(s): Jinpeng Shi, Chunyan Wu, Henghui Zhang, Caicun Zhou

      • Abstract

      Background

      The current study aimed to comprehensively depict the genomic landscape of Chinese lung squamous cell carcinoma (LSCC) and investigate its correlation with tumor mutation burden (TMB), CD8 tumor infiltrating lymphocytes (TILs) density and PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Whole-exome sequencing (WES) were performed on tumor tissue collected from 189 patients with surgically resected LSCC. TMB was defined as total number of nonsynonymous single nucleotide and indel variants. High TMB was defined as greater than 75th percentile. CD8+ TILs and PD-L1 expression were assessed by immunohistochemistry. We determined the 5% of CD8+ TIL or PD-L1 expression as the cut-off point for high/low CD8+ TIL or PD-L1 positive/negative expression.

      4c3880bb027f159e801041b1021e88e8 Result

      We found recurrent mutations (>5%) in 8 genes, including TP53, KMT2C, NFE2L2, KEAP1, CDKN2A, PTEN and FBXW7. FGFR1 and PIK3CA amplifications were found in 19% and 11% of samples. 24.9% of patients had high TMB. Except for expected differences by smoking status, baseline clinical variables were similar between those with high and low TMB. Interestingly, FGFR1, PIK3CA or SOX2 amplification was independently associated with higher TMB (P=0.020, P=0.017, P=0.029; respectively). Patients with copy number variations had significantly higher TMB than those without (P=0.009). Positive PD-L1 and CD8+ TILs expression were identified in 24.3% and 78.8% of all cases. Baseline features were comparable between those with positive and negative CD8+ TIL or PD-L1 expression. NFE2L2 mutation and PIK3CA amplification were independently associated with significantly higher PD-L1 expression (P=0.003, P=0.014; respectively). TP53 mutations were associated with higher CD8+ TILs expression (P=0.008), but FGFR1 amplification was correlated with lower CD8+ TILs expression (P=0.042). Of note, there is no association between TMB and PD-L1 expression (r=0.052, P=0.476), or CD8+ TILs expression (r=0.026, P=0.718). None of TMB, PD-L1 and CD8+ TIL expression could individually predict overall survival (OS). However, combination of TMB and PD-L1 could stratify total populations into two groups with distinct prognosis. Patients with negative PD-L1 expression and high TMB had the worst prognosis (P=0.008). Additionally, combination of TMB and CD8+ TIL expression could also divide total populations into two groups with different prognosis (worst prognosis in negative CD8+ TIL expression and high TMB, P=0.022).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This was the first and most large-scale study to comprehensively portray genomic landscape of Chinese LSCC. The current study provides several meaningful and referential findings for the future design of clinical trials in LSCC, especially immunotherapy based on immune checkpoint inhibitors.

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      MA09.12 - Discussant - MA 09.09, MA 09.10, MA 09.11

      16:30 - 16:45  |  Presenting Author(s): Philippe Joubert

      • Abstract

      Abstract not provided

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    MS09 - Tumour Board - Tissue Acquisition and Staging

    • Type: Mini Symposium
    • Track: Interventional Diagnostics/Pulmonology
    • Moderators:
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    MS10 - Part Solid Nodules, GGN and STAS

    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Moderators:
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      MS10.01 - Radiographic Differences Between Presumed AIS and MIA

      15:15 - 15:30  |  Presenting Author(s): Mini Pakkal

      • Abstract

      Abstract not provided

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      MS10.02 - Importance of CT in the Pathologic Assessment of Tumor Sized in Subsolid and Part-Solid Adenocarcinoma

      15:30 - 15:45  |  Presenting Author(s): Erik Thunnissen

      • Abstract

      Abstract

      Importance of CT in the Pathologic Assessment of Tumor Sized in Subsolid and Part-Solid Adenocarcinoma

      Non-solid nodules (previously also called ground glass opacity) is a finding on thin-section CT that is defined as “hazy increased attenuation of the lung with preservation of bronchial and vascular margins”.1This is in contrast to consolidation that is defined as a “homogeneous increase in pulmonary parenchymal attenuation that obscures the margins of vessels and airway walls” (also called ‘solid´ component).

      The resolution of the CT differs few orders of magnitude from the resolution of the microscope. Therefore, non-solid nodule is not one disease: pathological examination reveals several different diseases. The radiological GGO change is actually due to a reduction of air, while a certain amount of air remains present. At the microscopic level this may be caused by either i) partial filling of the alveolar airspaces, ii) thickening of the parenchymal interstitium and alveolar walls, iii) relative increase in perfusion, or iv) any combination of these factors.1,2Alveolar spaces may become partially filled by several ways, such as transudative fluid, blood, inflammatory cells or debris, or amorphous material as seen in cardiogenic pulmonary edema, diffuse alveolar hemorrhage, pneumonia, and pulmonary alveolar proteinosis. Alveolar walls and septal interstitium may become thickened secondary to edema, neoplastic proliferation, fibrosis, and noncaseating granulomatous deposition as seen in cardiogenic pulmonary edema, lung adenocarcinoma other malignancies, nonspecific interstitial pneumonia, and sarcoidosis. Partial alveolar filling and interstitial thickening coexist in many disease entities. Thus the non-solid nodule is a non-specific finding that may be caused by various disorders, including inflammatory disease, pulmonary fibrosis, alveolar haemorrhage or neoplasms3.

      Part-solid nodules (PSNs): Nodules with a solid component obscuring the underlying lung parenchyma other than blood vessels on thin-section CT scans viewed on CT lung window settings. Subsolid nodules comprise the non-solid and part-solid nodules.

      The histopathology of the solid component may be inflammation1) e.g. aspergillosis, organising pneumonia3,4, non-specific fibrosis and invasive adenocarcinomawith prominent lepidic component3,56and rarely lymphoma4or a combination of both. As subsolid nodules are an appearance on CT that may histologically represent different diseases, the term “Natural history of subsolid or part solid nodule” is a misnomer. Spread through air spaces is an immature concept under debate, where an underlying artifact is far from unrealistic.7

      The chance on lymph node metastases is very low in GGO with total and solid size < 1cm. Only one case with solid size between 0.5 and 1.0 cm8has been reported so far.

      Usually, in patients with multiple AIS sufficient molecular differences are detected to classify the individual lesions as multiple primary tumors. However, in an occasional patient with multiple GGO/AIS the differences in two of several comparisons were so limited that an argument for ‘early metastases was formulated9.

      Although it may be important for prognosis to measure the solid size for radiologists and invasive size for pathologists for prognostic reasons, sufficient reproducibility of these parameters has not been proven. These challenges emphasize the need for further standardization10.

      References

      1. El-Sherief, A. H. et al.Clear Vision Through the Haze: A Practical Approach to Ground-Glass Opacity. Curr. Probl. Diagn. Radiol.43,140–158 (2014).

      2. Hewitt, M. G., Miller, W. T., Reilly, T. J. & Simpson, S. The relative frequencies of causes of widespread ground-glass opacity: A retrospective cohort. Eur. J. Radiol.83,1970–1976 (2014).

      3. Kim, H. Y. et al.Persistent Pulmonary Nodular Ground-Glass Opacity at Thin-Section CT: Histopathologic Comparisons 1. Radiology245,267–275 (2007).

      4. Lee, H. J. et al.Nodular ground-glass opacities on thin-section CT: size change during follow-up and pathological results. Korean J. Radiol.8,22–31 (2007).

      5. Son, J. Y. et al.Quantitative CT Analysis of Pulmonary Ground-Glass Opacity Nodules for the Distinction of Invasive Adenocarcinoma from Pre-Invasive or Minimally Invasive Adenocarcinoma. PLoS One9,e104066 (2014).

      6. Kakinuma, R. et al.Natural history of pulmonary subsolid nodules: A prospective multicenter study.J. Thorac. Oncol.11,1012–1028 (2016).

      7. Blaauwgeers, H., Russell, P. A., Jones, K. D., Radonic, T. & Thunnissen, E. Lung Cancer. Pulmonary loose tumor tissue fragments and spread through air spaces ( STAS ): Invasive pattern or artifact ? A critical review. 123,107–111 (2018).

      8. Seok, Y. et al.Frequency of Lymph Node Metastasis According to the Size of Tumors in Resected Pulmonary Adenocarcinoma with a Size of 30 mm or Smaller. J. Thorac. Oncol.9,818–824 (2014).

