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K. Suda
Moderator of
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ORAL 22 - Moving Beyond a Smoking Related-Cancer to the Young, Never-smokers and Inherited Disease (ID 117)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 8
- Moderators:K. Suda, H.A. Wakelee
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL22.01 - Increasing Incidence of Never Smokers in Non Small Cell Lung Cancer (NSCLC) Patients (ID 707)
10:45 - 10:56 | Author(s): L. Pelosof, C. Ahn, L. Horn, A. Madrigales, J. Cox, J.N. Roberts, J. Minna, J. Schiller
- Abstract
- Presentation
Background:
It is estimated that 10-15% of lung cancer cases occur in never smokers. The cause of lung cancer in these patients includes many possible environmental factors but the precise cause in a given case is often uncertain. Additionally, there has been significant debate about whether the rate of lung cancer in these never smokers is increasing. Using our institutions’ cancer registry data, our objective was to determine if the proportion of never smokers with lung cancer is increasing.
Methods:
We conducted a retrospective study using lung cancer registry data from The University of Texas Southwestern Medical Center in Dallas, Parkland Hospital in Dallas, and Vanderbilt University in Nashville. These registries were queried between 1990 and 2013 for demographic information including gender, age at diagnosis, diagnosis [non small cell lung cancer (NSCLC) or small cell lung cancer (SCLC)], and self-reported smoking history. A total of 10,568 NSCLC cases and 1504 SCLC cases were analyzed. Logistic regression analysis was performed to assess the incidence of never smokers with lung cancer.
Results:
The percentage of never smokers increased among NSCLC pts between 1990 and 2013 [Table 1]. Univariate logistic regression demonstrated an increasing proportion of never smokers among NSCLC cases (p < 0.0001 for year) and multivariate logistic regression also demonstrates this increase (p < 0.0001 for year) after controlling for age and gender. Never smokers with NSCLC were more likely to be female (65.3%, p < 0.0001) than males. The increase in the percentage of NSCLC never smokers was seen at both university hospitals and the Dallas county hospital. In contrast, the percentage of never smokers among SCLC cases did not significantly increase during this time period. Table 1: Percentage of never smokers Figure 1
Conclusion:
This multi-institution study demonstrates an increasing proportion of never smokers with NSCLC between 1990 and 2013 in a large, geographically and demographically diverse population. Because the biology and, thus, often the treatment options of lung cancer in never smokers differs from that of smokers, further investigation is warranted as to the etiology of the increasing incidence of never-smoker lung cancer.
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ORAL22.02 - Spectrum of Cancer Types in Kindreds with NSCLC and EGFR T790M Mutations: Results from INHERIT EGFR (ID 3180)
10:56 - 11:07 | Author(s): G. Wiesner, R. Ashworth, J.C. Heng, I.R. Rainville, K. McReynolds, A. Sable-Hunt, J. Garber, D.P. Carbone, G.R. Oxnard
- Abstract
Background:
EGFR T790M is most commonly seen as a somatic mutation in non-small cell lung cancer (NSCLC) following resistance to EGFR targeted therapies. Rarely EGFR T790M can be seen as a germline mutation where, in case reports, it has been associated with inherited lung cancer risk. However, the penetrance of the T790M germline mutation for NSCLC is not known, nor is it known whether germline carriers are also at risk for other cancers. The INHERIT study (INvestigating HEreditary RIsk from T790M, NCT01754025) is designed to prospectively identify and study individuals and family members with this rare germline mutation.
Methods:
Eligible subjects had EGFR T790M identified on routine cancer genotyping (excluding acquired T790M after therapy), or if they or a relative had already been found to carry a germline EGFR mutation. Confirmatory testing of saliva or blood was done to identify germline T790M carriers. Detailed 3-4 generation pedigrees of probands were constructed and analyzed for type of cancer, age at diagnosis, and relationship to proband with T790M mutation.
