Survival and treatment trends in BRCA-mutated metastatic pancreatic adenocarcinoma.

Abstract

769 Background: Patients with metastatic pancreatic cancer and pathogenic germline BRCA mutations have improved survival with platinum-based chemotherapy and maintenance PARP inhibitor therapy. However, little is known about the impact of somatic BRCA mutations and BRCA Variants of Uncertain Significance (VUS) on treatment patterns and survival. Methods: The Flatiron Health Research Database contains de-identified patient-level data originating from over 280 cancer clinics in the United States. Using patient-level data from the Flatiron Health database collected between 2017 and 2024, we conducted multivariate analyses to evaluate the association of BRCA mutations with survival outcomes and treatment patterns in metastatic pancreatic cancer patients. A study protocol was developed prior to the implementation of the study. Results: Relative to benign variants, an overall survival benefit of germline and somatic pathogenic BRCA mutations was demonstrated. Multivariate Cox proportional analysis revealed a hazard ratio (HR) of 0.54 (95% CI: 0.41–0.70), p<0.001 for germline pathogenic and 0.61 (95% CI: 0.45–0.81), p<0.001 for somatic pathogenic mutations. Trend-level effects in germline variants of uncertain significance (VUS): HR = 0.74 (95% CI: 0.48–1.12), p=0.157, and somatic VUS: 0.82 (95% CI: 0.66–1.01), p=0.067 were also noted. Patients with germline pathogenic BRCA mutations were also more likely to receive first-line platinum therapy than their benign comparators. Multivariable OR: 2.12 (95% CI: 1.04 - 4.50), p=0.042. Other mutation categories, including VUS and somatic mutations, were not associated with different treatment patterns. Patients with germline pathogenic BRCA mutations had a longer time to next treatment (TTNT) than benign: TTNT = 6.35 months (95% CI: 4.5-7.82), p=0.003. Benign = 4.8 months (95% CI: 4.57-5.03). Somatic mutations did not have a significant relationship with treatment duration, but Germline VUS did show a trend-level effect: TTNT = 6.02 months (95% CI: 3.48-10.98), p=0.061. Patients with a germline pathogenic mutation were found to have significantly higher odds of receiving more systemic therapies: HR = 2.67 (95% CI: 1.43–4.93), p=0.002. Other categories were statistically indistinguishable from benign. Conclusions: Pathogenic BRCA mutations, both somatic and germline, are independently associated with enhanced survival outcomes in patients with metastatic pancreatic cancer. Treatment patterns do differ between groups. This data warrants further exploration but suggests patients with somatic BRCA mutations may benefit from the increased sensitivity to therapies as seen in patients with germline pathogenic BRCA alterations. Summary of key population and mutation demographics. Benign GermlinePathogenic GermlineVUS SomaticPathogenic SomaticVUS Total Total N (%) 2407 (86.0) 103 (3.7) 40 (1.4) 101 (3.6) 149 (5.3) 2800