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A. Sable-Hunt
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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: 2
- Moderators:K. Suda, H.A. Wakelee
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL22.02 - Spectrum of Cancer Types in Kindreds with NSCLC and EGFR T790M Mutations: Results from INHERIT EGFR (ID 3180)
10:45 - 12:15 | Author(s): A. Sable-Hunt
- 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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ORAL22.05 - The Genomics of Young Lung Cancer Study (ID 503)
10:45 - 12:15 | Author(s): A. Sable-Hunt
- 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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