Association of germline ATM mutations and survival in pancreatic cancer

Abstract

Background: Germline mutations in ataxia telangiectasia mutated (ATM) predispose patients to an increased risk of developing pancreatic cancer. There is mounting evidence that germline mutations in DNA damage response genes confer survival benefit in pancreatic cancer, however, the influence of ATM mutations in pancreatic cancer has not been established. Better understanding into the role of ATM mutations may have implications for prognosis and treatment modalities. Methods: Two hundred and thirty-nine patients who were seen at a single institution between 2007 and 2019 with biopsy confirmed pancreatic cancer were retrospectively identified; 219 patients with adenocarcinoma or adenosquamous carcinoma next-generation sequencing (NGS) testing of their tumors by March 20th, 2020. Sixty-seven of the 219 patients also had germline testing. Results: Germline ATM mutated pancreatic adenocarcinoma are associated with improved overall survival (OS) versus those with wildtype ATM or somatically mutated ATM. Furthermore, we show that somatic ATM mutations are associated with worse survival. Conclusions: We hypothesize that the function of germline ATM mutations in DNA double strand break repair likely renders tumor cells more responsive to overall treatment regimen, thus leading to clinical benefit. As pancreatic cancer has fully entered the era of precision medicine, this study further highlights the importance of routinely testing for germline mutations and suggests that germline ATM is a possible prognostic biomarker that may potentially be exploited therapeutically with targeted therapies such as PARP inhibitors. This study warrants more exploration of ATM with regard to clinical significance and actionability.