Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair gene mutations (DDRGM) as a predictive biomarker in PDAC patients treated with FOLFIRINOX.
Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with recurrent metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Chi-square or t-test was used for univariate analyses. Overall survival (OS) analyses was conducted by Kaplan-Meier method, logistic regression (OS categorized as above and below 3rd quartile) and Cox proportional hazard model. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage.
Overall, 36 patients were sequenced. DDRGM were found in 12 patients. Mutations were seen in BRCA1 (N = 7), BRCA2 (N = 5), BRCA1/2 (N = 3), PALB2 (N = 3), MSH2 (N = 1) and FANCF (N = 1) of all the DDR genes sequenced (BRCA1, BRCA2, PALB2, CHEK1, CHEK2, RAD51, MLH1, MSH2, ERCC1, ERCC4, PARP1, FANCF, ATR and MDC1). Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. There were no significant differences between those with DDRGM present and absent except age (64.6 vs. 66.0 years, p = 0.002). The median OS was near significantly superior in those with DDRGM present vs. absent (14 vs. 5 months; HR 0.58 [0.29-1.14], log-rank p = 0.08). Multivariate logistic (OR 1.47 [1.04-2.06], p = 0.04) and Cox regression (HR 0.37 [0.15-0.94], p = 0.04) showed presence of DDRGM was associated with improved OS. Similar analyses limited to only germline BRCA1/2 mutations also showed significantly improved OS with the presence of BRCA1/2 mutations.
In a single institution, retrospective study, we found that the presence of germline and somatic DDRGM as well as germline BRCA1/2 mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.
Clinical trial identification
Legal entity responsible for the study
Indiana University Institutional Review Board.
Walther Cancer Foundation.
All authors have declared no conflicts of interest.