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Keith M Kerr
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 15
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.01 - Cancer Testis Antigens and Mutational Load in Relation to the Immune Landscape of Non-Small Cell Lung Cancer (ID 9369)
15:45 - 15:50 | Presenting Author(s): Patrick Micke | Author(s): M.W. Backman, P. Kurppa, Dijana Djureinovic, Linnea La Fleur, J. Persson, Johanna Sofia Margareta Mattsson, J. Botling, E. Branden, H. Koyi, F. Ponten
- Abstract
- Presentation
Background:
The avoidance of immune surveillance by tumor cells is an accepted hallmark of cancer. The aim of this study was to describe the natural immune landscape of NSCLC tissue, to identify important regulatory associations and potential targets of immune response. This includes mutational load and cancer testis antigen (CTA) expression, and the comprehensive analysis of tumor infiltrating immune cells in connection with immune signaling and clinical information.
Method:
Tissue microarrays including duplicate cancer samples of 357 NSCLC patients were stained with antibodies against CD3, CD4, CD8, CD45RO, FoxP3, CD20, CD138, and CD44 to analyze the protein expression in the stroma and tumor compartment. For 197 of these cases, corresponding RNA-seq data were available. The immunological data were correlated to the transcriptomic data and to patients’ clinical outcome. The mutation status and the mutational load was based on a targeted next-generation sequencing panel of 82 genes (HaloPlex).
Result:
The immune cell infiltration was predominantly in the stroma, although CD8 and FoxP3 cells also showed relevant infiltration of the tumor cell compartment. The amount of T-cells of different subsets and CD20-positive B-cells correlated positively to each other. A higher mutational load was associated with higher CD8 T-cell infiltrates, CD45RO cells, FoxP3 regulatory cells as well as CD20-positive B-cells in the tumor compartment. In contrast, the number of expressed CTAs were associated with an abundance of CD45RO-positive cells in the stromal compartment. Only CD44-positivity (HR = 0.61, p< 0.01) as well as high CD20 positive B-cells (HR = 0.34, p< 0.01) and plasma cell (CD138, HR = 0.71, p< 0.05) counts in the tumor, and for plasma cells also the stromal (HR = 0.61, p< 0.01), compartment were associated with longer overall survival.
Conclusion:
Here we describe natural immune profiles in a large clinical NSCLC patient cohort. Interestingly both mutational load and CTA expression is associated with the abundance of distinct immune cell infiltrates. We could not confirm the impact of tumor infiltrating T-cells on survival. However, the consistent prognostic impact of both B-cell markers indicates a major role of the humoral immune response in lung cancer.
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MA 06.02 - Cytology and Surgical Pathology Specimens are Comparable Testing Substrates for PD-L1 Immunohistochemistry in Lung Cancer (ID 9063)
15:50 - 15:55 | Presenting Author(s): Paul Andrew Vanderlaan | Author(s): V. Torous, D. Rangachari, D.B. Costa
- Abstract
- Presentation
Background:
Immunohistochemical (IHC) testing for programmed death ligand 1 (PD-L1) expression by non-small cell lung cancer (NSCLC) specimens has become standard of care to help select immune checkpoint inhibitor therapy. The companion IHC assay for pembrolizumab has been validated and approved for use on surgical pathology specimens; however, the performance of this assay when applied to cytology specimens is not well characterized.
Method:
Following IRB approval, all NSCLC cytology or surgical pathology specimens obtained from 11/2015 to 5/2017 at our institution that were tested for PD-L1 expression by a commercial vendor (Integrated Oncology/LabCorp, NY) using the FDA-approved companion diagnostic PD-L1 clone 22C3 pharmDx kit on the Dako Automated Link 48 platform (Dako, Carpenteria, CA) were identified. Patient cohorts where testing was performed on diagnostic cytology vs. surgical pathology specimens were compared. Tumor PD-L1 expression was stratified by clinically relevant groups: <1%, 1-49%, and ≥50%. Tumor genotyping results for EGFR, KRAS, ALK, and ROS1 were also collected.
Result:
Cytology formalin-fixed paraffin-embedded (FFPE) cell blocks included endobronchial ultrasound transbronchial needle aspirates (57%), pleural/pericardial fluids (28%), fine needle aspirates (13%), and bronchial washings/lavages (2%). Surgical FFPE specimens included small core/incisional biopsies (60%), bronchial biopsies (12%), and large resections (28%). PD-L1 testing was successful for over 96% (223/232) of specimens (Table). Overall, EGFR mutations were more frequent with no/low PD-L1 expression, ALK rearrangements with high PD-L1 expression, but no relationship between KRAS mutations and PD-L1 expression.PD-L1 Tumor Proportion Score Stratified by Specimen Type
Chi-squared value=2.95, p>0.39 (not significant); TPS=tumor proportion scoreCytology Cell Block Surgical Pathology <1% PD-L1 TPS 35 (37.2%) 52 (37.7%) 1-49% PD-L1 TPS 20 (21.3%) 35 (25.4%) ≥50% PD-L1 TPS 33 (35.1%) 48 (34.8%) Failed Analysis 6 (6.4%) 3 (2.2%) Total 94 (100%) 138 (100%)
Conclusion:
For NSCLC, no statistically significant differences in PD-L1 expression patterns were observed between cytology cell block and surgical pathology specimens, implying that in clinical practice any adequate cytology cell block or surgical pathology specimen could be utilized for testing. Importantly, analysis of clinical outcomes with use of first line pembrolizumab based on cytology vs surgical pathology specimen PD-L1 ≥50% expression is currently ongoing.