      9. Li, R. et al.Early metastasis detected in patients with multifocal pulmonary ground-glass opacities (GGOs). Thorax73,290–292 (2018).

      10. Yip, R. et al.Controversies on lung cancers manifesting as part-solid nodules. Eur. Radiol.28,747–759 (2018).

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      MS10.03 - CT Versus Needle Biopsy Assessment Before Resection of Part Solid Nodules

      15:45 - 16:00  |  Presenting Author(s): Young Tae Kim

      • Abstract

      Abstract

      Increasing number of lung cancer screening program detects pulmonary ground glass nodules (GGN) and those are frequently found to be an adenocarcinoma or its precursors, particularly if they are persistent or increase in size.

      Preoperative diagnosis of GGNs by trans-bronchial or trans-thoracic fine-needle aspiration biopsy can be performed with reasonable diagnostic accuracy 1. However, they have limitation for the pathologic confirmation of GGNs as they can fail to sample small invasive foci 2, 3. In addition, hemoptysis has been reported to occur more frequently after needle biopsy in GGNs 4. Accordingly, needle biopsy for GGNs are not used in our current practice and if the suspicion for malignancy is high on CT, surgical biopsy is performed without preoperative needle biopsy. Recently published Fleischner recommendations for the management of GGNs may help to make a clinical decision.

      During the surgery, especially in minimally invasive surgery, GGNs are often difficult to palpate. Thus, preoperative marking techniques have been utilized for localization of the GGNs using various methods 5. That can be done either percutaneously or transbronchially, using various materials including a dye, colored collagen, barium, lipiodol, micro coil, metallic wire, or fiducial 6. In our center, we have been using various methods for preoperative localization and but currently, we favor to use electromangetive navigational bronchoscopy (ENB) guided dye marking technique.

      Once surgery is decided, deciding the extent of resection is another issue. The size of solid portion measured on the CT can be helpful. If it is less than 5 mm, a simple wide wedge resection can be performed by which the goal of diagnosis and treatment can be achieved. If it is larger than 5 mm, the specimen is examined by frozen section and if the malignancy is confirmed, anatomic lung resection is conducted.
      However, the CT findings have not yet proven sufficiently reliable to guide the management plan. Intraoperative frozen section diagnosis is an alternative that can guide the extent of the subsequent surgical procedure. The problem of frozen section is, however, the fact that deflated lung specimens often makes the correct diagnosis difficult. To obviate this problem, the technique of inflating the lung specimen with the embedding medium for frozen section (EMIT) has been used, which allows better interpretation, and facilitated correct diagnosis in the frozen section 7. In our center, we have been using EMIT and found a high diagnostic accuracy with the concordance rate of 90.6% between EMIT and permanent pathology. Based on our experience, it is our current practice to perform a wide wedge resection of the GGNs and send the specimen for EMIT. If the result of EMIT is pre-invasive lesions (benign, AAH, AIS, or MIA), we do not perform additional resection. If the invasive adenocarcinoma is diagnosed, we prefer to proceed anatomic lung resection with systematic lymph node dissection.

      Several studies showed that limited resection could be beneficial, especially in early stage lung adenocarcinoma, including GGN 8. On the contrary, in one prospective study that reported a long-term outcome, limited resection of GGNs showed a low disease-control rate. They reported adenocarcinomas developed in four out of 26 patients in the surrounding area of initial resection site after more than five years 9. However, as GGNs usually show favorable prognosis, limited resection could be generally recommended 10. Additionally, in cases of deeply located GGNs, where wedge resection is not technically feasible, direct segmentectomy without wedge biopsy for the purpose of diagnosis and treatment, is recommended. For the segmentectomy, various technics can be used, but it is our current practice to use ENB guided dye marking to define an adequate parenchymal resection margin during the segmentectomy.

      To summarize, although there are several CT findings that can differentiate between pre-invasive and invasive lesions, those findings have not yet proven sufficiently reliable to guide the management plan for GGNs. In addition, attempt to sample solid component in GGNs using a biopsy needle is often not feasible and therefore, not helpful for being used in clinical decision. Currently, the best practice for the management of GGNs is to carefully follow the patient with CT, and if malignancy is suspected, to perform a surgical biopsy with the guide of various localization methods and/or other innovative methods to differentiate between pre-invasive versus invasive adenocarcinoma.

      1. Yamagami T, Yoshimatsu R, Miura H, et al. Diagnostic performance of percutaneous lung biopsy using automated biopsy needles under CT-fluoroscopic guidance for ground-glass opacity lesions. Br J Radiol 2013;86:20120447.
      2. Kim TJ, Lee JH, Lee CT, et al. Diagnostic accuracy of CT-guided core biopsy of ground-glass opacity pulmonary lesions. AJR Am J Roentgenol 2008;190:234-239.
      3. Lu CH, Hsiao CH, Chang YC, et al. Percutaneous computed tomography-guided coaxial core biopsy for small pulmonary lesions with ground-glass attenuation. J Thorac Oncol 2012;7:143-150.
      4. Choi JW, Park CM, Goo JM, et al. C-arm cone-beam CT-guided percutaneous transthoracic needle biopsy of small (</= 20 mm) lung nodules: diagnostic accuracy and complications in 161 patients. AJR Am J Roentgenol 2012;199:W322-330.
      5. Ikeda K, Nomori H, Mori T, et al. Impalpable pulmonary nodules with ground-glass opacity: Success for making pathologic sections with preoperative marking by lipiodol. Chest 2007;131:502-506.
      6. Zaman M, Bilal H, Woo CY, et al. In patients undergoing video-assisted thoracoscopic surgery excision, what is the best way to locate a subcentimetre solitary pulmonary nodule in order to achieve successful excision? Interactive cardiovascular and thoracic surgery 2012;15:266-272.
      7. Marchevsky AM, Changsri C, Gupta I, et al. Frozen section diagnoses of small pulmonary nodules: accuracy and clinical implications. The Annals of thoracic surgery 2004;78:1755-1759.
      8. Cao C, Gupta S, Chandrakumar D, et al. Meta-analysis of intentional sublobar resections versus lobectomy for early stage non-small cell lung cancer. Ann Cardiothorac Surg 2014;3:134-141.
      9. Nakao M, Yoshida J, Goto K, et al. Long-term outcomes of 50 cases of limited-resection trial for pulmonary ground-glass opacity nodules. J Thorac Oncol 2012;7:1563-1566.
      10. Shao G, Ren W, Feng Z, et al. The role of video-assisted thoracoscopic surgery in management of the multiple ground-glass nodules. Indian J Cancer 2015;52 Suppl 2:e75-79

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      MS10.04 - Therapeutic Implications of Spread Through Air Spaces (STAS)

      16:00 - 16:15  |  Presenting Author(s): William D Travis  |  Author(s): Rania Gaber, Shaohua Lu, Takashi Eguchi, Natasha Rekhtman, Prasad S. Adusumilli

      • Abstract

      Abstract

      Spread through air spaces (STAS) is a recently recognized pattern of invasion in lung cancer defined as spread beyond the edge of the main tumor into the air spaces surrounding the tumor. It was originally described as a poor prognostic factor in Stage I lung adenocarcinoma.1 STAS has been observed in 15-62% of lung adenocarcinomas and associated with poor prognosis in multiple independent cohorts worldwide.2-4 In addition, it has now been shown to occur with prognostic significance in most all major types of lung cancer including squamous cell carcinoma (SQCC),5 small cell carcinoma SCLC),6 large cell neuroendocrine carcinoma (LCNEC),6 atypical carcinoid (AC)6 and pleomorphic carcinoma.7 Three dimensional evaluation has shown most STAS clusters are attached to alveolar walls rather than floating in air spaces suggesting a mechanism of detachment then reattachment perhaps by vessel co-option.8

      Criteria for STAS

      The original definition of STAS by Kadota et al and the 2015 WHO consisted of tumor cells within the first alveolar air spaces in the lung parenchyma beyond the edge of the main tumor. It can occur as one of three morphologic patterns including 1) micropapillary structures within air spaces; 2) solid nests or tumor islands and 3) scattered discohesive single cells.1, 9 The solid nest pattern is characteristic in other lung cancer histologies. Although other criteria have been proposed our group has used these same criteria for STAS to demonstrate its prognostic significance in SQCC, LCNEC, SCLC and AC. Warth et al defined STAS with different criteria including a detachment of small solid cell nests of least 5 tumor cells where < 3 alveolar spaces were regarded as limited STAS and tumor cells nests >3 alveolar spaces away from the tumor as extensive STAS.4

