Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma

Abstract

The frequency and significance of the germline variants in DNA damage repair genes still need to be elucidated in patients with sporadic pancreatic ductal adenocarcinoma (PDAC). Our purpose was to determine whether germline variants in DNA damage repair genes were associated with survival of patients with sporadic PDAC. We retrospectively identified 854 patients with sporadic PDAC with germline DNA sequenced in targeted 22 DNA damage repair genes by next-generation sequencing. Outcomes were compared in terms of clinicopathologic features, disease-free survival (DFS), and overall survival (OS). Nineteen patients had deleterious mutations; 103 had variant(s) of unknown significance (VUS). Germline DNA damage repair deleterious variant carriers had superior DFS (median, 19.1 months vs 11.9 months, p= 0.012) and OS (median, 29.7 months vs 20.2 months, p=0.034), as compared with wild-type patients. Germline DNA damage repair VUS variant carriers also had superior DFS when compared with wild-type patients. In subgroup analysis, this improved survival was limited to patients receiving adjuvant chemotherapy, deleterious variant carriers vs wild-type patients DFS (median 36.3 months vs 13.1 months, p= 0.006) and OS (median 43.7 months vs 24.3 months, p= 0.045), VUS variant carriers vs wild-type patients DFS (16.5 months vs 13.1 months, p= 0.007). Having a deleterious variant in a DNA damage repair gene is associated with improved survival after resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.