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MA 06.03 - Programmed Death-Ligand 1 (PD-L1) Expression in Clinical Practice: Comparison of Temporally or Spatially Separated Test Results (ID 10357)
15:55 - 16:00 | Presenting Author(s): Charuhas Deshpande | Author(s): K. Patel, L. Litzky
- Abstract
- Presentation
Background:
Advances in understanding of immune checkpoint inhibitors, have resulted in FDA approvals of anti-PD-1/PD-L1 inhibitor therapies for clinical use in nonsmall cell lung cancer (NSCLC). Detecting PD-L1 expression, as a predictive biomarker using companion diagnostic test (PD-L1 IHC 22C3 pharmDx), helps us identify NSCLC patients eligible for anti-PD-1 therapy (Pembrolizumab). Tumor Proportion Score (TPS) >50% and TPS >1% qualitatively estimated, by PD-L1 IHC 22C3 pharmDx test, are cut-offs which indicate use of Pembrolizumab as monotherapy in first line (TPS >50%) or second line (TPS >1%) settings for NSCLC. Intratumoral heterogeneity of PD-L1 expression in NSCLC is known. Approximately 60% of NSCLC present with advanced stage of disease. Tissue sampling of metastatic sites for initial diagnosis using core needle biopsy or fine needle aspiration techniques is common clinical practice. Significant body of literature is not available to address the issue of PD-L1 expression at metastatic sites and its concordance/discordance with primary lung tumor. We decided to look at cases with repeat request for PD-L1 testing at alternate sites or on subsequent tumor resections.
Method:
Our departmental anatomic pathology database was queried to search for NSCLC cases wherein PD-L1 immunohistochemistry was performed in our laboratory using companion diagnostic test (PD-L1 IHC 22C3 pharmDx) on AutoLink 48 autostainer as per protocol, and reported by one of our pathologists. Analysis was performed to determine additional PD-L1 IHC test requests for same patient and subsequent subgroup analysis to determine test results and other parameters such as type of specimens, tumor sites, and concordant/discordant results.
Result:
PD-L1 IHC 22C3 pharmDx test request was received on 460 NSCLC patient specimens in last six months. Of these, in twenty-five patients testing was attempted/performed on two tissue specimens, with final results reported in eighteen patients. Discordant results are noted in four patients (22.22%). In an additional patient, reported level of PD-L1 expression (low) was concordant; however reported TPS (5% & 45%) was different.
Conclusion:
Currently, in routine clinical practice, PD-L1 IHC test results are usually reported on a single tissue specimen. However, when tested on separate site/s or specimen type/s, our results suggest, that one can observe discordant results. At the lower end of results (PD-L1 negative or low expression), this can impact therapeutic decisions. Though a larger study is necessary to address this issue, one can suggest, that PD-L1 IHC testing should be performed on multiple site specimens, especially when temporally separated, in best interests of patient care.
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MA 06.04 - Development of Next-Generation Sequencing Based Cancer Panel and Its Clinical Implications in Lung Cancer (ID 9003)
16:00 - 16:05 | Presenting Author(s): Yoohwa Hwang | Author(s): Kwanyong Hyun, S. Im, N. Kwon, Y.J. Jung, S.B. Lee, Y.H. Kim, S. Park, H.J. Lee, In Kyu Park, Chang Hyun Kang, Young Tae Kim
- Abstract
- Presentation
Background:
To search actionable driver mutations, various cancer panels using next-generation target sequencing technologies are rapidly developed and adopted in the treatment of lung cancer. We developed a new cancer panel to detect 313 coding gene mutations, 30 fusion and 3 exon-skipping genes including either known or potential target genes. Performance of the panel was tested on our archived lung cancer tissue bank samples.
Method:
Two hundreds and two samples were tested (male 118, female 84, median age 63 (30-84) years). Histologic cell types were mainly adenocarcinoma (adenocarcinoma 158, squamous cell 25, large cell 6, sarcomatous 3, small cell 1, and mixed cell types 9).
Result:
With our cancer panel, 139 samples (68.8%) were identified to have mutations including 88 EGFR, 23 KRAS, 8 MET mutations, 7 ALK, 6 RET, 3 ROS1, 6 rare fusions (PTEN, BRAF, MET, CBFB, EWSR1, BCR), and 18 CNV alterations. Medical records revealed that traditional single-site tests including Sanger sequencing of EGFR, KRAS mutations and either immunohistochemical stain or FISH test for ALK or RET fusion had been performed in 191 patients. Among those patients, we identified 102 pathogenic mutations (53.4%) including 80 EGFR, 14 KRAS mutations, 6 ALK, and 2 RET fusions. Conventional single-site test results matched with that of cancer panel in 139 samples (72.8%). Cancer panel detected additional mutations in 48 samples (25.1%; 38 from the single-site test negative and 10 from positive samples). In two samples, the results showed discrepancy while in the other two, mutations were detected only in single-site test. However additional tests revealed cancer panel results to be correct. Excluding 4 patients with M1 stage, 198 patients’ long-term survival were analyzed according to the mutational status. In Cox’s proportional hazard model, presence of EGFR mutation was the only prognostic marker that predicted long-term survival along with clinical variables such as age, pT-stage, and pN-stage.
