Purpose: BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline BRCA1/2 alterations ( BRCA1/2 -associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non- BRCA1/2 -associated) cancer types, the association between BRCA1/2 alteration and HRD is less clear., Methods: A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD., Results: BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2 -associated and 37.2% of non- BRCA1/2 -associated cancers. The fraction of BRCA1/2 -altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2 -associated (89.9%) versus non- BRCA1/2 -associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency ( BRCA1/2 -associated cancers, 8.9%; non- BRCA1/2 -associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2 ; predicted germline or somatic mutations were both associated with elevated gLOH., Conclusion: Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). We demonstrate that biallelic BRCA1/2 alterations are associated with elevated gLOH across all cancer types evaluated and may therefore represent a therapeutic vulnerability targetable by PARPi. Biomarker development for PARPi should reliably distinguish biallelic/monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated as a pan-cancer biomarker in PARPi clinical trials. Ethan S. Sokol Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Dean Pavlick Stock and Other Ownership Interests: Roche Garrett M. Frampton Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jeffrey S. Ross Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Research Funding: Foundation Medicine Jeffrey P. Gregg Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Roche, Foundation Medicine, Luminex Speakers’ Bureau: AstraZeneca, Foundation Medicine, Bristol-Myers Squibb Primo N. Lara Consulting or Advisory Role: Janssen Pharmaceuticals, Merck, CellMax Life, Pfizer Research Funding: Aragon Pharmaceuticals (Inst), Janssen Biotech (Inst), TRACON Pharma (Inst), Merck (Inst), Pharmacyclics (Inst), Incyte (Inst), Taiho Pharmaceutical (Inst) Steffi Oesterreich Stock and Other Ownership Interests: Ocean Genomics (I) Research Funding: GE, Blueprint Medicine, H3 Biomedicine, AstraZeneca, Illumina Neeraj Agarwal Consulting or Advisory Role: Pfizer, Medivation, Astellas Pharma, Bristol-Myers Squibb, AstraZeneca, Nektar, Eli Lilly, Bayer AG, Foundation Medicine, Pharmacyclics, Exelixis, Janssen Oncology, Merck, Novartis Research Funding: Bayer AG (Inst), Bristol-Myers Squibb (Inst), GlaxoSmithKline (Inst), Takeda Pharmaceuticals (Inst), Novartis (Inst), Pfizer (Inst), BN ImmunoTherapeutics (Inst), Exelixis (Inst), TRACON Pharma (Inst), Rexahn Pharmaceuticals (Inst), Amgen (Inst), AstraZeneca (Inst), Active Biotech (Inst), Bavarian Nordic (Inst), Calithera Biosciences (Inst), Celldex (Inst),Eisai (Inst), Genentech (Inst), Immunomedics (Inst), Janssen Pharmaceuticals (Inst), Merck (Inst), NewLink Genetics (Inst), Prometheus (Inst), Sanofi (Inst) Andrea Necchi Employment: Bayer AG (I) Stock and Other Ownership Interests: Bayer AG (I) Honoraria: Roche, Merck, AstraZeneca, Janssen Pharmaceuticals, Foundation Medicine, Bristol-Myers Squibb Consulting or Advisory Role: Merck Sharp & Dohme, Roche, Bayer AG, AstraZeneca, Clovis Oncology, Janssen Pharmaceuticals, Incyte, Seattle Genetics, Astellas Pharma, Bristol-Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, Ferring Research Funding: Merck Sharp & Dohme (Inst), AstraZeneca (Inst), Ipsen (Inst) Travel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, AstraZeneca, Janssen Pharmaceuticals, Rainier Therapeutics Other Relationship: Bayer AG (I) Vincent A. Miller Employment: Foundation Medicine Leadership: Foundation Medicine, Revolution Medicines Stock and Other Ownership Interests: Foundation Medicine, Mirati Therapeutics, Revolution Medicines Patents, Royalties, Other Intellectual Property: Periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center Brian Alexander Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Eli Lilly (Inst), Puma (Inst), Celgene (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summary Siraj M. Ali Employment: Foundation Medicine, EQRX, EQRX (I) Leadership: Incysus Stock and Other Ownership Interests: Exelixis, Blueprint Medicines, Agios, Genocea Biosciences Consulting or Advisory Role: Revolution Medicines, Azitra (I), Princepx Tx (I) Patents, Royalties, Other Intellectual Property: Patents through Foundation Medicine, patents through Seres Health on microbiome stuff in non-neoplastic disease (I) Shridar Ganesan Employment: Merck (I) Stock and Other Ownership Interests: Ibris, Inspirata, Merck (I) Consulting or Advisory Role: Inspirata, Novartis, Roche, Foghorn Therapeutics, Foundation Medicine Patents, Royalties, Other Intellectual Property: Two patents for digital imaging that may be licensed to Ibris and Inspirata Travel, Accommodations, Expenses: Inspirata Jon H. Chung Employment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine No other potential conflicts of interest were reported.