Retrospective evaluation of the value of DNA damage repair gene signature in response to platinum-based chemotherapy in advanced pancreatic ductal adenocarcinoma.
Authors: Tian Tian , Fabregat Franco Carles , Castillo Gloria , Castet Florian , Verdaguer Helena , Lopez Valbuena Daniel , Carmona-Alonso Ana , Vivancos Ana , Macarulla Teresa 
Published: June 2023

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Background: Mutations affecting DNA Damage Repair (DDR) genes have been associated with clinical benefits from platinum-based chemotherapy (PBC) in ovarian and breast cancer. Mutations of DDR genes, including BRCA1/2, PALB2, ATM, ATR, CHK1, or RAD51, are found in around 15% of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, whether advanced PDAC patients harboring DDR gene mutations could benefit more from PBC has not been well established. In this study, we aimed to compare the prevalence of DDR gene mutations between advanced PDAC patients who benefited from PBC and those who did not. Methods: We retrospectively analyzed samples from patients with advanced PDAC who received PBC at our institution from 2008 to 2022. Patients with partial response or progression-free survival (PFS) > 6 months were considered responders, and those with progression disease as the best response were considered non-responders. Tumor molecular profiling was performed on tumor samples by Next Generation Sequencing (NGS) of DNA. Fisher’s exact test was used to compare DDR genomic alterations in responders vs. non-responders. Overall survival (OS) was defined as the time from the start of PBC to the date of death. PFS was defined as the time between the start of PBC and the first date of documented progression or death, whichever occurs first. Survival outcomes were estimated using Kaplan-Meier curves, and differences were tested using the long-rank test. Results: A total of 132 patients with advanced PDAC treated with PBC were included in this study. The median age at diagnosis was 55 years (range 27-79 years), and 71 (53.79%) patients were male. In this cohort, 88 (66.67%) patients were identified as responders. Tumor molecular profiling showed that among responders, 42 patients (47.7%) had genomic alterations in BRCA1/2 or PALB2, and 10 patients (11.3%) had alterations in other DDR genes. In contrast, only 17 patients (38.64%) showed DDR gene alternations among non-responders. Importantly, mutations in DDR genes are significantly associated with the responder group (OR=2.28; 95% CI 1.03-5.17, p=0.04). In line with these findings, patients with DDR gene mutations showed significantly longer PFS (median PFS 9.95 months) compared with patients without DDR gene mutations (median PFS 6.51 months) (HR= 0.57; 95%CI 0.39-0.85; p=0.005). Moreover, significantly longer OS was found in patients with DDR gene mutations (median OS 20.5 months) compared with those without DDR gene mutations (median OS 16.8 months) (HR=0.67; 95%CI 0.45-1; p=0.05). Conclusions: Genomic alterations in DDR genes are significantly associated with the benefit of PBC treatment in advanced PDAC patients. Our results argue in favor of using DDR genes as a decision-making tool for advanced PDAC patient stratification even before the stand-of-care chemotherapies.