Results:
23 eligible kindreds were enrolled between 12/12 and 4/15, with 17 probands identified to have germline T790M and 6 probands shown to have acquired T790M. Average age at diagnosis for probands with germline T790M mutation was 55.8 (range 29 to 76) compared to 62 years (range 47 to 74) for non-germline probands. Pedigrees from confirmed T790M probands had an average kindred size of 28 members (range 3 to 40). Among the 325 1[st] and 2[nd] relatives, there were a total of 61 (18.7%) cancer diagnoses; 25 (39.7%) in lung, 4 (6.3 %) breast, 3 (4.8 %) colon, 4 (6.3) esophagus, 4 (6.3 %) leukemia/lymphoma, 3 (4.8 %) prostate, 3 (6.8%) bladder, 2 (3.2%) testes with about 1% or less with pancreatic, renal, brain, cervical cancer. Further, 7 of these 17 kindreds (41%) had multi-generational lung cancers consistent with autosomal dominant inheritance. In contrast, the cancer profile from the non-germline T790M kindreds showed high prevelance of breast cancer (61%; 13 of 21 relatives with cancer) and low prevalence of lung cancer (9%; 2 of 21). None of these 6 kindreds showed an autosomal dominant pattern of inheritance.
Conclusion:
A wide variety of tumor types were reported in this unique set of kindreds identified by tumor typing of probands for EGFR T790M mutations, with lung cancer as the most frequently reported cancer in close relatives. A high proportion of germline T790M kindreds also had a strong family history consistent with dominant inheritance. Future research will be needed to clarify the cancer risks in relatives of patients with EGFR T790M germline mutations and to develop guidelines and standards for prevention and early detection.
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ORAL22.03 - Inter-, and Intratumoural Genomic Heterogeneity of Primary Pulmonary Adenocarcinoma in Never Smokers (ID 3231)
11:07 - 11:18 | Author(s): M. Daniels, L. Krause, J. Ellis, I.A. Yang, R.V. Bowman, V. Relan, K. Chee, F. Goh, B. Parris, L. Morrison, M. Martins, E. McCaul, L. Passmore, D. Courtney, E. Duhig, K. Fong, R. Naidoo, M. Windsor
- Abstract
- Presentation
Background:
Lung cancer in never smokers may be enriched with oncogenic drivers. To explore patterns genomic changes among and within NS-LC, we performed multi-region whole genome sequencing (WGS) of primary pulmonary adenocarcinoma (LUAC).
Methods:
An observational study was performed on 8 cases of never-smoking LUAC resected with curative intent. Post-diagnostic residual fresh tumor was procured with informed consent, with constitutional samples from normal lung or blood. Selection criteria included: histologically confirmed LUAC; never-smoker [< 100 cigarettes in a lifetime]; no prior malignancy, cytotoxic therapy or thoracic radiotherapy. Tissue samples were procured by an anatomical pathologist (Table 1). Quality criteria were >40% tumor cellularity and <20% necrosis as assessed visually by 2 anatomical pathologists (Table 1). DNA was extracted using Qiagen AllPrep DNA/RNA Mini Kit and Blood Maxi Kit. WGS was performed on paired end libraries using Illumina's HiSeq 2000 platform (Table 1). Single nucleotide variants (SNVs) called by MuTect, Varscan, Strelka and SomaticSniper were considered ‘high priority’ if their predicted functional significance was ‘moderate’ or ‘high’ according to SNPEff. Genotyping was performed using Illumina’s HumanOmni2.5-8 array for copy number calling using the Genome Alteration Print tool.
Results:
14 tumour samples and 8 constitutional samples were sequenced (table 1). Figure 1 Common CNVs and SNVs were observed among and within cases (figure 1). Figure 2 In case 1, 3 of 6 (50%) genes harboring high priority variants were altered in all 4 regions. Similarly, for cases 2 and 3, 8/10 (80%) and 4/8 (50%) genes were altered by high priority variants in all regions.
Conclusion:
Patterns of SNVs and CNVs in LUAC demonstrate areas of common genomic changes and significant inter-, and intratumoral heterogeneity. These findings have significant implications for our understanding of lung cancer biology, also diagnostic testing of lung cancer and clinical trial design.
