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N. Motoi
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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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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-009 - Accumulation of Mutations in Background Normal Lung Tissue Constitutes a Major Lung Cancer Risk (ID 9240)
09:30 - 09:30 | Author(s): N. Motoi
- Abstract
Background:
Accumulation of mutations in normal-appearing lung tissue is believed to be important for development of lung cancer, and to be heavily influenced by smoking. However, their very low levels have been hampering their measurement, and their links with cancer risk and smoking history have not been demonstrated. To overcome this limitation, we recently developed a novel method that can measure levels of somatic mutations at 10[-6]/bp levels [Yamashita et al., Cancer Lett, online].
Method:
Eleven healthy lung tissues (Group1:G1) were collected from the normal lungs of metastatic lung cancer patients without smoking history, and 11 exposed lung tissues (Group2:G2) were collected from those with smoking history. 11 high-risk lung tissues (Group3:G3) were collected from the lungs of lung cancer patients with smoking history. A sequence library (15,552 bases of 291 regions of 55 cancer-related genes) was prepared by multiplex PCR using 100 DNA molecules, and was sequenced using a next generation sequencer.
Result:
The accumulation levels of mutations were significantly higher in G3 (2.7 ± 0.8×10[-5] mutations/base) than those in G1 (1.8 ± 0.5×10[-5] mutations/base) (p = 0.0189). The accumulation appeared to be associated with smoking history (OR = 3.2; 95 % CI = 0.54–18.98), and the C>T mutation, a signature reported in cancer tissues [Alexandrov et al., Science, 354:2016], was significantly more frequent in G2 than in G1. The GCC>GTC and CCC>CTC mutations, a signature of exposure to the nitrosamines contained in tobacco smoke, were significantly more frequent in G2 and G3.
Conclusion:
The accumulation level of mutations was increased in exposed lung tissues, and the mutation accumulation was associated with cancer risk.
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P1.05 - Early Stage NSCLC (ID 691)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.05-002 - Characteristics and Prognosis of Ground Glass Opacity Predominant Primary Lung Cancer Larger Than 3.0 Cm on Thin-Section Computed Tomography (ID 7396)
09:30 - 09:30 | Author(s): N. Motoi
- Abstract
Background:
The solid component size of lung cancer showing ground glass opacity (GGO) on thin-section computed tomography (TSCT) has been regarded as a more important preoperative prognostic indicator than the whole tumor size. Moreover, previous study revealed that radiological early lung adenocarcinoma which has an excellent prognosis could be defined as an adenocarcinoma 3.0 cm or less with consolidation to tumor ratio (CTR) of 0.5 or less on TSCT. However, the characteristics and the prognosis of lung cancer larger than 3.0 cm showing GGO remain unclear.
Method:
From January 2002 through June 2012, we retrospectively reviewed 3,735 consecutive patients with primary lung cancer, which underwent complete resection at our institution. We extracted 686 (18.4%) patients with lung cancer larger than 3.0 cm in diameter and evaluated their preoperative TSCT findings. In total, 160 (4.3%) lung cancers larger than 3.0 cm showing GGO were eligible for this analysis. We divided the 160 lesions into three types based on CTR; type A: 0
Result:
Type A, type B, and type C were found in 16 (10%), 37 (23%), and 107 (67%) lesions, respectively. Regarding the operative mode, all patients except for two patients underwent lobectomy. All patients except for one patient was diagnosed as having adenocarcinoma. Lymph node metastasis was seen in none of types A and B, in 34 (32%) lesions of type C. Lymphovascular invasion was seen in 73(68%) lesions of type C, 6 (16%) lesions of type B but not in type A. The median follow-up period was 68 (2-162) months. Recurrence was not observed in patients with type A and type B. The 5-year overall survival (OS) and disease free survival (DFS) rates were both 100% in type A, both 97.2% in type B, and 88.4%, 66.7% in type C, respectively. Patients with type C had a significantly worse prognosis than did those with the other types with respect to OS (p = 0.033) and DFS (p < 0.001).
Conclusion:
Tumors with type A and type B on TSCT showed an excellent prognosis with no lymph node metastasis. Therefore, GGO predominant lung cancer could be considered “early” lung cancer even if tumor size was larger than 3.0 cm in diameter.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-035 - PD-L1 IHC Test on Cytological Cell Block Specimen; Potential Utility and Practical Issues (ID 9018)
09:30 - 09:30 | Author(s): N. Motoi
- Abstract
Background:
PD-L1 IHC test is an important biomarker for predicting the response of the immune checkpoint inhibitor against the PD1/PD-L1 axis. The FFPE tissue sample is an only validated specimen used in the clinical study, although it is sometimes difficult to obtain an enough tissue sample in advanced stage patients. Cytology specimen is an expected candidate. In this study, we evaluated the PD-L1 IHC expression on cytology cell block specimen (CB) and compared to the corresponding formalin-fixed-paraffin-embedded tumor tissue sample (FFPE-T).