      Distance of and Quantitation of STAS

      Gaber R et al found that circumferential STAS was associated with a higher risk of recurrence free probability (RFP) than focal STAS (5yr RFP in circumferential vs focal; 67% vs 87%, p=0.027) and that longer distance of STAS was associated with a higher risk of recurrence (5yr RFP >7 alveoli vs ≤ alveoli, 69% vs 91%, p=0.003).9 However, Quantitation of STAS was not prognostic (5yr RFP in >3/HPFs vs ≤3/HPF, 75% vs 88%, p=0.15).9 Uruga H et al found that high vs low STAS (≥5 vs 1-4 single cells or clusters) was an independent predictor of worse (p=0.015).2 Warth did not find a prognostic difference between extensive vs limited STAS as described above.4

      Implications of STAS for Radiation Therapy

      In the setting of sterotactic body radiation therapy (SBRT) for lung cancer, the documentation of microscopic extension has been appreciated for many years.10 Radiologic and pathologic studies have shown that tumor cells can extend beyond the edge of the tumor from 1.3 centimeters to 2.6 cm.10 Although the concept of STAS emerged many years later, it provides morphologic and clinical support to radiation therapists concerns to address microscopic extension and STAS in planning the radiation field.

      Implications of STAS for Surgical Management

      There is limited data evaluating pathologists ability to recognize STAS in frozen section. Kameda et al found the sensitivity and specificity of frozen section for prediction of STAS were 71%, 92.4% respectively and the accuracy was 80%.11 Kappa statistics for interobserver agreement were 0.4-0.74.

      Walts AE et al studied frozen section for evaluation of STAS and recommended that current evidence did not warrant frozen section evaluation for STAS.12 However, frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and an 8% negative predictive value. So from the two studies, it appears if a pathologist sees STAS on a frozen section there is a 92-100% likelihood it will be present on permanent sections. Both of these were retrospective studies where tissue sampling for frozen sections was not made to include the tumor edge and adjacent lung to search for STAS. More studies are needed to evaluate the potential role of frozen section in detecting STAS and guiding intraoperative decisions by surgeons.

      REFERENCES

      1. Kadota K, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      2. Uruga H, et al. Semiquantitative Assessment of Tumor Spread through Air Spaces (STAS) in Early-Stage Lung Adenocarcinomas. J Thorac Oncol 2017;12:1046-51.

      3. Toyokawa G, et al. Significance of Spread Through Air Spaces in Resected Pathological Stage I Lung Adenocarcinoma. Ann Thorac Surg 2018.

      4. Warth A, et al. Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma. The American journal of surgical pathology 2015;39:793-801.

      5. Lu S, et al. Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer-Specific Death in Squamous Cell Carcinoma. J Thorac Oncol 2017;12:223-34.

      6. Aly RG, et al. Spread through air apsaces (STAS) correlates with prognosis in lung neuroendocrine tumors (LNET). Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2018;31:724.

      7. Shintaro Y, et al. Tumor spread through air spaces identifies a distinct subgroup with poor prognosis in surgically resected lung pleomorphic carcinoma. Chest 2018;in press.

      8. Yagii Y, et al. Three-Dimensional Assessment of Spread Through Air Spaces in Lung Adenocarcinoma: Insights and Implications. J Thoracic Oncol 2017;12 (Suppl 2): S1797, 2017.

      9. Gaber R, et al. Circumferential distribution and distance from main tumor of tumor spread through air spaces (STAS) are prognostic. J Thoracic Oncol 2017;12:S1864.

      10. van Loon J, et al. Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features. Int J Radiat Oncol Biol Phys 2012;82:448-56.

      11. Kameda K, et al. Can tumor spread through air spaces (STAS) in lung adenocarcinomas be predicted pre- and intraoperatively? J Thoracic Oncol 2017;12:S209.

      12. Walts AE, et al. Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces. Arch Pathol Lab Med 2018;142:59-63.

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      MS10.05 - Should We Resect GGNs

      16:15 - 16:30  |  Presenting Author(s): Kenji Suzuki

      • Abstract

      Abstract not provided

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      MS10.06 - Q&A

      16:30 - 16:45

      • Abstract

      Abstract not provided

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    MS11 - Stigma and Lung Cancer: Unintended Translational Consequences of Effective Tobacco Control

    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Moderators:
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      MS11.01 - Identifying Consequences of Stigma on Lung Cancer Care Delivery and Patient Outcomes

      15:15 - 15:35  |  Presenting Author(s): Heidi Hamann

      • Abstract

      Abstract

      Lung cancer stigma (the experience and internalization of negative appraisal and devaluation from others) is a formidable barrier to fulfilling the promise of high quality patient care and reduced lung cancer burden. Attention to the robust causal connection between smoking and lung cancer, although crucial for tobacco control, may have unintended consequences that generate blaming responses and biased negative perceptions toward lung cancer patients. Lung cancer stigma can have far-reaching, deleterious effects that range from reduced involvement in prevention and early detection interventions, negative psychosocial impact, impaired patient-clinician communication, inadequate access to diagnosis and treatment, and limited funding and public support for lung cancer research and care. The goals of this presentation are to describe the nature of lung cancer stigma and highlight research that addresses consequences of stigma on lung cancer care delivery and patient outcomes. The presentation also focuses on multilevel interventional opportunities to mitigate the negative effects of stigma.

      Based on both qualitative and quantitative assessment, our team has identified three primary components of patient-reported lung cancer stigma: perceived stigma, internalized stigma, and constrained disclosure (Hamann et al., 2018). Cross-sectional data indicate associations between stigma and impaired patient/provider communication, higher rates of depressive symptoms, and reduced engagement in care among lung cancer patients. Recent work has also demonstrated potential provider-level stigma toward lung cancer patients, with implications for treatment decisions and other aspects of lung cancer care. Interventional opportunities include patient-based education and counseling to address the psychosocial and behavioral consequences of lung cancer stigma. Focusing on provider communication training also represents a promising opportunity to reduce stigma toward lung cancer patients.

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      MS11.02 - Stigma of Tobacco and Lung Cancer: A South American Perspective

      15:35 - 15:55  |  Presenting Author(s): Clarissa Baldotto

      • Abstract

      Abstract not provided

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      MS11.03 - Prevalence of Perceived Lung Cancer Stigma Among Medical and Nursing Students

      15:55 - 16:15  |  Presenting Author(s): Jamie L Studts

      • Abstract

      Abstract not provided

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      MS11.04 - Taking a Smoking History in the Context of Lung Cancer Treatment: Missed Opportunities for Stigma-Reducing Empathic Encounters with Throacic Oncologists

      16:15 - 16:35  |  Presenting Author(s): Peter G Harper

      • Abstract

      Abstract not provided

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      MS11.05 - Q&A

      16:35 - 16:45

      • Abstract

      Abstract not provided

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    MS12 - Immunotherapy and RT

    • Type: Mini Symposium
    • Track: Treatment of Locoregional Disease - NSCLC
    • Moderators:
    • +

      MS12.01 - Biology IO+RT

      15:15 - 15:35  |  Presenting Author(s): Dirk De Ruysscher

      • Abstract

      Abstract

      Checkpoint inhibitors have changed the outcome of patients with metastatic non-small cell lung cancer (NSCLC) in first and in second line, with improved progression-free survival (PFS), overall survival (OS) and quality of life.

      Radiotherapy has consistently been shown to activate key elements of the immune system that are responsible for resistance for immune therapy. Radiation upregulates MHC-class I molecules that many cancer cells lack or only poorly express, tumor-associated antigens, provokes immunogenic cell death, activates dendritic cells, decreases regulatory T-cells (Tregs) in the tumor, broadens the T-cell repertoire and increases T-cell trafficking, amongst many other effects. Radiation may convert a completely or partly poorly or non-immunogenic tumor immunogenic. Radiotherapy in combination with different forms of immune therapy such as anti-PD-(L)1, anti-CTLA4,immunocytokines, dendritic cell vaccination and Toll-like receptor agonists improved consistently local tumor control and very interestingly, lead to better systemic tumor control (the “abscopal” effect) and the induction of specific anti-cancer immunity with a memory effect. Moreover, as PD1/PD-L1 is upregulated by radiation and radiation can overcome resistance for PD-(L)1 blockage, their combination is logical. The best timing, sequencing and dosing of all modalities is a matter of intense research, but in pre-clinical models, the concurrent administration of anti-PD-(L)1 was superior to sequential.

