Whether somatic or germline, biallelic BRCA1/2 loss of function (LOF) results in homologous recombination deficiency (HRD) and is associated with sensitivity to PARP inhibitors (PARPi) in ovarian and breast cancer. We evaluate the pan-cancer landscape of BRCA1/2 GAs in tissue and ctDNA.
Hybrid capture-based CGP was performed in a CLIA/CAP lab using a tissue-based assay (FoundationOne) of 315 cancer-related genes or a blood-based ctDNA assay of 62 genes (FoundationACT), including the complete exonic regions of BRCA1 and BRCA2. Genomic profiles were available for >90,000 tissue and >5,000 ctDNA samples.
We identified pathogenic BRCA GAs in 5% of tissue and 6% of ctDNA specimens, with BRCA GAs most frequently identified in ovarian carcinoma (15%), prostate (11%), breast (9%), endometrial (6%), and colorectal [CRC] (4%). Somatic-like BRCA GAs were most frequent in CRC (85%), non-small cell lung cancer [NSCLC] (64%), and prostate cancer (56%), but were also frequent in breast (32%) and ovarian cancers (42%). In tissue-based testing, we observe high frequencies of BRCA loss-of-heterozygosity (LOH) in ovarian and breast carcinomas (94% and 82% of BRCA point GAs), intermediate levels in prostate and pancreatic carcinomas (69% and 66%), and low levels in NSCLC, melanoma, and CRC (40%, 20%, 18%). BRCA LOF was associated with an elevated % genomic LOH in most tumor types (ovarian, breast, pancreatic, NSCLC, CRC, melanoma, and prostate; p < 1e-10). An index case of a prostatic carcinoma with homozygous BRCA alteration, and a genomic LOH score in the top quintile, showed a robust response to a PARPi. Comparison of tissue versus ctDNA revealed highly similar BRCA alteration frequencies (r = 0.94) across disease groups. ctDNA concordance with BRCA-altered tissue (n = 56) was 73% (41/56) overall, and concordance was associated with ctDNA fraction.
The frequencies of BRCA GAs observed here suggest HRD-targeted therapies warrant further investigation in carcinomas beyond ovarian, breast, and prostate. CGP of ctDNA may be a convenient and highly sensitive method for identifying such cases although it may need to be complemented with tissue testing for bi-allelic assessment of BRCA loci.
Clinical trial identification
Legal entity responsible for the study
Huntsman Cancer Institute.
Has not received any funding.
N. Agarwal: Consultant or advisor: Pfizer, Exelixis, Cerulean Pharma, Medivation/Astellas, Eisai, Merck, Novartis, EMD Serono, Clovis Oncology, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca, and Nektar; Research funding: Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Medivation, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, Tracon Pharma, Rexahn Pharmaceuticals, Amgen. E.S. Sokol: Employment: Foundation Medicine, Inc. P. Lara Jr.: Consultant or advisor: Exelixis, Pfizer, Novartis, AstraZeneca, Bayer, Genentech/Roche, Celgene, Janssen Biotech, Bristol-Myers Squibb, Abbvie, Turnstone Bio; Research funding: Millennium, Polaris, GlaxoSmithKline, Genentech/Roche, Aragon Pharmaceuticals, Janssen Biotech, Heat Biologics, Tracon Pharma, Merck, Pharmacyclics, Incyte; Honoraria: Pfizer. J.S. Ross: Employment, leadership, stock, other ownership interests, research funding: Foundation Medicine, Inc. V.A. Miller: Employment, leadership, stock, other ownership interests: Foundation Medicine, Inc.; Patents, royalties, other intellectual property: Periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center. A.W. Welsh: Employment, travel, accommodations, expenses, stock, other ownership interests: Foundation Medicine, Inc. J.P. Gregg: Consultant or advisor: AstraZeneca, Bristol-Myers Squibb, Abbvie, Roche; Speakers' bureau: AstraZeneca, Foundation Medicine, Inc. G.M. Frampton: Employment, stock, other ownership interests: Foundation Medicine, Inc. S.M. Ali: Employment, patents, royalties, other intellectual property: Foundation Medicine, Inc.; Stock, other ownership interests: Exelixis, Blueprint Medicines, Agios; An immediate family member: Patent royalties: Seres Health. J. Chung: Employment, stock, other ownership interests: Foundation Medicine, Inc.