Conclusion:
In our results, we confirmed superior accuracy of our cancer panel compared to the traditional single-site tests. Furthermore, the new cancer panel discovered novel mutations, of which significance requires future functional investigation and potential development of new target agents.
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MA 06.05 - Discussant - MA 06.01, MA 06.02, MA 06.03, MA 06.04 (ID 10770)
16:05 - 16:20 | Presenting Author(s): Giuseppe Giaccone
- Abstract
- Presentation
Abstract not provided
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MA 06.06 - Assessment of RANK Prevalence and Clinical Significance in the NSCLC European Thoracic Oncology Platform Lungscape Cohort (ID 10006)
16:20 - 16:25 | Presenting Author(s): Erik Thunnissen | Author(s): U. Dafni, Lukas Bubendorf, A. Warth, W. Biernat, S. Pokharel, Rafal Dziadziuszko, H. Dienemann, R. Cheney, N. Marti, M. Kassapian, Stephen P Finn, Keith M Kerr, R. Kammler, Rolf A Stahel, Solange Peters, F. Etop Lungscape
- Abstract
- Presentation
Background:
Receptor Activator of Nuclear Factor κappa-B (RANK) is a pathway involved in bone homeostasis. Recent evidence suggests that RANK signalling may also play a role in bone metastasis, and primary breast and lung cancers. The European Thoracic Oncology Platform (ETOP) Lungscape project allows evaluation of the prevalence of RANK expression and its clinical significance in a cohort of surgically-resected NSCLCs.
Method:
RANK expression was assessed on tissue microarrays (TMAs) using immunohistochemistry. Up to 4 cores per patient were analysed based on sample acceptance criteria. An H-Score (staining intensity + % cells stained) was used to assess RANK expression (positivity), as defined by at least 1 core with any degree of positive staining. Prevalence of RANK positivity and its association with clinicopathological characteristics, other cancer-related biomarkers (IHC ALK/MET/PTEN/PD-L1 expression and EGFR/KRAS/PIK3CA mutations) and patient outcome [Relapse-free Survival (RFS), Time-to-Relapse (TTR), Overall Survival (OS)] was explored in a subset of the ETOP Lungscape cohort. The prevalence of RANK overexpression (proportion of positive cancer cells ≥50%) was also investigated.
Result:
RANK expression was assessed in patients from 3 centers, a total of 402 from the 2709 patients of the Lungscape cohort, with median follow-up 44 months; 32.6% female, 40.8/54.2/5.0% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 44.8/28.4/26.9% with stage I/II/III, 20.6/57.7/18.9% current/former/never smokers (and 2.7% with unknown smoking status). Median was 74 months for both RFS and OS, while median TTR was not reached. Prevalence of RANK positivity was 26.6% (107 of the 402 cases), with 95% confidence interval (95%CI):22.4%-31.2%; significantly higher in AC: 48.2% (79 of 164 cases), 95%CI:40.3%-56.1%; vs SCC: 9.2% (20 of 218 cases), 95%CI:5.7%-13.8%; (p<0.001). RANK positivity was more frequent in females (38.9% vs 20.7% in males, p<0.001) and tumors≤4cm (30.7% vs 21.1% in tumors>4cm, p=0.031). Significant associations were also detected between RANK and PTEN expression in AC (RANK positivity 57.4% in PTEN expression vs 30.5% in PTEN loss; p=0.0011) and with MET status in SCC (RANK positivity 27.8% in MET+ vs 7.6% in MET-; p=0.016). No association with outcome was found. RANK overexpression was identified in 43 (10.7%; 95%CI: 7.9%-14.1%) cases.
Conclusion:
In this early-stage NSCLC cohort, RANK positivity (26.6% overall) is found to be significantly more common in adenocarcinomas (48.2%), females, patients with tumors of smaller size, with PTEN expression (in SCC) and MET positivity (in AC). No prognostic significance of RANK expression was found. Analysis of additional cases is ongoing and results will be presented.
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MA 06.07 - JAK Pseudokinase Domain Variants Highlight nRTK nsSNPs Identified with Next-Generation Sequencing in NSCLC Patients (ID 10429)
16:25 - 16:30 | Presenting Author(s): Matthew K Stein | Author(s): L.K. Morris, M.G. Martin
- Abstract
- Presentation
Background:
Non-receptor tyrosine kinase (nRTK) pathways are aberrantly activated in cancer, and mutations in nRTKs have potential therapeutic and prognostic importance. Tumor profiling with next-generation sequencing (NGS)enables a gene’s entire coding sequence to be evaluated, facilitating the identification of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in nRTKs.
Method:
We searched nsSNPs in 14 nRTKs in the tumors of advanced NSCLC patients (pts) at our institution that received NGS with Caris from 2013-2015. All mutations test-defined as pathogenic (PATH) or nsSNPs labelled variants of undetermined significance (VUS) were included. To classify VUS, nsSNPs underwent PolyPhen-2’s in silico analysis to predict pathogenicity. Any VUS predicted-damaging with PolyPhen-2 we denote pnsSNP. nsSNPs were then classified as occurring within or outside of the tyrosine kinase domain (TKD); JAK1-3 pseudokinase domain (PSKD) lesions were also described.