      Clinical studies in NSCLC such as the subgroup analysis of the KEYNOTE-001 trial, the PACIFIC trial and the phase II results of NICOLAS support the rationale to view radiation as an immunotherapeutic drug that may enhance the immune response without limiting side effects when combined with the correct immunotherapy drugs for a given tumor and patient.

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      MS12.02 - Clinical Data Available

      15:35 - 15:55  |  Presenting Author(s): Feng-Ming (Spring) Kong

      • Abstract

      Abstract

      The role of radiation is evolving in the era of immunotherapy. The abscopal effect of radiation on immune modulation has been discussed and researched greatly during recent days, and there is a significant amount of laboratory data suggesting its positive effect on tumor control. This presentation will focus on an objective review of clinical evidences for the clinical significant outcomes of radiation on immune function aiming to maximize the positive effect of Radiation Immunomodulation. Standing from the clinic, I will not only review the GOOD side of abscopal effect, i.e. the increased tumor control distant from a focused local radiation, and examine the BAD effect of radiation immunomodulation, i.e. radiation immunosuppressive effect which can worsen the tumor control outcome and overall survival. Starting from an overview of these two conflicted effects of all solid tumors in general, the presentation will specifically focus on the literature of radiation immunomodulation effects in patients with non-small cell lung cancer. Predictive and correlative biomarkers for both GOOD and BAD effects will also be reviewed through thorough literature search. The ultimate goal of this presentation is to motivate us, the oncologists to search, and research on finding a way to deliver a more effective radiation therapy and a more effective way of combined therapy with radiation and immunotherapy, to maximize the GOOD abscopal benefit while minimize the BAD effects of radiation on immunofunction.

      e353dbe42c8654f33588d4da0b517469

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      MS12.03 - Ongoing Studies

      15:55 - 16:15  |  Presenting Author(s): Francoise Mornex

      • Abstract

      Abstract not provided

    • +

      MS12.04 - Implications for Routine Practice

      16:15 - 16:35  |  Presenting Author(s): Paul Mitchell

      • Abstract

      Abstract

      Over the last 3 years checkpoint inhibitors (CPI) have become established as key components in the treatment of stage III and IV NSCLC. The established CPI are PD-1 and PD-L1 inhibitors and more recently CTLA4 inhibitors, with ongoing research into other modulators of T-cell function. Used alone, these agents have their greatest efficacy in a subset of patients while combination with other treatment modalities may enhance efficacy. Already concurrent pembrolizumab and chemotherapy has been shown to be more effective than chemotherapy alone for first-line metastatic NSCLC. 1 In the clinic there are two major issues to consider when combining immunotherapy and radiotherapy. The first is safety, particularly when irradiating lung or the brain. The second issue is, can we harness radiotherapy to improve the efficacy of immunotherapy?

      Pneumonitis is a major concern when combining radiotherapy to the lung. Lower dose palliative radiotherapy is less of a concern but when treating primary lung cancer with curative intent, especially concurrent with chemotherapy, toxicity may impact on patient survival. In the phase III PACIFIC trial, of the 476 stage III NSCLC patients who received concurrent chemoradiation to the lung followed by durvalumab consolidation, grade ≥3 pneumonitis was 4.5% and no different from chemoradiation alone. 2 In 93 stage III patients treated with concurrent chemoradiation followed by 12 months pembrolizumab consolidation grade ≥3 pneumonitis was 6.5%. 3 We now have safety data for stage III patients with nivolumab given concurrently with thoracic chemoradiotherapy, followed by consolidation nivolumab. For the 58 patients evaluable for toxicity in the NICOLAS trial, grade ≥3 pneumonitis was 10.3%. 4

      We now also have safety data for SABR (Stereotactic Ablative Radiotherapy) combined with CPI. Seventy nine patients (53 NSCLC) received SABR to multiple metastases, followed within 7 days by pembrolizumab. The toxicity was as expected for pembrolizumab alone. 5 Similarly Campbell has reported on treatment with concurrent SABR and pembrolizumab with either melanoma or NSCLC, with no increased toxicity. 6 Treating brain melanoma metastases with radiosurgery concurrent with ipilimumab in 57 patients, Mortier found toxicity to be as expected for immunotherapy alone 7 , while a similar study by the same group found toxicity was not increased beyond that for pembrolizumab alone.

      There have been multiple reports, mostly of single cases, whereby local radiotherapy to a tumour causes shrinkage of a distant non-irradiated metastasis, termed an abscopal effect. 8 It is hoped that likewise radiotherapy will enhance the effectiveness of CPI. Prior to CPI entering the clinic, in the START trial stage III patients treated with consolidation tecemotide (liposomal MUC1) vaccine following concurrent chemoradiation showed a 10 month survival advantage not seen in those who had received sequential chemoradiotherapy. 9,10 Although overall the START trial was negative for the primary endpoint, this suggested that concurrent chemoradiotherapy might enhance immunogenicity. In the PACIFIC trial of stage III NSCLC, all patients received concurrent chemoradiation. Patients randomised to a year of consolidation durvalumab had markedly improved PFS (HR 0.52) irrespective of tumour PD-L1 expression, and overall survival data are awaited. 2 There are also now data suggesting an outcome benefit for NSCLC patients treated with concurrent SABR and CPI. In the PEMBRO-RT trial 74 NSCLC patients were randomised to receive SABR (3 x 8GY) to a single metastasis followed within 7 days by pembrolizumab, or pembrolizumab alone. 11 All endpoints trended in favour of the combination. The primary endpoint of response rate at 12 weeks was 39% vs 21% (p=0.28), for SABR + CPI vs CPI respectively, while PFS (HR 0.61 p=0.08) and OS (HR 0.58 p=0.1) favoured combined SABR and pembrolizumab. A similar trial, NIVORAD, is being conducted by the ALTG co-operative group, where patients are randomised to receive nivolumab with or without SABR to a metastasis site during week 2. 12

      There are now good data to indicate that combining CPI and radiotherapy is safe, including radiotherapy to the lung and to the brain. Sequential concurrent chemoradiation in stage III NSCLC followed by durvalumab is highly effective. Emerging data suggest that radiotherapy may enhance the effectiveness of immunotherapy in stage IV disease but further randomised data are required.

      1 Gandhi L. Pembrolizumab plus chemotherapy in metastatic NSCLC. N Engl J Med 2018: 378; 2078-2092

      2 Antonia S. Durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2017; 377: 1919-1929

      3 Durm G. Phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III NSCLC. J Clin Oncol 2018; 36: suppl. abstract 8500

      4 Peters S. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first-line chemo-RT regimen in unresectable locally advanced NSCLC – the ETOP NICOLAS phase II trial. J Clin Oncol 2018; 36: suppl. abstract 8510

      5 Luke J. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumours. J Clin Oncol 2018; 36: 1611-1618

      6 Campbell AM. Final results of a phase 1 prospective trial evaluating the combination of stereotactic body radiotherapy with concurrent pembrolizumab in patients with metastatic NSCLC or melanoma. J Cin Oncol 2018; 36: suppl. abstract 9099

      7 Mortier L. Ipilimumab combined with stereotactic radiosurgery in melanoma patients with brain metastases: A multicentre, open label, phase 2 trial. J Clin Oncol 2018; 38: suppl. abstract 9250

      8 Siva S. Asbcopal effects after conventional and stereotactic lung irradiation of NSCLC. J Thorac Oncol 2013.

      9 Butts C. Tecemotide (L-BLP-25) versus placebo after chemoradiotherapy for stage III NSCLC (START): a randomized double-blind phase 3 trial. Lancet Oncol 2014; 15(1): 59-68

      10 Mitchell PL. Tecemotide in unresectable stage III NSCLC in the phase III START study: updated overall survival, further endpoints and biomarker analysis. Ann Oncol 2015; 26; 1134-1142

      11 Theelen WSME. Randomized phase II study of pembrolizumab after stereotactic body radiotherapy versus pembrolizumab alone in patients with advanced NSCLC: The PEMBRO-RT study. J Clin Oncol 2018; 36: suppl. abstract 9023

      12 Mitchell PLR. NIVORAD: a randomised phase 2 trial of nivolumab and stereotactic ablative radiotherapy in advanced NSCLC progressing after first or second line chemotherapy. J Clin Oncol 2017; 35: suppl. TPS9097

      e353dbe42c8654f33588d4da0b517469

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      MS12.05 - Q&A

      16:35 - 16:45

      • Abstract

      Abstract not provided

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    OA07 - Oligometastasis: What Should Be the State-Of-The-Art?