Method:
Nine primary lung cancer patients who have both surgical resected FFPE-T and pleural effusion CB were recruited. CB was prepared as following; pleural fluid was centrifuged to collect the cell pellet, then fixed in formalin and embedded in paraffin. PD-L1 expression was evaluated using two clones (DAKO PharmDx kit, 22C3 and 28-8). Three pathologists (two certified, one path-trainee) and one cytotechnologist reviewed the slides independently. The proportion score of tumor cell (TPS) was evaluated and divided into 2-tier (positive, negative for 28-8) and 3-tier (no, low, high expression for 22C3) categories, according to the manufactural protocols. The correlation between CB and FFPE-T and the inter-observer agreement (kappa value) were calculated.
Result:
All samples were acceptable for PD-L1 evaluation. FFPE-T resulted in 2 positive, 7 negative (28-8); 3 low and 6 no expression (22C3), respectively. CB resulted in 5 positive, 2 negative (28-8); 3 low and 6 no expression (22C3), respectively. The TPS and tiered-category of CB did not correlate to those of FFPE-T, statistically. The concordant rate of tiered-category between FFPE-T and CB resulted in 4/9 (45.4%) for both clones. It can be explained by the heterogeneity of PD-L1 expression. The TPS and category judgment of two tests (28-8 and 22C3) within each observer were statistically correlated (R=0.588-0.951, p-value <0.001). The kappa value of the inter-observer agreement varied from 0.18 to 1.0, depending on the experience and education. Two certified pathologists reached moderate (kappa=0.59 for 28-8) to high (1.0 for 22C3) agreement on CB, but low (0.05 and 0.14) on FFPE-T. The kappa value between certified pathologist and path-trainee/ cytotechnologist was 0.6/ <0.01 for FFPE-T, and 0.18/0.57 for CB, respectively. These results seem to be influenced by the recognition of appropriate target tumor cells.
Conclusion:
Our study suggested that the properly processed cytology sample has a potential clinical utility for PD-L1 evaluation. The difficulty of target cell recognition on cytology specimen seems to be one of the critical issues of standardization.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-035 - Mutational Signatures and Their Association with Clinicopathological Features in Lung Adenocarcinoma of Smokers (ID 8623)
09:30 - 09:30 | Author(s): N. Motoi
- Abstract
Background:
Lung adenocarcinoma (LADC) harboring druggable driver oncogene such as EGFR mutation and ALK fusion can be treated with molecular-targeted drugs. These oncogene aberrations are frequently observed in LADCs of never-smoker, while LADCs of smokers often lack such druggable oncogene aberrations. Therefore, understanding mutation profile of LADCs of smokers is required to improve precision lung cancer medicine..
Method:
We analyzed mutational signatures of somatic mutations in 373 LADCs (smoker 220 cases; 59%, never-smoker 153 cases; 31%) of Japanese using whole exome sequencing data. Four mutational signatures were identified by non-negative matrix factorization and logistic regression analysis. We are now analyzing significantly mutated gene (SMG)s by MutSigCV1.5 of LADCs of smokers and associations of each signature with clinicopathological factors including histological subtype and prognosis.
Result:
Indel mutations as well as well-characterized C>A mutations were defined as mutational event more prevalent in LADC of ever-smokers than in never-smokers (P=8.76E-15 and P=0.000417 respectively). A novel set of genes were identified as a main target for indel mutations (7.4%; 22 of 296 samples), and their mutations were significantly associated with smoking and with UIP co-occurrence in their lung (P=0.0068 and P=0.037, respectively). Indel mutations in 3’-UTRs of these genes caused specific reduction in mutant transcripts, while those in coding region caused truncation of polypeptide.
Conclusion:
A novel gene set including those in 3’-UTR, would contribute to LADC development in smokers and associated with usual interstitial pneumonia, by promoting undifferentiation of tumor cells.
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P3.02-041 - EGFR Amplification Mediates Resistance to TAS121, A Third-Generation EGFR-TKI, in EGFR T790M-Positive Non-Small Cell Lung Cancer (ID 9168)
09:30 - 09:30 | Author(s): N. Motoi
- Abstract
Background:
Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown promising efficacy in EGFR T790M-mutation-positive non-small cell lung cancer (NSCLC). However, acquired resistance to third-generation EGFR-TKIs has been reported in EGFR T790M-positive NSCLC. The mechanism of resistance to these third-generation EGFR-TKIs has not been fully elucidated. We report a case of metastatic NSCLC harboring an EGFR T790M mutation in which EGFR amplification mediated acquired resistance to TAS121, a novel third-generation EGFR-TKI.
