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K. Shane-Carson
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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 06.08 - Lung Cancer Patients with Germline Mutation: A Retrospective Study (ID 8670)
15:45 - 17:30 | Author(s): K. Shane-Carson
- 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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OA 06 - Global Tobacco Control and Epidemiology I (ID 662)
- Event: WCLC 2017
- Type: Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:G. Kovács, Yun Fan
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 511 + 512
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OA 06.02 - Final Report of the INHERIT EGFR Study - 33 Unrelated Kindreds Carrying Germline EGFR Mutations (ID 9370)
15:45 - 17:30 | Author(s): K. Shane-Carson
- Abstract
- Presentation
Background:
Anecdotal reports of families carrying germline EGFR mutations force us to reconsider our understanding of inherited lung cancer risk in non-smokers. We launched this prospective trial (NCT01754025; ALCMI-002) to remotely enroll and characterize these rare families.
Method:
Eligible subjects were recruited at participating cancer centers or through an online referral system. Following consent (in person or by phone), subjects received genetic counseling and sequencing of saliva or blood for germline EGFR mutations. Cancer specimens and CT scans were additionally analyzed when available.
Result:
Between 12/2012-6/2017, 105 participants were enrolled from 30 US states. Germline EGFR mutations were found in 63% of patients (31 of 49) with EGFR T790M in their lung cancer at diagnosis, and in 62% (16 of 27) and 44% (4 of 9) of first- and second-degree relatives of germline carriers. Pedigrees were available for 32 unrelated kindreds (31 germline T790M, 1 germline R776H): 4 with no family history of lung cancer, 8 with a family history of lung cancer in non-smokers, 18 with multiple relatives with lung cancer. Characteristics of 31 lung cancer probands: median age of lung cancer diagnosis was 57 (range 28-82); 81% white, 19% black; 52% never-smokers; 65% stage IV at diagnosis; 65% were from states in or bordering the US Southeast. Tumor genotyping revealed somatic EGFR co-mutations in 29 (94%) of probands: 6 exon 19 del, 12 L858R, 6 G719X, 1 exon 19 del & G719R, 1 L861Q, 2 H773R, 1 V774M. Imaging analysis suggests a unique pattern of cancer evolution including an indolent multi-focal nodular phase which then progresses to lymph nodes and then remote metastatic disease. Of 8 probands with sensitizing EGFR co-mutations treated with osimertinib, no unexpected toxicities were seen, and 4 have had durable benefit exceeding 12 months. Of 9 relatives with germline EGFR mutations and CT imaging available, 2 have a lung cancer diagnosis and 6 others have lung nodules.
Conclusion:
This study confirms the high likelihood of a germline mutation in lung cancer patients with EGFR T790M detected at diagnosis, and suggests a risk of lung nodules and lung cancer in germline carriers. The regional enrichment in the US Southeast suggests a possible founder effect; haplotyping is planned. A registry is under development to continue follow-up of these rare individuals. Further investigation of germline risk alleles associated with lung cancer risk in non-smokers is needed. Funding: Bonnie J. Addario Lung Cancer Foundation, Conquer Cancer Foundation of ASCO.
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