Result:
157 NSCLC pts were identified with median age 65 (range 26-85); 51% were male; 65% Caucasian, 35% African-American. 98 nRTK variants were found (93 nsSNPs and 5 PATHs). 5/5 PATHS were PIK3CA. 31/93 (33%) nsSNPs were pnsSNPs and spread among 30 pts. pnsSNPs were found in 12/14 nRTKs with median 2 (range 0-6). The most frequent were JAK3 (6/20 nsSNPs were pnsSNPs), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). 66% were extra-TKD (28% were pnsSNP), 23% TKD-restricted (44%) and 11% PSKD of JAK1-3 (100%). There were 6 N-lobe PSKD, 3 C-lobe PSKD and 1 C-lobe TKD JAK1-3 pnsSNPs (Table 1) at PSKD-TKD contact sites known to harbor the majority of activating JAK mutations. 6/12 JAK pnsSNPs were in pts whose tumors were EGFR-/KRAS-/ALK-/ROS-/PDL1-. Table 1: JAK1-3 pnsSNPs in NSCLC patients.JAK VUS; allele frequency Location Accession Number; Minor allele frequency (ExAC) Histology Age, race, gender Genomics (EGFR, KRAS, ALK or ROS1-rearranged, PDL1 (%)) JAK1 D660N; 66% PSKD; N-lobe rs368904859; T=2.0e-5 Adeno-carcinoma 66, C, M Negative P674S; 9% PSKD; N-lobe None Squamous 76, C, M PDL1+ (5%) D739N; 47% PSKD; N-lobe rs759709239; T=3.3e-5 Large cell 43, C, M KRAS+ JAK2 E621D; 30% PSKD; N-lobe None Unspecified 65, AA, M Negative D686H; 13% PSKD; N-lobe None Adeno-carcinoma 55, C, M Negative C1105F; 41% TKD; C-lobe None Adeno-carcinoma 73, C, F KRAS+, ROS1-rearranged JAK3 V55E; 13% FERM None Adeno-carcinoma 74, C, F Negative Y105H; 21% FERM None Squamous 68, C, F PDL1+ (20%) R537Q; 47% PSKD; N-lobe rs587778413; T=4.1e-5 Adeno-carcinoma 60, C, F PDL1+ (65%) L702P; 53% PSKD; C-lobe rs772117537; G=1.7e-5 Squamous 80, C, M Negative P745L; 50% PSKD; C-lobe rs776106625; A=8.3e-6 Adeno-carcinoma 68, C, M EGFR+ (E746_A750del) L788I; 7% PSKD; C-lobe None Squamous 68, AA, M Negative
Conclusion:
>19% NSCLC pts held a pnsSNP with 77% occurring outside of the TKD-proper. The majority of JAK1-3 pnsSNPs localized to the PSKD; their frequency and functional impact should be examined on a larger scale.
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MA 06.08 - Lung Cancer Patients with Germline Mutation: A Retrospective Study (ID 8670)
16:30 - 16:35 | Presenting Author(s): Sandipkumar Patel | Author(s): T. Shukuya, K. Shane-Carson, K. He, E. Bertino, K. Shilo, G. Otterson, David P Carbone
- Abstract
- Presentation
Background:
Genetic testing for alterations of oncogenic driver genes has become essential and standard in clinical practice. Germline mutations predisposing to lung cancer are rare, but there have been reports regarding germline mutations in EGFR, HER2, BRCA2, CDKN2A, BAP1, SFTPA2, and PARK2. Next generation sequencing is being introduced to clinical practice of lung cancer, enabling investigation of multiple oncogenic driver genes simultaneously. In addition, liquid biopsy, which analyzes cell free DNA in blood, increases the opportunity to detect germline mutations in lung cancer patients. We examined the frequency and characteristics of lung cancer patients with germline mutations.
Method:
Between February 2012 and January 2017, 3,869 patients with a diagnosis of lung cancer were seen by Division of Medical Oncology in Ohio State University. Of these, seven were found to have germline mutations. The patient characteristics and treatment outcomes were retrospectively investigated.
Result:
Table 1 shows characteristics and treatment outcomes of the seven lung cancer patients with germline mutations. Median age was 50 (range, 34-72). Three had BRCA2 germline mutations, two had germline TP53 mutations(of which one patient also had a PARK2 mutation), one had a BRCA1 mutation, and one had an EGFR mutation. Testing for other oncogenic drivers were done in five patients, and interestingly, four patients had oncogenic driver mutations. The frequency of detecting germline mutations in lung cancer patients has been increasing in recent years, but is often unrecognized by providers. In our series, one patient was found to have a germline mutation by Foundation ONE, and another was found to have a germline mutation by Foundation ACT.Year Age Sex Histology Stage Smoking hisory Other cancer Germline mutation Other somatic gene alteration Targeted therapy Respnse 2014 37 F Ad IA former smoker (2py) No BRCA2 not evaluated － － 2014 72 F Ad IV former smoker breast cancer, lung cancer EGFR T790M EGFR G719S rociletinib SD 2015 69 F Ad IIIA former smoker breast cancer, uterine cancer BRCA2 EGFR L858R － － 2015 50 F SCLC IA never smoker breast cancer TP53 Y236*, PARK2 Q347* FGFR2 amplification － － 2016 34 F Ad IV former smoker No BRCA2 L3061* MET 3028+2T>C crizotinib PR 2016 44 F Ad IV never smoker orbital rhabdomyosarcoma TP53 ALK fusion crizotinib PR 2017 62 F SCLC IV former smoker breast cancer BRCA1 not evaluated － －
Conclusion:
Introduction of next generation sequencing technology and liquid biopsies to clinical practice can raise the probability of detecting germline mutations in lung cancer patients. Clinicians should be alert to the potential existence and importance of germline mutations in their lung cancer patients.