    • Type: Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Moderators:
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      OA07.01 - Phase II Study of Pembrolizumab for Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT)

      15:15 - 15:25  |  Presenting Author(s): Joshua Michael Bauml  |  Author(s): Rosemarie Mick, Christine Ciunci, Charu Aggarwal, Christiana Davis, Tracey Evans, Charuhas Deshpande, Linda Miller, Pooja Patel, Evan Alley, Christina Knepley, Faith Mutale, Roger B Cohen, Corey J Langer

      • Abstract

      Background

      Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide benefit after LAT. We completed a Phase II study evaluating the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy would be effective in the setting of a minimal disease burden.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligibility stipulated oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts began pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for up to a year in the absence of progression (PD) or toxicity. Progression-free survival (PFS) and overall survival (OS) were measured from the start of LAT. A sample size of 42 pts would provide 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.

      4c3880bb027f159e801041b1021e88e8 Result

      Since January 2015, 45 pts have been enrolled. Median age is 64 years; 53% male; 89% Caucasian; 89% current and former smokers. Most common metastatic sites are lung (16 pts), brain (18), liver (9), and bone (9). LAT included surgery (30 pts), SRT (30), and chemoradiotherapy (23). Adverse events have been mostly mild. There were two episodes of Grade 3 pneumonitis, two episodes of Grade 3 colitis, and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 20.1 mos. To date, 19 pts have had PD or died. Median PFS was 25 mos. PFS rates (+ SE) at 12, 18 and 24 mos are 72%+7%, 54%+9% and 50%+9%, with 10 free of PD/death beyond 24 mos. To date, 10 pts have died. Median OS has not yet been reached. OS rates (+ SE) at 12, 18 and 24 mos are 91%+4%, 82%+7% and 73%+8%, with 14 pts alive beyond 24 mos. Median PFS was 16.9 mos for pts with metachronous disease (n=33), not yet reached for pts with synchronous disease (n=12). Median OS has not yet been reached in either group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. PFS appears quite favorable, preliminarily Final analysis will be performed September 2018. Updated survival estimates and biomarker data will be presented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.02 - ATOM: A Phase II Study to Assess Efficacy of Preemptive Local Ablative Therapy to Residual Oligometastases After EGFR TKI

      15:25 - 15:35  |  Presenting Author(s): Oscar S.H. Chan  |  Author(s): Kwok Chi Lam, Jacky Yu Chung Li, Frankie Choi, Catherine Wong, Amy Chang, Frankie Mo, Ki Wang, Rebecca Yeung, Tony S. Mok

      • Abstract

      Background

      NSCLC patients (Pts) harboring EGFR mutation invariably develop resistance to EGFR TKI at a median time of 9-13 months. Prior studies have showed that local ablative therapy (LAT) upon oligoprogression (OP) can extend the duration of TKI therapy effectively. We postulate that residual positron emission tomography (PET) avid lesions after initial treatment of EGFR TKI may harbor resistant clones and preemptive LAT may improve progression free survival (PFS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This single-arm phase II study aims to determine the efficacy of preemptive LAT to residual metabolic active oligo-metastases after initial TKI. Pts with stage IIIB/ IV EGFR M+ NSCLC who possessed oligoresidual (OR) disease (≤ 4 PET-avid lesions with SUV ≥2.5) after a 3-mth TKI therapy were enrolled. Those with initial PR underwent screening PET-CT. PET avid ORs would be treated by LAT, either by stereotactic ablative radiotherapy (SABR) or surgery per clinicians’ discretion. TKI was continued after LAT until it was considered ineffective. PET-CT was done on the 3rd and 12th month post-LAT (or at progression), apart from regular imaging. Further LAT was allowed if OP was detected. Primary endpoint was PFS rate at 1 year from enrollment. Overall survival (OS), treatment safety and comparison with screen failure cohorts were secondary endpoints.

      4c3880bb027f159e801041b1021e88e8 Result

      18 Pts were enrolled from 2014-17. Recruitment was stopped before the planned number (n = 34) due to slow accrual. Two were not analyzed due to consent withdrawal and significant protocol violation. Median follow up was 28.7 mth. Among the 16 analyzed Pts, the 1 year PFS rate (i.e. 15 mth post TKI) was 62.5%. OS data was not yet mature. All LAT were done by SABR, and none experienced ≥grade 3 SABR related toxicities. Compared with screen failure cohort (n = 43, metabolic CR or PR with residual disease not fulfilling LAT criteria), the 1 year and 2 year PFS favored treatment arm, though statistically not significant (62.5% vs 47.1%, 30.0% vs 7.9%; p = 0.15).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The 1-yr PFS rate is encouraging. A trend of improved long term PFS is noted in Pts receiving preemptive LAT to residual PET-avid OM after initial TKI compared with Pts without LAT. Further studies are warranted.

      Clinical Trial information: NCT01941654

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.03 - Addition of Local Therapy to EGFR TKI Showed Survival Benefit in EGFR-Mutant NSCLC pts with Oligometastatic or Oligoprogressive Liver Metastases

      15:35 - 15:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Caicun Zhou, Huijuan Wang, Qian Chu

      • Abstract

      Background

      Our previous study demonstrated that EGFR-mutant NSCLC patients (Pts) with liver metastases (LM) showed poor response to EGFR-TKIs than those without LM, suggesting that additional treatment is warranted. Recently, several clinical studies indicated that local therapy (e.g. surgery and radiotherapy) could significantly improve progression-free survival (PFS) in NSCLC Pts with oligometastatic or oligoprogressive disease. This study aimed to investigate whether addition of local therapy to EGFR-TKIs could provide a better survival benefit than TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pts with EGFR-mutant NSCLC and LM were enrolled. Oligometastatic LM was defined as < 5 sites in liver without extrahepatic metastases at initial diagnosis. Oligoprogressive LM was defined as < 5 sites in liver without extrahepatic metastases during TKIs therapy. For oligoprogressive cohort, PFS1 was calculated from time of initiation of TKI therapy to first RECIST 1.1 defined progress disease (PD) or death. PFS2 was calculated from time of initiation of TKI therapy to off-TKI PD.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally, 135 cases with EGFR-mutant NSCLC and LM were eligible (64 with oligometastatic LM and 71 with oligoprogressive LM). In oligometastatic cohort, 20 Pts received EGFR-TKIs (E) and 23 Pts received EGFR-TKIs plus local therapy (E+LT) as first-line treatment. The addition of local therapy showed a significantly longer PFS (12.9 vs. 7.9 m, P = 0.041) and OS (36.8 vs. 21.3 m, P = 0.034) than EGFR-TKIs alone. In oligoprogressive cohort, 24 Pts received continuation of EGFR-TKIs plus local therapy (cE+LT) and 25 Pts received switch therapy (ST). Median PFS1 was similar. Median PFS2 (13.9 vs. 9.2 m, P = 0.007) and OS (28.3 vs. 17.1 m, P = 0.011) was significantly longer in cE+LT group than in ST group. Multivariate analysis revealed that addition of local therapy was independently associated with prolonged PFS (HR = 0.435, P = 0.028) and OS (HR = 0.434, P = 0.071) in Pts with oligometastatic LM. Distant metastatic sites were the major pattern of failure in EGFR-TKI plus local therapy group while locoregional recurrence including primary lesions and LM was the major reason in TKI alone group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current study suggested that EGFR-TKIs plus local therapy demonstrated the prolonged survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM. These findings suggest that local therapy should be further explored in large-scale, strictly designed clinical trials as a standard treatment option in this clinical scenario.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA07.04 - Discussant - OA 07.01, OA 07.02, OA 07.03

      15:45 - 16:00  |  Presenting Author(s): Gregory M.M. Videtic

      • Abstract

      Abstract not provided

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      OA07.05 - Local Ablative Therapy Improves Survival in Patients with Synchronous Oligometastatic NSCLC Harboring EGFR Mutation Treated with EGFR-TKIs

      16:00 - 16:10  |  Presenting Author(s): Yaping Xu  |  Author(s): Qinghua Xu, Fei Zhou, Hui Liu, Caicun Zhou

      • Abstract

      Background

      Non-small-cell lung cancer (NSCLC) is the most common cause of cancer deaths worldwide. Patients with oligometastatic disease can represent an indolent phenotype that could benefit from local ablative therapy(LAT). Howerver, whether first-line continual EGFR-TKIplus LAT could have potential benefit in EGFR-mutant NSCLC patients with oligometastatic disease remains undetermined.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with stage IV EGFR-mutant NSCLC and no more than five metastases at diagnosis in 2 months were enrolled. All patients were treated with first-line EGFR-TKIs. Consolidation LAT included radiotherapy or surgery. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves.

