Germline mutations in pancreatic cancer and potential new therapeutic options

Abstract

Due to short-lived treatment responses in unresectable disease, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest cancers. There is availability of new information about germline and sporadic mutations in the deoxyribonucleic acid (DNA) damage repair pathway in PDAC in recent decades and the expectation is that novel targeted therapies will thus be developed. A variety of germline mutations (BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6) have been reported in these patients with the highest prevalence being BRCA1/2. Positive results have been reported with the use of targeted therapies, particularly poly (ADP-ribose) polymerase inhibitors in BRCA-mutated ovarian and breast cancers, and their use is currently being investigated in germline-mutated pancreatic cancer. The aim of this review is to provide an outline of germline DNA damage repair mutations in pancreatic cancer and their effect on the incidence, outcomes and responses to different therapeutic options.