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MA 06.09 - Detection of EGFR T790M Mutations by Four Testing Platforms in ctDNA from Chinese Patients with Advanced NSCLC (ID 8615)
16:35 - 16:40 | Presenting Author(s): Xu-Chao Zhang | Author(s): Z. Liang, Y. Chen, H. Zhang, G. Wu, Y. Lu, Z. Liang, Ying Cheng, Y. Hu, J. Wang, J. Ying, W. Liu, Y. Wu
- Abstract
- Presentation
Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) targeting sensitizing mutations and T790M mutation, which causes ~60% of acquired resistance after first-line TKI treatment. T790M testing provides guidance for second-line treatment decisions. This study evaluated four T790M detection platforms using plasma circulating tumor DNA (ctDNA).
Method:
ADELOS is a multicentre, open-label, single-arm study (NCT 02997501) of Chinese patients with advanced non-small cell lung cancer (NSCLC) and progression on previous EGFR-TKI treatment. Plasma ctDNA testing for T790M was performed by Cobas[®] real-time polymerase chain reaction (PCR), super amplification refractory mutation system (Super-ARMS) PCR, capture-based next-generation sequencing (NGS, 168 gene panel), and QuantStudio3D digital PCR (3D dPCR). T790M-positive patients detected by these platforms received osimertinib 80 mg/day orally until progression. Matched tissue re-biopsy samples were also tested by Cobas[®] or NGS. The primary objectives were to evaluate concordance between the Cobas[®] test and the other three platforms and to assess the efficacy of osimertinib in ctDNA T790M-positive patients.
Result:
Of 256 patients enrolled, 181 were ctDNA T790M-positive, among which 167 received osimertinib monotherapy. T790M plasma positive rate was from 37.4% to 63.5% (Cobas[®]< Super-ARMSCobas[®] PCR n=254 Super-ARMS PCR n=256 NGS n=256 3D dPCR n=255 T790M detected, n (%) 95 (37.4) 108 (42.2) 138 (53.9) 162 (63.5) Comparison vs Cobas plasma test (n=254) Concordance %, (95% CI) -- 91.3 (87.2, 94.5) 82.7 (77.5, 87.1) 66.8 (60.6, 72.6) Sensitivity %, (95% CI) -- 94.7 (88.1, 98.3) 98.9 (94.3, 100.0) 90.5 (82.8, 95.6) Specificity %, (95% CI) -- 89.3 (83.4, 93.6) 73.0 (65.3, 79.7) 52.5 (44.4, 60.5) Comparison vs Tissue (n=73) Concordance %, (95% CI) 67.1 (55.1, 77.7) 64.4 (52.3, 75.3) 69.9 (58.0, 80.1) 61.6 (49.5, 72.8) Sensitivity %, (95% CI) 57.1 (42.2, 71.2) 61.2 (46.2, 74.8) 71.4 (56.7, 83.4) 69.4 (54.6, 81.7) Specificity %, (95% CI) 87.5 (67.6, 97.3) 70.8 (48.9, 87.4) 66.7 (44.7, 84.4) 45.8 (25.6, 67.2)
Conclusion:
Super-ARMS showed highest concordance and NGS showed highest sensitivity compared with Cobas® plasma T790M testing. Concordance and specificity of 3D dPCR was lower using other ctDNA tests or tissue as reference. Subsequent osimertinib treatment in these patients will justify the effectiveness of T790M testing by different technologies.
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MA 06.10 - Discussant - MA 06.06, MA 06.07, MA 06.08, MA 06.09 (ID 10771)
16:40 - 16:55 | Presenting Author(s): K. Soejima
- Abstract
- Presentation
Abstract not provided
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MA 06.11 - Distinct Mutational Landscape and Evolutionary Trajectories of Brain Metastasis and Liver Metastasis in Lung Adenocarcinoma (ID 9282)
16:55 - 17:00 | Presenting Author(s): Tao Jiang | Author(s): B. Du, Caicun Zhou
- Abstract
- Presentation
Background:
Distant metastases confer mainly resistance to improving the long-term survival of patients with lung cancer. The major reason was that the genetic heterogeneity and evolutionary patterns between primary tumor and their distant metastases or among distinct metastatic sites remains poorly understood. The current study aimed to depict the distinct mutational landscape of primary lung adenocarcinoma and their distant metastases (brain or liver) and reconstruct the evolutionary history of metastases.
Method:
Seventeen patients with primary lung adenocarcinoma and distant metastases [5 with primary lesion and matched brain metastases (BM), 6 with primary lesion and matched liver metastases (LM), 6 with sole BM] were included. All tissues (by either biopsy or surgical resection) and matched peripheral blood samples were collected before systemic treatment. We performed whole-exome (150×) and targeted 416-gene panel sequencing for these samples.
Result:
In the matched cases, the mutational landscape of primary lesions for BM was distinctly different from those for LM. Compared to the primary lesions, BM had the significantly different patterns of somatic genome alterations while LM had the similar ones. In six cases with sole BM, both intratumoral and intertumoral genetic homogeneity of BM were observed. By using a set of genes which were frequently found in the primary lesions, we can clearly segregate the copy number variations (CNV) pattern of patients with BM from those with LM. Moreover, when we performed the hierarchical clustering based on these genes, we saw clear segregation between BM and LM. Patients with BM had dramatically higher tumor mutational burden (TMB) than those with LM in both primary (P < 0.01) and metastatic lesions (P < 0.001). Significant differences in TMB were also observed between primary and metastatic lesions in patients with BM (P < 0.001) instead of LM (P > 0.05). Phylogenetic analysis showed that LM followed the liner progression whereas BM followed the parallel progression. In patients with sole BM, both intratumoral and intertumoral lesions have a monoclonal origin and descend from a common ‘metastatic precursor’.