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ORAL22.04 - Discussant for ORAL22.01, ORAL22.02, ORAL22.03 (ID 3356)
11:18 - 11:28 | Author(s): P. Boffetta
- Abstract
- Presentation
Abstract not provided
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ORAL22.05 - The Genomics of Young Lung Cancer Study (ID 503)
11:28 - 11:39 | Author(s): B.J. Gitlitz, D. Morosini, A. Sable-Hunt, B.J. Addario, M.B. Jennings, S. Novello, T. Vavala, S. Mach, C. Jones, G.R. Oxnard
- Abstract
- Presentation
Background:
Primary lung cancer is increasingly understood as a heterogeneous disease made up of genomically defined subtypes requiring distinct treatment strategies. We hypothesize young age at diagnosis (< 40 years) is a clinical characteristic associated with an increased chance for a targetable genomic alteration. Our ALCMI study prospectively characterizes the somatic and germline genomics of young lung cancer (GYLC). Our goals are to identify a genomically enriched subtype of lung cancer, facilitate delivery of targeted therapy and lay groundwork for further studies of heritable and environmental lung cancer risk factors.
Methods:
Accrual opened July 2014. Patients are eligible if they were diagnosed with bronchogenic lung cancer less than age 40. A study website allows for virtual consenting so patients can participate remotely from anywhere in the world; and use social media to share our trial. We have an integrated data and bio repository that allows for seamless communication and completion of study activities like remote consenting and routing of blood and tumor specimens. We have defined 7 genomic alterations of interest based on the Lung Cancer Mutational Consortium (LCMC) (EGFR, KRAS, HER2, BRAF, ALK, ROS1, RET). We aim to demonstrate that the prevalence of targetable genomic alterations will be greater in our population compared to the LCMC and have powered our study to show an increase from 35% to 50%; and an improvement in use of targeted therapy from 22% to 40%. On study subjects without a known genotype will undergo comprehensive genomic profiling with the FoundationOne test to ensure that all of these genes have been tested. Subjects with advanced adenocarcinoma who are wild type for all 7 genes will receive additional genomic profiling using the FoundationOne Heme test; with the goal of identifying novel oncogenic drivers. Additional investigational genomics will include blood for germline analysis and plasma genomics. All on study genomic analysis is at no cost to the participant.
Results:
Preliminary results of the first 33 subjects show: Average age at diagnosis: 33 years; Range 22-39; Histology: adenocarcinoma n=29, squamous cell n=4; Stage at diagnosis: stage 4 n=26 (79%) stages 1-3 n=7 (21%). Of those with stage 4 adenocarcinoma (n=24); 18:24 (75%) have either an ALK re arrangement n=10 (42%), an EGFR activating mutation n=5 (21%) or a ROS1 fusion n=3 (13%).
Conclusion:
The trial is currently accruing (NCT02273336) https://www.openmednet.org/site/alcmi-goyl. We have accrued patients from the USA, Europe and Australia. Thus far in our prospective series those diagnosed with primary NSCLC < age 40 tend to have stage 4 adenocarcinoma. Preliminary results exceed our statistical expectation with 75% of our metastatic adenocarcinoma patients having an actionable mutation. We plan on presenting data for the first time at WCLC-2015 on the first 50 subjects. (Study, supported by grants from BJALCF, Beth Longwell Foundation, Peter Barker Foundation, Genentech, Schmidt Legacy Foundation, and Upstage Lung Cancer)
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- Abstract
Background:
The incidence of NSCLC in pts 45 years of age or younger is ~2% of total cases, with annual newly diagnosed cases reaching 4,500 in the United States alone. Majority of these pts are diagnosed at an advanced stage with poor outcomes. Although several specific genomic alterations have been identified in young NSCLC pts particularly in light-/never smokers, e.g. EGFR mutations, the overarching underlying causative mechanisms in the pathogenesis and progression in these young pts remain largely unknown, and likely are different from older pts. The objective of this study is to examine the genomic landscapes of NSCLC in young pts through comprehensive whole exomic survey with the objective to arrive at novel predictive and prognostic genomic biomarkers and therapeutic opportunities in young NSCLC pts.
Methods:
We initially identified a cohort of 20 pts (40% male) diagnosed with NSCLC at an age of ≤45, who underwent surgical resection for the primary tumors or metastatic lesions at Cleveland Clinic from 2000-2012. Matching genomic DNA from FFPE lung tumor samples and paired-normal lung tissue/peripheral blood was subjected to whole exome sequencing using Illumina HiSeq 2000 platform. Exome variant calling was performed using GATK and/or SOAPsnp algorithms to identify somatic mutations in individual tumors. Pathway and protein-protein interaction (PPI) network analysis on mutant genes was performed using KEGG/NCI-PID databases and HotNet suite, respectively. Second cohort of young NSCLC tumor cases (n=50) were identified from the Sun Yat-sen University Cancer Center and genomic analysis is underway.
