The Germline/somatic DNA Damage Repair Gene Mutations Modulate the Therapeutic Response in Chinese Patients With Advanced Pancreatic Ductal Adenocarcinoma

Abstract Background: PDAC is a fatal disease with molecular heterogeneity, inducing differences in biological behavior and therapeutic strategy. NGS profiles of pathogenic alterations in Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precise medicine. Methods: NGS were performed on resected tissues or peripheral blood from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics, and survival status were collected. The Kaplan–Meier survival analyses were performed by the R version 3.6.1.Results: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed worse OS than those without (p=0.048). DDR deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n=9, 4.62%), ATM (n=8, 4.10%) and RAD50 genes (n=3, 1.54%). There was no significant improvement of OS between patients with or without DDR mutations (p=0.88). Treatment with platinum-based chemotherapy (p=0.0096) or olaparib (p=0.018) respectively improved the overall survival of patients with DDR mutation. No statistical correlation between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significiantly improved OS to DDR-mutated patients than intact DDR group (p=0.14). Conclusions: In this multi-center retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy. However, DDR alteration has shown limited value in prediction of hypermutational status and the sensitivity to PD-1 blockade.