The effect of germline DNA repair mutations on radiosensitivity in pancreatic ductal adenocarcinoma.
Authors: Bryant John Michael , Peterson John , Park Margaret , Hodul Pamela Joy , Malafa Mokenge Peter , Denbo Jason , Kim Dae Won , Biachi de Castria Tiago , Fleming Jason B. , Oliver Daniel Eli , Grass G. Daniel , Frakes Jessica M. , Torres-Roca Javier , Hoffe Sarah E. , Palm Russell F 
Published: January 2024

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Background: The association between homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC) and sensitivity to platinum-based chemotherapy highlights the need to further understand how germline DNA repair mutations influence the efficacy of different therapies. Given the recent ALLIANCE data that chemotherapy alone is an acceptable standard of care to enhance R0 resection, the focus has shifted towards the contribution of radiotherapy. However, the relationship between germline DNA repair mutations in general and radiosensitivity remains less understood. This study explores the relationship between germline mutations and the Radiosensitivity Index (RSI) gene signature. Methods: After obtaining institutional review board approval, a retrospective analysis was performed of patients who had both RSI and germline mutation testing (i.e., BRCA1, BRCA2, BLM, ATM, MLH1, MSH2, MSH6, PMS2, and BARD mutations) between 1999 and 2023 at a single institution. Student T, Chi squared, Kaplan Meier (KM), Cox univariate log regression (UVA), and Mann-Whitney U (MWU) tests were used for statistical analyses. Results: A total of 25 patients were included, 13 with mutations and 12 without. MWU analysis demonstrated a significant difference in RSI values, where patients with mutations exhibited greater radiosensitivity (mean 0.379 vs. 0.464, p=0.040). The median age at diagnosis, max diameter of tumor, and baseline CA 19-9 were 67 years (range 47 – 77), 3.4 cm (range 0.8 – 8.2), and 288 (9.5 – 26,100), respectively. Most of the tumors were resectable (84%), stage IIB (36%), and grade 2 (68%). All patients underwent resection, with the majority without neoadjuvant therapy (96%). Most patients received chemotherapy (n=18; 72%), most commonly gemcitabine monotherapy (n=14/18). A majority also received radiation therapy (n=15; 60%), with 93% receiving chemoradiation (n=14/15). The median follow-up was 20.8 months. KM analysis yielded a median overall survival (OS) of 20.0 months (95% CI: 7.1-33.0) and progression-free survival (PFS) of 15.1 months (95% CI: 12.3-18.0) for the entire cohort. At the time of analysis, 15.4% of patients with mutations were alive (>10 years), compared to none without mutations (p=0.157). There were no statistically significant differences between the two cohorts for clinical outcomes on KM analysis. On UVA, worse OS was correlated with stage III (HR 7.9, 95% CI 1.2 – 50.2) and IV (HR 11.8, 95% CI 1.4 – 102.3). No other variables were associated with OS on UVA or on mutant-only subgroup analysis. Conclusions: Our findings demonstrate an increased radiosensitivity in patients with germline DNA repair mutations, suggesting these cancers might be more susceptible to radiation-induced DNA damage. Since our results are constrained by the small sample size, further studies are needed to understand the relationship between PDAC with DNA repair mutations.