Diagnostic yield and clinical utility of germline genetic testing following somatic testing in breast cancer patients.

1092 Background: Germline genetic testing is recommended for breast cancer patients with specific presentations or family histories. Separately, tumor DNA sequencing is increasingly used to inform therapy, most often in patients with advanced disease. Recent NCCN and ESMO guidelines recommend germline testing following somatic testing, under specific circumstances and for specific genes. We examined the utility of germline findings in patients referred for both test modalities. Methods: We reviewed somatic and germline mutations in a consecutive series of patients who: (a) had a current or previous breast cancer diagnosis, (b) were referred for germline testing, and (c) previously received tumor sequencing. Diverse reasons for germline testing included: a tumor finding of potential germline origin, treatment or surgical planning, personal or family history, and patient concern. Results: 227 patients met study criteria of whom 88 (39%) harbored a pathogenic germline variant (PGV) in a high or moderate risk cancer predisposition gene. Mutations in certain genes were most likely to be of germline origin, and most PGVs were potentially actionable (Table). 13% of PGVs were not reported by tumor tests as either germline or somatic findings, usually a result of tumor test limitations. Of note, 27 of the patients with PGVs (31%) had these variants uncovered only after presenting with a second, possibly preventable, malignancy. Conclusions: Germline testing following tumor sequencing often yielded findings that may impact care. Indeed, the 39% PGV rate we observed suggests that such testing may be underutilized. We observed actionable PGVs missed by somatic tests, PGVs uncovered in patients’ second malignancies, and PGVs not within germline reflex testing criteria. These results reinforce the utility of germline testing separate from somatic testing in appropriate patients. [Table: see text]