Clinical significance of germline CFTR mutations in pancreatic cancer.

Abstract

10591 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a malignancy with high cancer-related mortality. The majority of PDAC is sporadic, but approximately 10% are implicated by germline mutations. We recently reported that CFTR was one of the most mutated germline genes occurring in 11.9% of 1203 patients with PDAC. However, the clinical implications of germline CFTR mutations remain unknown. This study sought to evaluate the differences in clinical outcomes in PDAC patients with and without germline CFTR mutations. Methods: Eligible patients were ≥18 years who consented for BioBank specimen collection and Invitae genetic testing (n = 66). Patients were separated into two groups: patients with a known CFTR mutation (pathogenic variant or variant of uncertain significance (VUS)) (n = 35), and an age- and stage-matched cohort with no known CFTR mutation (n = 31). Subgroups were further stratified by stage at diagnosis: Stage I-III (early stage) vs Stage IV. Survival analysis was performed using Kaplan-Meier method and log-rank testing. A P-value < 0.05 was considered significant. Multiple linear regression was performed to investigate any associations between clinical variables (age at diagnosis, pathogenic variant vs VUS, history of smoking, alcohol use, pancreatitis) and survival. Results: A total of 35 patients with germline CFTR mutations and 31 age- and stage-matched patients were analyzed. Across all stages, the CFTR group had a median OS of 868 days vs 462 days (95% CI 1.014-3.48, P = 0.0390) in the non-mutated group. There was no difference in median OS between CFTR-mutant and non-mutant groups when stratified by early stage (I-III) disease: 929 days vs 765 days (95% CI 0.5950-2.478, P = 0.8543), respectively. Notably, CFTR mutated patients with stage IV disease derived greater OS benefit compared to the non-mutated group (572 days vs 182 days, 95% CI 1.025-9.639, P = 0.0140). Within the pathogenic (n = 25) and VUS (n = 10) subgroups of the germline CFTR mutant group, there was no difference in survival between those with pathogenic variants vs VUS (868 days vs 535 days, 95% CI 0.5233-5.031, P = 0.3573). Within the CFTR group, there was no difference in outcomes when analyzing for exposure to risk factors including smokers and non-smokers (868 days vs 572 days, 95% CI 0.2290-1.897, P = 0.5137), history of pancreatitis and no pancreatitis (929 vs 868 days (95% CI 0.3719-3.080, P = 0.5877), and alcohol use (chronic and social) and no alcohol use (939 days vs 622 days, 95% CI 0.5245-4.345, P = 0.0612). Multiple linear regression did not show any significant associations between pre-specified clinical variables and survival. Conclusions: This study suggests there is an association between germline CFTR mutation and improved survival in patients with advanced PDAC. CFTR may be a potential prognostic biomarker, which underscores the need for further studies focusing on the implications of CFTR mutations and PDAC.