      4c3880bb027f159e801041b1021e88e8 Result

      From October 2010 to May 2016, 145 patients were enrolled, including 51 (35.2%) who received consolidation LAT to all oligometastatic sites (All-LAT group), 55 (37.9%) who received consolidation LAT to either primary tumor or oligometastatic sites (Part-LAT group), and 39 (26.9%) who did not receive any consolidation LAT (Non-LAT group). The median PFS in All-LAT, Part-LAT, and None-LAT group were 20.6 months, 15.6 months, and 13.9 months, respectively (P<0.001). The median OS in All-LAT, Part-LAT, and None-LAT group were 40.9 months, 34.1 months, and 30.8 months, respectively (P<0.001). The difference was significant between All-LAT group and Part-LAT or Non-LAT group but was not significant between Part-LAT and Non-LAT group. The median OS was significantly improved with consolidation LAT for primary tumor (40.5 versus 31.5 months, P<0.001), brain metastases (38.2 versus 29.2 months, P=0.002), adrenal metastases (37.1 versus 29.2 months, P =0.032). Adverse events (Grade≥3) due to radiotherapy included pneumonitis (7.7%) and esophagitis (16.9%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current study demonstrated that consolidation LAT to all sites was a feasible option among patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with consolidation LAT to partial sites or observation alone.

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      OA07.06 - Efficacy of Local Consolidative Therapy for Oligometastatic Lung Adenocarcinoma Patients Harboring EGFR Mutations.

      16:10 - 16:20  |  Presenting Author(s): Fang Hu  |  Author(s): Jianlin Xu, Bo Zhang, Changhui Li, Wei Nie, Ping Gu, Ping Hu, Huimin Wang, Yujun Zhang, Yinchen Shen, Shuyuan Wang, Baohui Han, Xueyan Zhang

      • Abstract

      Background

      For oligometastatic lung adenocarcinoma patients with sensitive EGFR mutations, the role of local consolidative therapy (LCT) remains debatable. The purpose of this study was to investigate the efficacy of LCT in these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced stage patients with oligometastatic lung adenocarcinoma who harboring EGFR mutation were identified at the Shanghai Chest Hospital from 2010 to 2016.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 253 patients (149 patients who received LCT plus EGFR-TKIs [combination group] and 104 patients who received EGFR-TKIs [TKI monotherapy group] were included. The median PFS time in the combination group was 14 months versus 9 months in the TKI monotherapy group (HR=0.57, 95% [CI] 0.44, 0.79, p<0.01, Figure 1 A). The median OS time in the combination group was 33 months versus 20 months in the TKI monotherapy group (HR=0.56, 95% [CI] 0.41, 0.75, p<0.01, Figure 1D). Survival benefit was independent of EGFR mutation type (PFS: 19del, p=0.02, Figure 1B; 21L858R, p<0.01, Figure 1C; OS: 19del, p=0.0189, Figure 1E; 21L858R, p<0.01, Figure 1F) and metastatic sites .figure 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      LCT combined with TKI therapy was feasible and significantly improved PFS and OS among oligometastatic lung adenocarcinoma patients with sensitive EGFR mutations, and thus, should be considered as an important medical treatment during clinical management.

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      OA07.07 - PFS and OS Beyond 5 years of NSCLC Patients with Synchronous Oligometastases Treated in a Prospective Phase II Trial (NCT 01282450)

      16:20 - 16:30  |  Presenting Author(s): Dirk De Ruysscher  |  Author(s): Rinus Wanders, Lizza Hendriks, Angela Van Baardwijk, Bart Reymen, Ruud Houben, Gerben Bootsma, Cordula Pitz, Anne-Marie C. Dingemans

      • Abstract

      Background

      There is increasing interest in the treatment of synchronous oligometastases of NSCLC. Two randomized studies demonstrated an increased PFS by adding a radical local treatment to systemic therapy in responding patients, but long-term data are lacking. We previously reported a median PFS of 12 months and a median OS of 13.5 months in 39 radically treated patients with synchronous oligometastases in a prospective study (De Ruysscher J Thorac Oncol 2012). As the minimal follow-up is now exceeding 6 years, we here report the long-term PFS and OS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was required.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment.

      Median overall survival (OS) was 13.5 months (95% CI 7.6-19.4); 1-, 2-, 3-, 4-, 5, 6-year OS was 56.4%, 23.3%, 12.8 %, 10.3 %, 7.7 %, 5.1 % (2 patients), respectively.

      Median progression-free survival (PFS) was 12.1 months (95% CI 9.6-14.3); 1-, 2-, 3-, 4-, 5, 6-year PFS was 51.3%, 13.6 %,12.8 %, 7.7 %, 7.7 %, 2,5 % (1 patient), respectively.

      Of the 3 patients with a PFS after 5 years, 1 had a squamous cell cancer T2N2 with a single pathologically proven bone metastasis in the sternum, 1 had a NSCLC-NOS T4N0 with a single adrenal metastasis, and 1 a T1N2 adenocarcinoma with a pathologically proven contralateral lung metastasis. The latter patient is still free of disease.

      Two patients developed a second primary cancer: 1 tongue carcinoma after 70 months and 1 an adenocarcinoma in the contralateral lung after 71 months. Both patients died of their second cancer.

      Three patients (7.7 %) had a local recurrence, all in the PTV of their primary tumor.

      Only one patient was treated with a TKI (gefitinib) at progression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      After radical treatment of oligometastases, approximately 8 % of the patients achieve a PFS after 5 years. Entering patients in trials combining local therapy with novel systemic agents (e.g. chemo-immunotherapy) remains mandatory.

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      OA07.08 - Discussant - OA 07.05, OA 07.06, OA 07.07

      16:30 - 16:45  |  Presenting Author(s): Sue S Yom

      • Abstract

      Abstract not provided

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    OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment

    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Moderators:
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      OA08.01 - Long-Term Efficacy and Safety of Nivolumab in Second- or Third-Line Japanese Malignant Pleural Mesothelioma Patients (Phase II: MERIT Study)

      15:15 - 15:25  |  Presenting Author(s): Takashi Nakano  |  Author(s): Morihito Okada, Takashi Kijima, Keisuke Aoe, Tatsuya Kato, Nobukazu Fujimoto, Kazuhiko Nakagawa, Yuichiro Takeda, Toyoaki Hida, Kuninobu Kanai, Fumio Imamura, Satoshi Oizumi, Toshiaki Takahashi, Mitsuhiro Takenoyama, Hiroshi Tanaka, Yuichiro Ohe