Conclusion:
The current evidence suggested that BM had distinctly different mutational landscape from LM in lung adenocarcinoma. Patients with BM had higher TMB than those with LM. BM followed the parallel progression whereas LM followed the liner progression. Intratumoral and intertumoral lesions of BM had genetic homogeneity and originated from the same precursor. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung adenocarcinoma and distant metastases.
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- Abstract
- Presentation
Background:
A subset of lung adenocarcinoma is transformed by fusion genes, i..e. EML4-ALK, KIF5B-RET. Practically, fusion genes are detected using PCR, FISH and/or RNAseq. Although TCGA project sequenced many lung cancer genomes, little is known about the genomic landscape of driver-fusion positive lung adenocarcinoma. In particular, we wondered the frequency and impact of complex genomic rearrangements, such as chromothripsis, chromoplexy, and chromoanasynthesis, in the pathogenesis of lung adenocarcinomas.
Method:
We performed whole-genome sequencing analyses for 38 pairs of driver-fusion-positive lung adenocarcinoma and its normal counterpart samples. These 38 tumors harbored one driver fusion genes such as EML4-ALK, KIF5B-RET, and CD74-ROS1. We mapped reads using Burrows-Wheeler Aligner, and processed aligned reads with Picard and Genome Analysis Toolkit. We analyzed tumor purity, ploidy and copy number variations using Sequenza. We called point mutations and indels using Mutect and Strelka. And we also called structural variations using Delly.
Result:
The number of somatic point mutations of these samples was lower than general lung adenocarcinomas. Mutational signature analysis revealed that signature 1 and 5 are major factors in these samples. More than 70% of driver fusion genes were established by complex genomic rearrangements rather than simple events. Based on the copy number change and the microhomology, replication-based mechanism is presumed to be a main cause of these complex events. Somatic mutation on TP53 was rare in these samples.
Conclusion:
Much of driver fusion genes in lung adenocarcinomas are made by complex genomic rearrangements. TP53-independent replication-based mechanism is critical to these phenomena.
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MA 06.13 - Direct Metabolomic Profiling of Lung Cancers (ID 10319)
17:05 - 17:10 | Presenting Author(s): Elizabeth Starren | Author(s): J. McDonough, Andrew G Nicholson, M. Moffatt, W. Cookson
- Abstract
- Presentation
Background:
Lung cancers rely on metabolites to fuel growth and to signal to surrounding tissues. Systematic study of these molecules may identify biomarkers for early diagnosis and novel pathways tractable to therapy. Previous studies of the metabolome in lung cancer have been confined to the serum and to sputum. We have therefore interrogated biochemical profiles in human lung cancers and matched adjacent normal tissues with the aim of identifying metabolites and metabolic signatures associated with lung cancer.
Method:
Global biochemical profiles were determined in human lung tumour and adjacent normal tissue. 12 tumours and 12 matched normal samples were tested from adenocarcinoma (ADC) patients, and 12 tumour/normal pairs were similarly tested from squamous cell carcinoma (SCC) patients. Samples were analysed on the Metabolon GC/MS and LC/MS/MS platforms, with the inclusion of technical replicates.
Result:
Application of PCA as a function of the tissue metabolome demonstrated that the normal, ADC and SCC groups were clearly distinguishable. We observed general metabolic changes associated with tumour tissue (q<0.10 throughout), with reductions in glucose and concomitant elevations in sorbitol and lactate indicative of Warburg metabolism in both ADC and SCC. Levels of reduced glutathione (GSH) were higher in SCC compared to ADC and normal tissue, indicating elevated antioxidant capacity in SCC. Conversely, alternative antioxidants including taurine, biliverdin, ascorbate, alpha- and gamma-tocopherol, and ergothioneine were higher in ADC than SCC. The neurotransmitters serine, NAA, GABA, and NAAG were also significantly elevated in ADC but not SCC. Finally, elevations in prostaglandin D2 and 6-keto prostaglandin F1alpha were confined to SCC and prostaglandin E2 was elevated to a much greater extent (8-fold versus 3-fold) in SCC vs. ADC, as compared respectively to normal lung tissue.
Conclusion:
Results from this pilot global profiling study confirm greater glucose utilization and lactate production, increased fatty acid synthesis, and changes in membrane biology in ADC and SCC. However, changes in glutathione metabolism, antioxidant capacity, neuroactive metabolites, and inflammation appear to vary according to tumour type. A larger scale study may identify differential therapeutic avenues and response to therapy. Profiling of matched serum/plasma from lung cancer patients may allow for identification of disease-specific biomarkers to supplement histological-based diagnostic techniques.
