107P - Germline pathogenic variants identified in tissue- and blood-based whole exome sequencing in advanced solid tumors

Background

Molecular profiling of cancer has been incorporated in routine clinical practice. The identification of germline pathogenic variants (GPVs) is important not only for drug selection but also for early detection and prevention of cancer patients and at-risk relatives. SCRUM-Japan MONSTAR-SCREEN-2 (UMIN000043899) is a Japanese nation-wide molecular profiling project for various cancer types.

Methods

GPVs in 36 cancer susceptibility genes including 28 genes recommended by the American College of Molecular Geneticists (ACMG SF ver 3.2) were investigated in tissue-based whole exome sequences (WES) with formalin-fixed paraffin-embedded advanced solid tumor samples. Blood-based GPVs were examined by WES with buffy-coat samples.

Results

Tissue-based WES data were available in 2365 patients. The most frequent cancer type was colorectal (n = 534) followed by stomach and breast cancers. At least one putative germline pathogenic variant (PGPV) defined as a variant allelic fraction of ≥30% was identified in 1320 patients (55.7%), with a total of 2074 PGPVs. The most frequent PGPVs were TP53 (n=1038, 50.0%) and APC (n=448, 21.6%). Blood-based WES data were available in 1920 patients. The conversion rate of PGPVs to bona fide GPVs was the highest in PALB2 (85.7%, 6/7) followed by BRCA2 (80.8%, 42/52) and BRCA1 (73.7%, 14/19). GPVs were most commonly observed in patients with ovarian cancer (10.9%, 21/186) followed by those with breast cancer (10.9 %, 20/186) and melanoma (9.7%, 3/31), with BRCA1 the most frequent GPVs in ovarian cancer, and BRCA2 the most frequent in breast cancer and melanoma. BRCA2 GPVs were also identified in five patients with stomach cancer. Other cancer susceptibility genes in which GPVs were repetitively discovered in this study included MLH1, PMS2, APC and BRIP1.

Conclusions

In cancer molecular profiling in routine clinical practice, the possibility of identifying GPVs should be considered. BRCA1/2 as well as PALB2 alterations observed in molecular profiling may indicate the existence of GPVs.

Clinical trial identification

UMIN000043899.

Editorial acknowledgement

Legal entity responsible for the study

National Cancer Center Hospital East.

Funding

SCRUM Japan.

Disclosure

T. Kuwata: Financial Interests, Personal, Writing Engagement: Astellas; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, FALCO Biosystems, MSD, Roche Diagnostics; Financial Interests, Institutional, Research Grant: Takeda. Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health Pte Ltd, MSD K.K, Eisai, Zeria Pharmaceutical, Miyarisan pharmaceutical, CareNet, Inc., Hisamitsu Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Co., Ltd., Becton Dickinson, Guardant Health Japan Corp.; Financial Interests, Personal, Advisory Board: Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda, Exact Sciences, Gilead Sciences, Guardant Health Pte Ltd; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics, Guardant Health AMEA, Inc., Tempus; Financial Interests, Institutional, Coordinating PI: Seagen. T. Fujisawa: Financial Interests, Personal, Invited Speaker: Amelieff Co Ltd.. M. Imai-Sumida: Financial Interests, Personal, Advisory Board: Sumitomo Corporation Ltd., Exact Science Inc.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Caris Life Sciences. S. Kadowaki: Financial Interests, Personal, Invited Speaker: Taiho, MSD, Ono, Daiichi Sankyo, BMS, Bayer, Merck, Eisai, Otsuka; Financial Interests, Institutional, Funding: Eli Lilly, MSD, Ono, Daiichi Sankyo, Chugai, Nobelpharma, Yansen, AstraZeneca. M. Ueno: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Incyte, MSD, Nihon Servier, Ono Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, J-pharma, Eisai, Yakult Honsha; Financial Interests, Personal, Advisory Board: Nippon Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Local PI: Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, DFP, Daiichi Sankyo, Eisai, Incyte, MSD, Merck Biopharma, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis, J-pharma, Novocure, Chiome Bioscience. S. Boku: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bristol Myers Squibb, MSD Japan, Eisai Co., Ltd., Nippon Kayaku Co.,Ltd., Asahi Kasei Pharma Co.; Financial Interests, Institutional, Funding: Kyo Diagnostics Co., Ltd.. N. Nonomura: Financial Interests, Invited Speaker: Janssen Pharmaceuticals, Pfizer, Astellas, Takeda, Ono, Novartis, MSD, AstraZeneca, Merc Biopharma, Bayer, Bristol Myers Squib; Financial Interests, Advisory Board: Merc Biopharma, Janssen Pharmaceuticals, Bayer, Bristol Myers Squib, Pfizer; Financial Interests, Licencing Fees or royalty for IP: Shionogi. E. Oki: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly, Bristol Myers Squibb, MSD, Takeda Pham; Financial Interests, Institutional, Research Grant: Guardant Health. M. Radovich: Financial Interests, Full or part-time Employment: Calis Life SciencesCalis Life Sciences; Financial Interests, Stocks/Shares: Caris Life Sciences. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., Falco Biosystems Ltd., Merus N.V., Bristol Myers Squibb K.K., Medical & Biological Laboratories Co., LTD., Takeda Pharmaceutical Co., Ltd.. All other authors have declared no conflicts of interest.