BACKGROUND: Yields for (likely) pathogenic germline variants (PGVs) in cancer predisposition genes (CPGs) in pancreatic cancer (PCA) cases range from 5% to 10% in initial literature to 15% to 20% in recent literature. PGVs can impact therapy recommendations and cancer surveillance for individuals and families.

PATIENTS AND METHODS: We retrospectively evaluated prospective cancer predisposition testing in 125 patients with exocrine PCA from a single-center clinical genetics clinic (n = 41) and a multicenter precision oncology program (n = 84) within 64 genes, including 14 established PCA risk genes. Associations with clinical and somatic molecular parameters, as well as therapy recommendations, were assessed.

RESULTS: PGVs were identified in 21.6% of patients (n = 27/125) across 14 CPGs. A genetic tumor syndrome was diagnosed in 17.6% of patients (n = 22/125). Existing inclusion criteria for germline testing [European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN)] would have missed up to 23.8% of PGV carriers (n = 5/21). Age of onset was not associated with PGV yield. A meta-analysis of 10 other PCA cohorts showed a median PGV yield of 14.1%.In a precision oncology program, 10.7% (n = 9/84) of PCA patients received treatment recommendations supported by PGVs. Genetic testing was carried out on relatives of 73.3% of PGV-positive patients (n = 11/15), with one family demonstrating PGV confirmation in 7 of 13 tested relatives.

CONCLUSIONS: These findings support ASCO and NCCN recommendations for germline testing in all PCA patients. We suggest offering large-panel genetic diagnostics early in clinical management, regardless of clinical parameters, with ongoing evaluation and adjustment of the gene panel.