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MA 06.14 - Oncogenic SOS1 Mutations in Lung Adenocarcinoma (ID 9166)
17:10 - 17:15 | Presenting Author(s): Diana Cai | Author(s): P.S. Choi, Matthew Meyerson
- Abstract
- Presentation
Background:
Lung adenocarcinomas are characterized by genetic alterations along receptor tyrosine kinase pathways. Around 50% of lung adenocarcinomas contain alterations in KRAS and EGFR alone. Nonetheless, genetic drivers in a large proportion of other cases remain to be determined. Recent exome sequencing analysis of lung adenocarcinomas in our lab has identified SOS1, a guanine nucleotide exchange factor, as being significantly mutated in lung cancers lacking canonical oncogenic mutations. However, the functional significance of the mutations is unclear.
Method:
In vitro cellular assays as well as in vivo transplatation experiments were performed to determine the phenotype of SOS1 mutants. Biochemical approaches were used to determine the mechanism by which SOS1 mutants confer an oncogenic phenotype. RNA sequencing of SOS1 mutant cells was performed to transcriptionally profile the cells, and inhibitors of the RTK/Ras/MAPK pathway were tested for their efficacy against SOS1 mutants.
Result:
We demonstrate that ectopic expression of mutated SOS1 induces anchorage-independent cell growth in vitro and tumor formation in vivo. Biochemical experiments suggest mutant SOS1 drives over-activation of the Ras pathway, and through RNA sequencing, we identify an upregulation of MYC targets in cells expressing mutant SOS1. Furthermore, we demonstrate that cancer cells with mutant SOS1 are dependent on SOS1 for survival and are also sensitive to inhibitors of the MAPK pathway.
Conclusion:
Our work provides experimental evidence for the role of SOS1 as a novel oncogene and suggests possible therapeutic mechanisms to target SOS1-mutated cancers.
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MA 06.15 - Discussant - MA 06.11, MA 06.12, MA 06.13, MA 06.14 (ID 10772)
17:15 - 17:30 | Presenting Author(s): Akihiko Yoshida
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.06 - Assessment of RANK Prevalence and Clinical Significance in the NSCLC European Thoracic Oncology Platform Lungscape Cohort (ID 10006)
16:20 - 16:25 | Author(s): Keith M Kerr
- Abstract
- Presentation
Background:
Receptor Activator of Nuclear Factor κappa-B (RANK) is a pathway involved in bone homeostasis. Recent evidence suggests that RANK signalling may also play a role in bone metastasis, and primary breast and lung cancers. The European Thoracic Oncology Platform (ETOP) Lungscape project allows evaluation of the prevalence of RANK expression and its clinical significance in a cohort of surgically-resected NSCLCs.
Method:
RANK expression was assessed on tissue microarrays (TMAs) using immunohistochemistry. Up to 4 cores per patient were analysed based on sample acceptance criteria. An H-Score (staining intensity + % cells stained) was used to assess RANK expression (positivity), as defined by at least 1 core with any degree of positive staining. Prevalence of RANK positivity and its association with clinicopathological characteristics, other cancer-related biomarkers (IHC ALK/MET/PTEN/PD-L1 expression and EGFR/KRAS/PIK3CA mutations) and patient outcome [Relapse-free Survival (RFS), Time-to-Relapse (TTR), Overall Survival (OS)] was explored in a subset of the ETOP Lungscape cohort. The prevalence of RANK overexpression (proportion of positive cancer cells ≥50%) was also investigated.
Result:
RANK expression was assessed in patients from 3 centers, a total of 402 from the 2709 patients of the Lungscape cohort, with median follow-up 44 months; 32.6% female, 40.8/54.2/5.0% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 44.8/28.4/26.9% with stage I/II/III, 20.6/57.7/18.9% current/former/never smokers (and 2.7% with unknown smoking status). Median was 74 months for both RFS and OS, while median TTR was not reached. Prevalence of RANK positivity was 26.6% (107 of the 402 cases), with 95% confidence interval (95%CI):22.4%-31.2%; significantly higher in AC: 48.2% (79 of 164 cases), 95%CI:40.3%-56.1%; vs SCC: 9.2% (20 of 218 cases), 95%CI:5.7%-13.8%; (p<0.001). RANK positivity was more frequent in females (38.9% vs 20.7% in males, p<0.001) and tumors≤4cm (30.7% vs 21.1% in tumors>4cm, p=0.031). Significant associations were also detected between RANK and PTEN expression in AC (RANK positivity 57.4% in PTEN expression vs 30.5% in PTEN loss; p=0.0011) and with MET status in SCC (RANK positivity 27.8% in MET+ vs 7.6% in MET-; p=0.016). No association with outcome was found. RANK overexpression was identified in 43 (10.7%; 95%CI: 7.9%-14.1%) cases.
Conclusion:
In this early-stage NSCLC cohort, RANK positivity (26.6% overall) is found to be significantly more common in adenocarcinomas (48.2%), females, patients with tumors of smaller size, with PTEN expression (in SCC) and MET positivity (in AC). No prognostic significance of RANK expression was found. Analysis of additional cases is ongoing and results will be presented.
