Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine.MethodsThe NGS profiles were performed on resected tissues 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.ResultsThe main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic 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%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14).ConclusionsIn this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy
The vast majority of patients were recruited from West China Medical Center between January 2016 and December 2019, and the rest came from the Cancer Hospital of Fudan University and the People’s Hospital of Sichuan Province
The overall incidence of DNA damage repair (DDR) mutation in our cohort was 15.38%, which is a little higher than what has been reported in other NGS studies: Wang et al conducted a study of 540 Chinese PDAC patients and found that germline mutations were identified in 60 patients (11.1%) [18]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. Poly (ADPribose) polymerase (PARP) inhibitors used in BRCA mutated patients may lead to disruption of two redundant DDR pathways and accumulation of DNA damages [6], presenting the phenomenon of synthetic lethality and triggering the apoptosis or necroptosis of tumor cells [7]. Platinum is a chemotherapeutic agent to cross-link purines on DNA and cause DNA damages. These DNA breaks induced by PARP inhibitors or platinum cannot be effectively repaired when DDR genes are mutated. Another indirect DNA repairrelated therapy is an immune checkpoint inhibitor (ICI) [8]. Highmutational status, such as a high level of tumor mutation burden and high expression of PD-L1, may result in high sensitivity to immunotherapy, especially ICIs [9]
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