      • Abstract

      Background

      Malignant Pleural Mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and no treatment is approved for patients (pts) progressing after 1st line pemetrexed-platinum doublet. Here, we report latest analysis of MERIT study in previously treated Japanese MPM pts to update the previous report (WCLC 2017, Goto Y, et al).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including pemetrexed-platinum doublet. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable lesion and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-four pts received Nivolumab in this study. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6% and PD-L1 (≧1%)/PD-L1 (<1%)/not evaluable: 58.8%/35.3%/5.9%. At a median follow-up of 16.8 months (range: 1.8-20.2), ORR was 29.4 % (n=10, 95%CI: 16.8-46.2). DCR was 67.6% (n=23, 95%CI: 50.8-80.9). Median DOR was 11.1 months (95%CI: 3.5-16.2). Median PFS was 6.1 months (95%CI: 2.9-9.9) in all pts, 7.2 months (2.8-15.0) in PD-L1 (≧1%) and 2.9 months (1.4-9.3) in PD-L1 (<1%). Median OS was 17.3 months (95%CI: 11.5-NR) in all pts, 17.3 months (8.2-NR) in PD-L1 (≧1%), 11.6 months (5.8-NR) in PD-L1 (<1%), across tissue types, 15.7 months (95%CI: 8.0-NR) in epithelioid and not reached in sarcomatoid/biphasic pts. Six- and 12-month survival rates were 85.3% (95%CI: 68.2-93.6) and 58.8% (95%CI: 40.6-73.2). Twenty-six (76.5%) pts experienced treatment-related adverse event (TRAE), and 11 (32.4%) experienced grade 3/4 TRAEs. Most commonly reported TRAEs were skin disorder (n=6, 17.6%), elevated lipase (n=5, 14.7%), elevated amylase and diarrhea (n=4, 11.8%). Four pts required dose discontinuation because of interstitial pneumonia (n=2, grade2 and 3) and pneumonitis (n=2, grade3).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab shows durable long term efficacy and manageable safety profile in Japanese 2nd/3rd line MPM pts.

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      OA08.02 - DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result

      15:25 - 15:35  |  Presenting Author(s): Anna K. Nowak  |  Author(s): Peey-Sei Kok, Willem Joost Lesterhuis, Brett G.M Hughes, Chris Brown, Steven Chuan-Hao Kao, Deme Karikios, Thomas John, Nick Pavlakis, Kenneth O’byrne, Sonia Yip, Wei-Sen Lam, Karen Briscoe, Chris S. Karapetis, Martin R Stockler

      • Abstract

      Background

      We report here the final results of a single-arm, phase 2 trial designed to determine the activity, safety and tolerability of durvalumab, cisplatin and pemetrexed as first line therapy in MPM. ANZ Clinical trial registry number: ACTRN12616001170415

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Participants were considering first line chemotherapy for MPM, were unsuitable for radical surgery, had an un-irradiated target lesion, and had good performance status (ECOG PS 0-1). Objective tumour response (OTR) and progression free survival (PFS) were assessed primarily according to the modified Response Evaluation Criteria in Solid Tumors for MPM (mRECIST) and as secondary endpoints according to RECIST modified for immunotherapy (iRECIST). Study treatment was durvalumab 1125mg, cisplatin 75mg/m2, and pemetrexed 500mg/m2 all given intravenously on day 1, and repeated every 3 weeks for a maximum of 6 cycles, followed by durvalumab 1125 mg every 3 weeks until progression, unacceptable toxicity, or a maximum total of 12 months. The primary endpoint was PFS at 6 months (PFS6). The sample size of 54 provided 90% power to distinguish the observed proportion PFS6 from a null hypothesis of 45% versus an alternative of 65% with a 1-sided alpha of 5%. Tissue and blood samples were required and collected for translational correlative studies.

      4c3880bb027f159e801041b1021e88e8 Result

      We recruited 54 participants from Dec 2016 to Sep 2017. Median age was 68 (range 42-82), 82% were male, 60 had ECOG PS 0, and 82% had epithelioid histology. Dose intensities were 97% for cisplatin and 94% for durvalumab. The proportion PFS6 was 57% (31/54, 90% CI 45-68%); median PFS was 6.9 months (95% CI 5.5-9.0). The OTR rate was 48% (95% CI 35-61%) according to mRECIST and 50% (95% CI 37-63) according to iRECIST. The median duration of response was 6.5 months. Grade 3-5 adverse events occurred in 36 participants, including neutropenia in 13%, nausea in 11%, anaemia in 7%, fatigue in 6% and any grade peripheral neuropathy in 35%. There were 4 deaths on study, none attributed to durvalumab. Immune-related adverse events occurred in 17 participants, and were of grade 3 or worse in 8, including increased lipase (1), pancreatitis (1), and renal impairment (1).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of durvalumab, cisplatin, and pemetrexed has demonstrated sufficient activity, safety, and tolerability as first line therapy in MPM to warrant further evaluation in a large-scale, randomised phase 3 trial.

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      OA08.03 - Phase II Trial of Pembrolizumab (NCT02399371) In Previously-Treated Malignant Mesothelioma (MM): Final Analysis

      15:35 - 15:45  |  Presenting Author(s): Arpita Desai  |  Author(s): Theodore Karrison, Pamela Rose, Yi-Hung Carol Tan, Bianca Hill, Erika Pemberton, Christopher Straus, Tanguy Seiwert, Hedy Lee Kindler

      • Abstract

      Background

      We conducted a phase II trial to assess the activity of pembrolizumab in a non-selected population of mesothelioma patients and determine a PD-L1 expression threshold.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients had histologically-confirmed pleural or peritoneal MM, PS 0-1, prior pemetrexed/platin, disease progression on ≤2 prior regimens. Pembrolizumab 200 mg was administered Q21 days; CT scans were obtained Q9 weeks. The primary endpoints determined: 1) the objective response rate (ORR) in an unselected and a PD-L1 positive population; 2) the optimal threshold for PD-L1 expression using the 22C3 IHC tumor cell/tumor proportion score (TPS) assay. Proceeding to a second stage required ≥3 responses in 35 PD-L1 unselected patients in Part A. Part B would PD-L1 preselect only if a threshold was determined in Part A. At WCLC 2016, we reported 7 responses in Part A, and no PD-L1 threshold was identified (ROC 0.62). Thus, Part B enrolled 30 additional patients without biomarker enrichment.

      4c3880bb027f159e801041b1021e88e8 Result

      65 patients enrolled 5/15-2/18; 1 withdrew. PS 0: 53%; male: 77%; median age: 68 (range 26-85); 1 prior chemotherapy 61%; pleural 87.5%; epithelioid 76.6%, biphasic 15.6%, sarcomatoid 7.8%. Mean cycles: 9 (range 1-34). Partial response: 19%, stable disease: 47%, disease control rate: 66%. ORR by histology: epithelioid 16%, biphasic 10%, sarcomatoid 40%. ORR by disease site: pleural 20%, peritoneal 12.5%. Median progression-free survival: 4.5 months (95% CI: 2.3, 6.2). Median overall survival: 11.5 months (95% CI: 7.6, 14). Grade ¾ toxicity: adrenal insufficiency 3%, pneumonitis 3%, rash 3%, colitis 1.6%, confusion 1.6%, hepatitis 1.6%, hyperglycemia 1.6%. Grade 5: hepatitis 1.6%, unknown 1.6%. PD-L1 expression by TPS (N = 62): none (< 1%) 45%; low (1-49%) 32%; high (≥50%) 23%. ORR by TPS: none 7%, low 26%, high 31%. PD-L1 did not correlate with RR as a continuous metric (ROC area 0.65; 95% CI: 0.48, 0.82), though there was a trend towards a higher ORR in PD-L1 ≥1% (28%) compared with PD-L1 <1% (7%). Median PFS by TPS: none 3.1 months, low 6.2 months, high 6.1 months; 1-year PFS by TPS: none 7%; low 7%; high 31%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Single-agent pembrolizumab has robust activity in PD-L1 unselected, previously-treated mesothelioma. There were no unexpected toxicities. Responses were more frequent in pleural and sarcomatoid MM. Although an optimal PD-L1 threshold could not be identified, a trend towards a higher response rate and more durable PFS with increasing PD-L1 expression was observed. Funded in part by a Mesothelioma Foundation grant.

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      OA08.04 - Discussant - OA 08.01, OA 08.02, OA 08.03

      15:45 - 16:00  |  Presenting Author(s): Thomas John

      • Abstract

      Abstract not provided

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      OA08.05 - Quantifying Tumour Infiltrating Lymphocytes (TILs) in Malignant Pleural Mesothelioma (MPM) -Defining the Hot, the Warm and the Cold Tumours.