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PC 03 - 3-2 Which Do you Prefer: Liquid Biopsy or Tissues Biopsy for Molecular Diagnosis? (ID 596)
- Event: WCLC 2017
- Type: Pros & Cons
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Rafal Dziadziuszko, Y.O. Tan
- Coordinates: 10/18/2017, 11:40 - 12:30, Room 303 + 304
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PC 03.04 - Tissues Biopsy (ID 7833)
12:00 - 12:20 | Presenting Author(s): Keith M Kerr
- Abstract
- Presentation
Abstract not provided
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PL 03 - Immunology in Lung Cancer Update 2017 (ID 584)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:David P Carbone, Keunchil Park
- Coordinates: 10/18/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 03.03 - Blueprint 2: PD-L1 Immunohistochemistry Comparability Study in Real-Life, Clinical Samples (ID 7836)
09:05 - 09:25 | Author(s): Keith M Kerr
- Abstract
- Presentation
Abstract:
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each having been developed as a predictive biomarker for specific anti-PD-1/PD-L1 immunotherapies.[1] The Blueprint phase 1 was conducted as a feasibility study to assess the staining (analytical) comparability of four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263) that were developed for their respective immune checkpoint inhibitor therapies.[2] Without correlation with treatment outcome, the study also assessed the putative diagnostic performance of these assays through comparisons of PD-L1 status classification above and below selected expression cutoffs associated with the clinical use of various assays. Serial sections from paraffin blocks of 39 resected non-small cell lung cancers (NSCLC) were stained using assays that were used in the clinical trials, and three experts in interpreting the four respective assays independently assessed the percentages of tumor and immune cells staining positive at any intensity. The results demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells, while the SP-142 PD-L1 assay appeared to stain less tumor cells compared to the other assays.[2] In contrast, all assays stained tumor infiltrating immune cells, but with poor concordance between assays. The phase 1 study had several limitations: (1) samples were obtained from a commercial source and did not necessarily reflect the real-world samples tested clinically, and (2) the number of pathologists involved in the scoring was small. In addition, a fifth PD-L1 assay (73-10) has since been developed as a potential biomarker for avelumab (EMD Serono/Merck KGaA/Pfizer). The goals of Blueprint phase 2 are: (1) to validate the assay comparability results obtained in Blueprint phase 1 study using real world clinical lung cancer samples and all five clinically used PD-L1 assays (28-8, 22C3, SP142, SP263, and 73-10), (2) to assess the comparability and heterogeneity of PD-L1 assay results in surgical tumor resection, core needle and FNA samples prepared from same tumor, and (3) to assess the concordance of PD-L1 scoring by pathologists from around the world using standard light microscopy vs. digital images accessed by a web-based system. In blueprint phase 2A, 18 participating pathologists, with respective institutional research ethics board approval, contributed unstained serial sections from altogether 81 lung cancer cases that came through routine clinical practice. These included 40 adenocarcinomas, 25 squamous cell carcinomas, 5 poorly differentiated non-small cell carcinoma and 11 small cell carcinomas. The cases included resected tumor (n=20), core/bronchial biopsies (n=20), tumor positive lymph node biopsy/resection (n=20) and cytology cell block (n=21) samples. In blueprint phase 2B, 9 pathologists prepared from 30 freshly resected NSCLC specimens, paraffin blocks of matched resection, core needle and fine needle aspiration samples. Each slide set of 81 cases from phase 2A were stained with the FDA-cleared (28-8, 22C3, SP142) or clinical trial (SP263 and 73-10) PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. The slides were scored by 24 experienced pulmonary pathologists (IASLC Pathology committee Blueprint phase 2 members),[4] all having received group training on scoring the PD-L1 IHC on tumor and immune cells. PD-L1 stained tumor cells were scored as continuous number (0% to 100%), and placed into 1 of 7 categories (<1%, 1-4%, 5-9%, 10-24%, 25-49%, 50-79%, 80-100%). These categories represent cut-offs that have been used in various immune checkpoint inhibitor trials. All assays were also scored for immune cell PD-L1 staining based on the scoring system developed for the SP-142 assay. As only one set of glass slides is available for each assay, each pathologist was randomly assigned to conduct the scoring using microscope (2 glass assays) or by web-based digital images (3 digital assays). The inter-assay concordance of PD-L1 staining on tumor cells and tumor infiltrating immune cells will be assessed using the mean scores from all pathologists. The large sample size scores should provide more reliable data on their analytical comparability. Inter-pathologist concordance results should provide evidence on reliability of scoring with different cut-points. Importantly, the above concordance results across different sample types should also provide insights on potential variability and feasibility in PD-L1 scoring across different sample types, especially cytology samples. This may then allow for a broad implementation strategy on PD-L1 testing in clinical practice. The results of phase 2A will be presented at the meeting.IASLC Pathology Committee Blueprint phase 2 members: Mary-Beth Beasley, Alain Borczuk, Johan Botling, Lukas Bubendorf, Gang Chen, Lucian Chirieac, Teh-Ying Chou, Jin-Haeng Chung, Sanja Dacic, Fred R. Hirsch, Keith M. Kerr, Mari Mino-Kenudson, Sylvie Lantuejoul, Andre Moreira, Andrew Nicholson, Masayuki Noguchi, Guiseppe Pelosi, Claudia Poleri, Prudence Russell, Jennifer Sauter, Erik Thunnissen, William D. Travis, Ming S. Tsao, Ignacio Wistuba, Murry Wynes, Yasushi Yatabe, Hui Yu. References: IASLC ATLAS of PD-L1 Immunohistochemistry Testing in Lung Cancer. M.S.Tsao, K.M. Kerr, Y. Yatabe, S. Dacic, F.R. Hirsch (Editors), International Association for Study of Lung Cancer (IASLC) Press, 2017 Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the "Blueprint PD-L1 IHC Assay Comparison Project". J Thorac Oncol. 2017 Feb;12(2):208-222. Feng Z, Schlichting M, Helwig C, et al. Comparative study of two PD-L1 expression assays in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 35, 2017 (suppl; abstr e20581)
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