Characterization of DNA Damage Response-Associated Somatic Mutations in Borderline Resectable and Locally Advanced Pancreatic Cancer

Abstract

The role of radiation for pancreatic cancer remains controversial, with recent studies showing conflicting results, highlighting the need to develop biomarkers of radiation response. Despite its potential utility in predicting radiosensitivity, the landscape of somatic mutations in borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), as related to DNA damage response (DDR), has not been well characterized. This study aimed to characterize the frequency of such mutations in a cohort of patients with BRPC/LAPC treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT). Mutational data was collected from patients with BRPC/LAPC treated at a single institution with neoadjuvant chemotherapy and SBRT, followed by surgical resection from 2016-2021. Chemotherapy consisted of modified FOLFIRINOX or gemcitabine/nab-paclitaxel, and patients were treated with SBRT in 33 Gy in 5 fractions. Genomic data was obtained from either endoscopic biopsy or surgical specimens, and next-generation sequencing was performed either in-house with a Solid Tumor Panel or with FoundationOne CDx. Specific emphasis was placed on the characterization of double-strand DNA break (DSB) repair genes, as this is the type of tumor cell damage traditionally induced by radiation therapy. Genes associated with the two main pathways of DSB repair, non-homologous end joining (NHEJ) and homologous repair (HR), were analyzed. Specific HR pathway mutations assessed were BLM, BRCA1/2, MRE11, NBN, PALB2, RAD50, RAD51B-D, and RAD54L, while PRKDC mutations were assessed for the NHEJ pathway. Mutations in ATM, an important initiator of DDR pathways, were also analyzed. Additionally, the frequency of mutations in TP53, CDKN2A and SMAD4 in patients with concomitant KRAS mutations was assessed. Eighty-five patients were included in the study. Five (5.9%) patients had mutations in the NHEJ pathway of the PRKDC gene. Twenty (23.5%) patients had mutations in the HR pathway, including BRCA2 (10/85; 11.8%), PALB2 (5/85; 5.9%), BRCA1 (3/85; 3.5%), and RAD50 (1/85; 1.2%). Six (7.1%) patients had mutations in ATM. No patients were found to have mutations in BLM, RAD51B-D, RAD54L, or NBN. Amongst patients with KRAS mutations (72/85), concomitant mutations were observed in TP53 (47/85; 55.3%), CDKN2A (16/85; 18.8%), and SMAD4 (9/85; 10.6%). Herein, we characterized the frequency of somatic mutations associated with DSB repair genes in patients with BRPC/LAPC. Data analysis on outcomes related to radiation response in patients with mutations in DDR pathways is ongoing, but will likely also benefit from multi-institutional efforts to increase the power to answer this question.