3328 - Biological difference of tumor mutational burden (TMB) and microsatellite instability (MSI) status in patients (pts) with somatic vs. germline BRCA1/2-mutated advanced gastrointestinal (GI) cancers using cell-free DNA (cfDNA) sequencing analysis in the GOZILA study

Background

A novel approach to differentiate somatic vs. germline BRCA1/2 mutations in cfDNA using a beta binomial model (AACR 2018, abst #4272) may enable identification of pts with advanced GI tumors who are likely to benefit from a PARP inhibitor. The results from the GOZILA study, the Nationwide Cancer Genome Screening Project utilizing Guardant360, are presented here.

Methods

Pts with advanced GI tumors who were appropriate for any systemic therapy and had progressed following at least one prior treatment were eligible. We investigated the prevalence of somatic vs. germline BRCA1/2 mutations and the association between BRCA1/2 mutations, TMB and MSI.

Results

From Jan 2018 to Mar 2019, 850 pts were prospectively enrolled among 26 major cancer centers in Japan. Of 40 (4.7%) actionable BRCA1/2 mutations, 14 were germline: esophagus (squamous cell carcinoma only), 2 pts (N = 62, 3.2%); stomach, 2 pts (N = 131, 1.5%); colorectum, 3 pts (N = 377, 0.8%); pancreas, 3 pts (N = 157, 1.9%); biliary tract, 4 pts (N = 77, 5.2%); and others, none (N = 31, 0%). Notably, the majority of BRCA1/2 mutations (75%) in pts with esophageal, pancreas and biliary tract cancers were germline, while 81% of BRCA1/2 mutations in pts with stomach and colorectal cancers were somatic (p = 0.001). Median TMB of pts with germline BRCA1/2 mutations was significantly lower than those with somatic BRCA1/2 mutations (p = 0.042). In addition, all pts with germline BRCA1/2 mutations were microsatellite stable, while 19% of pts with somatic BRCA1/2 mutations were MSI-high.

Conclusions

Analysis of cfDNA identified a unique subset of pts with germline BRCA1/2 mutations in advanced GI cancers. Given the association of these findings with efficacy of PARP inhibitor and immune-based therapies, these findings suggest that the identification of BRCA1/2 mutations and their germline-somatic origin may have future implications for therapy selection.

Clinical trial identification

UMIN000029315.

Editorial acknowledgement

Legal entity responsible for the study

SCRUM-Japan GI-SCREEN.

Funding

Guardant Health, Ono Pharmaceutical.

Disclosure

Y. Kawamoto: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Daiichi Sankyo Co., Ltd.; Honoraria (self): Takeda Pharmaceutical Co., Ltd.; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Merck Biopharma Co., Ltd.; Honoraria (self): Eli Lilly Japan K.K.. Y. Nakamura: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho Pharmaceutical. M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Yakult; Advisory / Consultancy: Otsuka Pharmaceutical; Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Honoraria (self): EA Pharma; Honoraria (self): MSD; Advisory / Consultancy, Research grant / Funding (institution): ASLAN Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nano Carrier; Honoraria (self): Gilead. H. Bando: Honoraria (self): Taiho Pharmaceutical company; Honoraria (self): Eli Lilly; Research grant / Funding (self): Sysmex; Research grant / Funding (self): AstraZeneca. T. Esaki: Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self): Chugai; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Eli Lilly; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Novartis. M. Ueno: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Shire; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): MSD; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): ASLAN Pharmaceuticals. T. Nishina: Honoraria (self), Research grant / Funding (institution): Taiho pharmaceutinal; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Suibb; Honoraria (self): Nihonkayaku; Honoraria (self), Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Diichi Sankyo. E. Oki: Speaker Bureau / Expert testimony: Taiho Pham; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Chugai Pham; Speaker Bureau / Expert testimony: Takeda Pharm; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Bayer. T. Denda: Speaker Bureau / Expert testimony: DAIICHI SANKYO COMPANY, LIMITED. T. Mizukami: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly Japan; Advisory / Consultancy: Bristol-Myers Squibb Company; Speaker Bureau / Expert testimony: Takeda Pharmaceutical; Research grant / Funding (institution): TAIHO Pharmaceutical. N. Okano: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Eisai; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Yakult Honsha; Honoraria (self): Takeda; Honoraria (self): J-Pharma; Honoraria (self): Kyowa Hakko Kirin. M.I. Lefterova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. J.I. Odegaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. H. Taniguchi: Honoraria (self): Chugai; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): Taiho; Honoraria (self): Eli Lilly; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Sysmex. C. Morizane: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Yakult Honsha; Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (institution): Nobelpharma; Honoraria (self): Fujifilm; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Eisai; Advisory / Consultancy: Abbvie; Research grant / Funding (institution): ONO PHARMACEUTICAL; Research grant / Funding (institution): J-Pharma. T. Yoshino: Research grant / Funding (self): Novartis Pharma K.K.; Research grant / Funding (self): MSD.K.K.; Research grant / Funding (self): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (self): CHUGAI PHARMACEUTICAL Co., Ltd.; Research grant / Funding (self): Sanofi K.K.; Research grant / Funding (self): DAIICHI SANKYO Co., Ltd.; Research grant / Funding (self): PAREXEL International Inc.; Research grant / Funding (self): ONO PHARMACEUTICAL Co., Ltd. All other authors have declared no conflicts of interest.