Results:
Majority of the tumors from the first cohort had adenocarcinoma (n=12) or squamous cell (n=4) histology. Six (6) pts were never-smokers, while the others had a median 30 pack-year cigarette smoking history. A significantly higher mutation burden was found in smokers (Median, 3.47/Mb) compared to never-smokers (Median, 0.76/Mb). We also found that the G:C→T:A transversions were more common in smokers, and C:G→T:A transitions more common among never-smokers. Key driver cancer genes such as TP53 (50%) and KRAS (17%) harbored mutations exclusively in smokers, whereas EGFR mutations (14%) were observed specifically in never-smokers. Interestingly, global pathway/PPI analysis of the mutant genes revealed distinct sub-networks associated with cell adhesion and epithelial mesenchymal transition (EMT) processes with a 7-fold enrichment in mutation frequency in these young pts when compared to their overall frequencies in the COSMIC/TCGA lung cancer dataset.
Conclusion:
Our study nominated novel candidate genes/pathways especially relating to cell adhesions and EMT processes, that potentially play a key role in early-onset NSCLC. Further analysis and validation of our findings could improve our understanding of lung cancer pathogenesis and eventually lead to precision therapies to benefit younger NSCLC pts.
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ORAL22.07 - Oncogenic Profiling in Lung Adenocarcinoma Emerged in the Youth (ID 686)
11:50 - 12:01 | Author(s): K. Tanaka, Y. Oya, T. Yoshida, J. Shimizu, Y. Horio, T. Hida, Y. Yatabe
- Abstract
- Presentation
Background:
EGFR, Kras mutations and EML4-ALK translocations were frequently positive in adenocarcinoma among lung cancer, and in fewer cases HER2, BRAF mutations or RET, ROS1 translocations were identified. Although adenocarcinomas emerged in the youth are estimatedly associated with some driver oncogenes including these mutations/translocations, the detail remains unknown.
Methods:
We retrospectively screened 55 consecutive patients who were diagnosed as stage I-IV adenocarcinoma at the age of 40 years or less in 2009-2014. We analyzed clinical and genetic characteristics among them.
Results:
Out of 55 patients, 21 (38%) were male, 24 (44%) were never-smoker, and 38 (69%) were stage IV, with the median age of 36 years (range; 26-40). Forty-five patients (82%) were identified some driver oncogene. 26 (47%) had EML4-ALK translocation, 13 (24%) had EGFR mutation, and 2 (4%) had Kras mutation. We examined rare oncogenes in 10 out of 14 triple-negative patients, which revealed three patients had HER2 mutation and two had RET translocation.
Conclusion:
82% of adenocarcinomas emerged in the youth were identified some targetable driver oncogenes. Not only EGFR mutation or EML4-ALK translocation, rare oncogene examination is necessary especially among these populations.
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ORAL22.08 - Discussant for ORAL22.05, ORAL22.06, ORAL22.07 (ID 3562)
12:01 - 12:11 | Author(s): B.P. Levy
- Abstract
- Presentation
Abstract not provided
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Author of
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ORAL 42 - Drug Resistance (ID 160)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:R.C. Doebele, J.V. DeGregori
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 4a-4f
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ORAL42.02 - Qualitative and Quantitative Heterogeniety in Acquiring Resistance to EGFR Kinase Inhibitors in Lung Cancer (ID 572)
18:41 - 18:52 | Author(s): K. Suda
- Abstract
- Presentation
Background:
Acquisition of resistance to EGFR- tyrosine kinase inhibitors (TKIs) is one of important issues in lung cancer researches. Several resistance mechanisms have been identified. However, inter-tumor heterogeneity in acquisition of resistance to EGFR-TKIs is currently unclear.
Methods:
Eleven autopsied patients who developed acquired resistance to EGFR-TKI monotherapy were included in this study. All patients harbored activating EGFR mutations (exon 19 deletion or L858R mutation), and developed acquired resistance to EGFR-TKI after initial response to the drug. Details of patient characteristics are summarized in Table 1. The resistance mechanisms of seven patients have been reported in our previous analyses (Suda K, et al. Clin Cancer Res 2010, and Suda K, et al. APLCC 2014). In this study, we analyzed acquired resistance mechanisms in twenty-eight tumor samples obtained from the four additional patients using target sequencing technique by next-generation sequencer.