Method:
A 68-year-old woman with metastatic lung adenocarcinoma, harboring an EGFR L858R mutation, received gefitinib in September 2013. Although the patient achieved a partial response, the tumor progressed and she was treated with 4 cycles of chemotherapy using cisplatin and pemetrexed followed by pemetrexed maintenance therapy. In April 2015, computed tomography (CT) showed disease progression (PD) with liver metastases, and re-biopsy of hepatic lesions was performed. Tumor genotyping with the PNA LNA PCR-Clamp method revealed an original mutation of EGFR L858R in exon 21 and a secondary mutation of EGFR T790M in exon 20. Tumor progression was noted after completion of one cycle of docetaxel, and she was enrolled into a phase 1 trial of TAS121 in June 2015. Although she showed a partial response to TAS121, PD was confirmed on CT, which indicated progression of liver metastases. She discontinued TAS121 and received supportive care. She died in October 2015, and an autopsy was performed. To determine the mechanism of resistance to TAS121, we performed next-generation sequencing (NGS) (NCC OncoPanel, Agilent) with post-TAS121 samples obtained from progressing liver lesions during TAS121 treatment. We also conducted fluorescence in situ hybridization (FISH) analysis for EGFR in pre-TAS121 liver lesions, post-TAS121 liver lesions, and autopsy samples from the lung and liver. The study protocol was approved by the Ethical Review Committee of the National Cancer Center Hospital.
Result:
NGS with the post-TAS121 liver samples showed EGFR amplification in the tumor cells (log2 ratio 2.2). On FISH analysis, EGFR amplification was not detected in the pre-TAS121 liver lesions (the ratio of EGFR signals to CEP signals 1.7), but was detected in the post-TAS121 liver lesions (2.1) and those obtained at autopsy (3.0). EGFR amplification was not detected in the autopsy samples of the lung lesions (1.0), which remained stable during TAS121 treatment.
Conclusion:
Our case revealed that genomic instability of the EGFR domain contributed to the development of resistance to TAS121. Further molecular analysis is warranted to understand the role of EGFR amplification in acquired resistance to third-generation EGFR-TKIs.
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P3.13 - Radiology/Staging/Screening (ID 729)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.13-009 - Rapid Detection of Lung Cancer by Fluorescent Imaging using a γ-Glutamyltranspeptidase-activatable Fluorescent Probe (ID 8326)
09:30 - 09:30 | Author(s): N. Motoi
- Abstract
Background:
Visualizing the spread of cancer cells in lung cancer surgery is sometimes difficult. γ-Glutamyl-transpeptidase (GGT) is a cell surface-associated enzyme that is overexpressed in various type of human cancers. γ-Glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), an activatable fluorescent probe, is non-fluorescent under a neutral pH and normal cellular environment. However, it becomes highly fluorescent upon reaction with GGT. We evaluated ex vivo fluorescent imaging of lung cancers using the GGT-activatable fluorescent probe.
Method:
Between April 2011 to November 2014, 116 resected cancer cells (91 primary lung cancers, 21 pulmonary metastases, and 4 pleural disseminations) were prospectively included in this study. Each tumor was analyzed by first taking a baseline image before gGlu-HMRG was sprayed onto the freshly resected specimen (termed N0; fluorescent intensity of normal lung, T0; that of lung cancer), and then by taking fluorescent images 30 min after spraying (N30 and T30) with the Maestro In-vivo imaging system (PerkinElmer Inc.). Positive fluorescent activity was defined as follows: in cases where fluorescence was observed only in tumor tissues, ΔN(=N30-N0) < 0 and ΔT(=T30-T0) < 0, in cases where fluorescence was observed in both normal and tumor tissues, ΔN > 0 and ΔT/ΔN > 1.
Result:
Figure 1In primary lung cancer, 61 of 91 (67%) cases rapidly developed fluorescent activity. In cases with pulmonary metastases, 15 of 21 (71.4%) cases showed positive fluorescent activity. Four disseminated pleural nodules all showed positive fluorescent activity (100%). Age, gender, tumor size, tumor marker, histology (adenocarcinoma (Ad) vs. non-Ad, squamous cell carcinoma (Sq) vs. non-Sq), pleural invasion, and angio-lymphatic invasion were not significant factors influencing fluorescent intensity.
Conclusion:
Fluorescence imaging with gGlu-HMRG may become one of the most powerful tools for accurate staging by rapidly detecting cancer cells and thus become highly useful for cancer resection.
