Real-World Germline Testing Patterns and Clinical Implications of HRR-Associated Germline Variants in Pancreatic...

Background and Aim: Germline testing (GT) is increasingly relevant in pancreatic ductal adenocarcinoma (PDAC) because of therapeutic and familial implications. We evaluated real-world GT uptake, the diagnostic yield of pathogenic/likely pathogenic germline variants (P/LP), and their clinical implications. Methods: We retrospectively evaluated 674 consecutive patients with PDAC. GT was performed using targeted single-gene testing or multigene panels. Survival analyses among patients receiving platinum-based chemotherapy according to P/LP germline variant status in HRR-associated genes were exploratory. Results: Overall, 28.9% of patients underwent GT, increasing to 45.9% in 2021-2025 (p < 0.001). Results were available for 194 patients; 28 (14.4%) harbored P/LP variants, most commonly BRCA2 (4.6%) and ATM (3.1%). P/LP variants were identified in 6.8% of patients who did not meet classical referral criteria. Among the 28 carriers, 12 (42.9%) harbored BRCA1/2 or PALB2, variants with established therapeutic relevance, while eight (28.6%) carried ATM, FANCA, or FANCM, variants with potential therapeutic relevance. Of these 20 patients, 11 (55.0%) received matched therapy, and treatment was modified because of the germline result in six (30.0%). In exploratory analyses, among platinum-treated patients, carriers of P/LP germline variants in HRR-associated genes had longer PFS than non-carriers (23.9 vs. 4.8 months; log-rank p = 0.017), although only six HRR-associated variant carriers were included in this platinum-treated survival analysis. Conclusions: GT remained underused despite increasing implementation. Early systematic GT may identify clinically relevant variants missed by selective referral strategies and inform treatment, genetic counseling, and cascade testing. Survival findings require prospective validation.