Results:
Among eleven patients, four developed T790M EGFR secondary mutation in all TKI-refractory lesions. One patient developed MET amplification in all TKI-refractory lesions. Three patients harbored both TKI-refractory lesions with T790M mutation and those with MET amplification. The other three patients showed respective resistance mechanisms (Table 1).Table 1. Summary of resistant mechanisms in eleven patients.
In the target sequence analysis, allele count data were further analyzed in tumor samples with T790M mutation, and we observed diverse T790M/activating EGFR mutation allele ratio ranging from 2 – 51%. In the analysis for time to treatment failure (TTF), we observed longer TTF in patients who developed single resistance mechanism compared with those who developed multiple resistance mechanisms (Fig. 1; p = 0.055). Figure 1Pt. ID Age/Sex Pack-Year Resistant Mechanisms TTF (m) C1 57/F 0 T790M or MET 13.8 C2 48/F 0 T790M or MET 11.0 C3 58/M 34 MET 14.5 C4 75/M 0 T790M 43.9 C5 93/F 0 T790M 14.8 C6 62/M 26 T790M 9.1 P1 86/F 0 T790M 10.8 P2 72/M 27 T790M or MET 3.8 P3 89/F 0 EGFR loss with MET or Unknown 9.0 P4 84/F 0 Unknown 22.6 A1 76/F 0 SCLC transformation or T790M 5.0
Conclusion:
In this study, we observed qualitative heterogeneity and quantitative heterogeneity of T790M allele ratio in acquisition of resistance to EGFR-TKIs in lung cancers. Qualitative heterogeneity in resistance mechanisms would have a correlation with TTF of EGFR-TKIs.
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P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.02-016 - Prevalence of Preoperative DVT in Japanese Patients Who Underwent Thoracic Surgery by Intensive Screeng (ID 3038)
09:30 - 09:30 | Author(s): K. Suda
- Abstract
Background:
Pulmonary thromboembolism (PTE) is a well-recognized potentially fatal complication after thoracic surgery. In Japan, PTE had been relatively uncommon. However, it has recently been increasing probably due to changes in lifestyle. Therefore the first guideline for the prevention of venous thromboembolism (VTE) were published in February 2004 in Japan. In this guideline, the patients with history of VTE are classified as highest risk group for PTE. Recently, it has been reported that the presence of normal D-dimer levels can exclude acute-phase deep vein thrombosis (DVT). Therefore, in our institution, DVT had been intensively screened by measuring preoperative D-dimer. The objective of this study was to investigate prevalence of preoperative DVT in Japanese patients scheduled for thoracic surgery.
Methods:
A total of 276 patients who underwent thoracic surgery from June 2013 through July 2014 in our institution were reviewed. The patients who were deemed high-risk for DVT (those with elevated preoperative D-dimer (≧1.0μg/ml), with past history of thrombosis, or with varicose veins in their lower extremities) were defined as preoperative screening positive. They were examined with venous ultrasonography of lower extremities. Those with DVT underwent contrast-enhanced computed tomographic scan (CT) for PTE.
Results:
Of all patients, only 1 failed to undergo preoperative measurement of D-dimer because of emergency surgery. Among the remaining 275 patients, a total of 113 patients ( 95 with elevated D-dimer, 15 with varicose veins in their lower extremities, one with swelling in his extremities, one with paralyzed inferior limbs, and one with previously diagnosed PTE ) were examined with venous ultrasonography of lower extremities. Of them, 34 patients (12.6%) were diagnosed DVT (Figure 1) Proximal and distal DVT were diagnosed in ten patients ( three with isolated DVT, three with multiple DVT, and four with a wide range of huge clots ) and 24 patients ( 15 with isolated DVT and nine with multiple DVT ) , respectively. Of them, none was diagnosed preoperative PTE. For a peri-operative management, all the patients received unfractionated heparin. In addition, of four patients with a wide range of huge clots, three had prophylactic inferior vena cava filter placed. Of 34 patients, one was diagnosed asymptomatic exacerbation of DVT by ultrasonography one week after surgery, but none developed symptomatic PTE. Figure 1
Conclusion:
This study showed an DVT prevalence of 12.6% in patients undergoing thoracic surgery in Japan. However, none developed symptomatic PTE in the peri-operative period.