      16:00 - 16:10  |  Presenting Author(s): Thomas John  |  Author(s): Bibhusal Thapa, Marzena Walkeiwicz, Gareth Rivalland, Carmel Murone, Khashayar Asadi, Stephen Arthur Barnett, Simon Knight, Shona Hendry, Prudence Russell

      • Abstract

      Background

      Immunological infiltrates into tumor tissues have been associated with improved prognosis in many cancers including breast, colorectal, cervical, melanoma and lung. While most studies evaluating TILs have been based on evaluation of individual types of T lymphocytes, more recently, a morphological assessment of the TILs based on a simple hematoxylin & eosin (H&E) slide examination has been shown to be an independent positive prognostic factor in HER2 positive early stage breast cancer and lung cancer. We used similar methods to explore the immune microenvironment in a large mesothelioma cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using full face sections of MPM tumour samples, we assessed lymphocytes infiltrating tumour stroma.TILs score was calculated as a % of stromal area assessed to be covered by TILs by an experienced pathologist. Tissue microarrays (TMA) were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. We explored the clinical and pathological correlates of the level of TILs.

      4c3880bb027f159e801041b1021e88e8 Result

      Amongst 329 patients evaluated, 308 samples were evaluable for TILs characterisation. The scores ranged from 0-90 (median 30). Stratified using tertiles, 142 patients had low TILs, 68 had medium and 98 had high TILs. High TILs were seen in patients who were PD-L1 (Chi square test p = 0.002) and PD-L2 positive (Chi square test p <0.0001) and of non-epithelioid histological subtype (Fischer’s exact test p = 0.01). On univariate analysis, PD-L2 positivity (HR = 3.2; CI = 2.2-4.6; Log rank P < 0.0001), high TILs (HR = 2.03; CI = 1.5-2.6; Log rank P < 0.0001), and high TIM3+ lymphocytes (HR = 1.3; CI = 1.0-1.7; Log rank P < 0.04) were found to be related to poorer overall survival (OS). On multivariate analysis, higher TILS was found to remain significantly associated with poorer OS along with non-epithelioid histology and poor physiological status.

      8eea62084ca7e541d918e823422bd82e Conclusion

      High TILs correlated with non-epithelioid histology and greater expression of PD-L1 and PD-L2. In contrast to other tumor types, a high TIL infiltrate was negatively prognostic.

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      OA08.06 - Tumour Suppressor MicroRNAs Modulate Drug Resistance by Targeting Anti-Apoptotic Pathways in Malignant Pleural Mesothelioma (MPM)

      16:10 - 16:20  |  Presenting Author(s): Yuen Yee Cheng  |  Author(s): Marissa Williams, Monica Phimmachanh, Patrick Winata, Glen Reid

      • Abstract

      Background

      Malignant Pleural mesothelioma (MPM) is an aggressive thoracic malignancy with limited treatment options. MPM has a poor prognosis, predominately due to its inherent drug resistance and its limited response to current therapies. Aberrant microRNA expression is a common event in neoplasms with many implicated in chemo-resistance, however their role in MPM drug resistance is largely unexplored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To investigate the role of microRNAs in MPM drug resistance, we generated MPM cell lines with acquired drug resistance to cisplatin, gemcitabine and vinorelbine by periodic treatment with the IC50 of each chemotherapeutic agent. Expression levels of mature microRNAs were compared between parental MPM cell lines and cell lines with acquired drug resistance using RT-qPCR. BCL2 is an anti-apoptotic gene and a known target of miR-15a/16-1 and miR-34a. To determine if microRNAs potentiate drug sensitization via a Bcl-2 mediated anti-apoptotic pathway, drug sensitivity assays were carried out following reverse-transfection with microRNA mimics and Bcl-2 siRNAs combined with cisplatin, gemcitabine and vinorelbine treatment. Following microRNA mimic transfection in 6-well plates, levels of apoptosis and necrosis were determined by PI and annexin V staining while Bcl-2 mRNA and protein expression was determined by RT-qPCR and Western blotting respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      Expression of miR-15a/16-1 and miR-34a was downregulated in MPM cells with acquired resistance to cisplatin, gemcitabine and vinorelbine, compared to the parental counterpart. Transfection with mimics corresponding to miR-15a/16-1 were most effective in improving sensitivity to all chemotherapeutics tested in drug resistant cell lines. In parental cell lines, miR-15a/16-1 mimic induced sensitization was also observed but restoration of miR-34a and miR-34b was also capable of improving response to cisplatin and vinorelbine. Forced miR-15/16 and miR-34a expression also sensitized both parental and resistant cell lines to cisplatin, gemcitabine and vinorelbine via induction of apoptosis; their ability to increase levels of drug-induced apoptosis suggest they may sensitize cells to chemotherapeutics via an anti-apoptotic mechanism involving Bcl-2. miR-15a/16-1 and miR-34a transfection caused Bcl-2 mRNA and protein reduction, confirming their regulation of Bcl-2 in MPM. Furthermore, siRNA induced knockdown of Bcl-2 also induced a modest improvement in drug sensitivity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Restoration of microRNA expression sensitized both drug resistant and parental cell lines to chemotherapeutic agents and increased levels of drug-induced apoptosis. Taken together, this data suggests that miR-15a/16-1 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells in part by modulation of apoptotic mechanisms via targeting Bcl-2.

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      OA08.07 - In Silico Discovery of Unannotated miRNAs in Malignant Pleural Mesothelioma Reveals Novel Tissue-of-Origin Markers

      16:20 - 16:30  |  Presenting Author(s): Brenda C. Minatel  |  Author(s): Erin A Marshall, Christine Anderson, Kevin W. Ng, Katey S.S. Enfield, Adam P Sage, Zhaolin Xu, Wan Lam, Victor D Martinez

      • Abstract

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive disease. One of the major clinical challenges associated with MPM is the lack of biomarkers capable of distinguishing primary MPM from cancers that have metastasized to the pleura. The current gold standard consists of a panel of positive and negative protein markers to confirm tissue-of-origin; however, many cases remain undistinguishable from other thoracic cancers. Recent studies have suggested that the human genome encodes more microRNAs (miRNAs) than currently annotated. These undescribed sequences have been shown to display enhanced tissue and lineage specificity. Therefore, we hypothesize that MPM tumors express a specific set of previously unannotated miRNA sequences with tissue-specific expression capable of distinguishing MPM from other thoracic diseases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Novel miRNA candidates were detected from small RNA-sequencing data generated by The Cancer Genome Atlas (TCGA) (n=87 MPM) using the miRDeep2 algorithm, a well-established novel-miRNA prediction algorithm. The possible biological roles of these miRNA candidates were investigated by performing a genome-wide 3’UTR target prediction analysis. Additionally, their tissue-specificity was assessed using expression profiles of 1,093 lung tumors from four independent cohorts of adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Finally, we developed a miRNA-based classifier model using the weighted voting class prediction method to distinguish MPM from other thoracic cancers.

      4c3880bb027f159e801041b1021e88e8 Result

      Our initial analysis revealed 424 miRNA candidates, which were subsequently filtered by RNA structure, abundance of sequencing reads, and genomic location, resulting in 154 previously unannotated miRNA sequences. Interestingly, the novel miRNAs were predicted to target protein-coding genes involved in MPM biology, including the Ataxia Telangiectasia Mutated (ATM) gene, a tumour-supressor gene frequently mutated in MPM. Likewise BRCA1 Associated Protein 1 (BAP1), involved in the DNA damage response pathway, was also a predicted target. Principal component analyses revealed that novel-miRNA expression was able to distinguish MPM from LUAD and LUSC. Furthermore, our miRNA-based classifier model revealed 10 novel miRNAs capable of successfully identifying 86 out of the 87 MPM cases (98.80%) and 100% of LUAD cases (true positive rate = 98.85%, false positive rate = 1.150%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Here, we provide evidence for the presence of 154 previously unannotated miRNA species relevant to MPM. These miRNAs not only significantly expand the miRNA repertoire but also unveil specific roles in MPM biology. Most importantly, the strikingly high sensitivity and specificity of the novel miRNA-based classifier in distinguishing MPM from LUAD illustrates the potential of using these novel miRNAs to supplement current clinical markers to define MPM.

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      OA08.08 - Discussant - OA 08.05, OA 08.06, OA 08.07

      16:30 - 16:45  |  Presenting Author(s): Emanuela Felley-Bosco

      • Abstract

      Abstract not provided