Identification and management of pathogenic mutations in BRCA1, BRCA2, and PALB2 in a tumor-only genomic testing program.

10528 Background: Tumor-genomic testing is increasingly used to guide treatment decisions in cancer patients. Although tumor-only testing cannot definitively distinguish between germline versus somatic alterations, the identification of pathogenic or likely pathogenic (P/LP) variants in certain genes should prompt consideration of germline testing. Germline P/LPs in BRCA1, BRCA2 and PALB2 ( B1B2PAL) are associated with hereditary cancer syndromes. Methods: We reviewed tumor-only genomic data (Dana-Farber Oncopanel) between 10/2016 and 6/2018 to examine the prevalence of P/LPs in BRCA1, BRCA2, PALB2 among adult cancer patients at Dana-Farber Cancer Institute/Brigham and Women’s Hospital. We characterized the frequency of P/LPs by primary tumor type, confirmation by germline testing before or within 12 months after Oncopanel testing or not, and factors associated with germline testing. Results: Among 7,575 patients, the median age was 62 (range 18-99); 53.9% were female. A total of 272 (3.6%) had P/LPs in BRCA1 (n = 90), BRCA2 (n = 162) and/or PALB2 (n = 29). P/LPs in B1B2PAL were detected in 5.3% (38/712) of breast, 11.9% (34/285) of ovarian, 6.6% (18/272) of pancreatic, and 5.1% (12/234) of prostate cancers. P/LPs in B1B2PAL were also detected in other neoplasms (12.9% (8/62) of non-melanoma skin, 5.0% (43/855) of colorectal, 7.6% (20/264) of endometrial, and 4.6% (10/216) of head and neck cancers). Of 169 patients who had not had prior germline testing, 29/169 (17.2%) completed germline testing within 12 months after Oncopanel; 13 (7.7%) referred for testing declined or did not complete testing within 12 months, 14 (8.3%) died before or within 3 months of the Oncopanel results, and 113 (66.9%) had no documented germline testing within 12 months. Among 132 patients who had germline testing, 117 (88.6%) had a clinical indication based on personal or family history compared to 66/140 (47.1%) who did not undergo germline testing. Among 132/272 (48.5%) germline-tested patients, 70.5% were positive for a germline mutation in B1B2PAL; the remainder had somatic B1B2PAL mutations only. Germline testing was more often performed in patients with B1B2PAL-associated tumors (breast, ovarian, pancreatic and prostate cancers) or other clinical indications for germline testing. Conclusions: A low but clinically meaningful rate of P/LPs in BRCA1, BRCA2 and PALB2 was detected by tumor-only genomic testing in diverse malignancies. Given the implications of B1B2PAL alterations on treatment and familial cancer risk, our data support current NCCN guidelines recommending germline testing among patients with cancer and P/LPs in B1B2PAL detected on tumor-genomic testing and highlights the need for systems to ensure germline testing when indicated.