Alterations in the CTRB2 gene and response to chemotherapy in pancreatic cancer.

[BACKGROUND] Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal malignancy due partly to treatment resistance in many patients. We previously identified a functional germline deletion overlapping exon 6 of CTRB2 (CTRB2ex6) at a PDAC genome-wide risk locus on chr16q23.1. This variant leads to a nonfunctional truncated chymotrypsin protein that accumulates intracellularly and induces endoplasmic reticulum stress. Here, we performed a retrospective study to determine whether CTRB2ex6 deletions are associated with response to chemotherapy, time to cancer progression, or overall survival (OS) in PDAC patients.

[METHODS] The study included CTRB2 genotype data from two independent PDAC cohorts (Cohort 1: n = 633; Cohort 2: n = 3,896). We examined associations between CTRB2ex6 deletion status and OS and time-to-progression (TTP) using Cox proportional hazard modeling. TTP was also evaluated in a subset of chemotherapy-treated patients in Cohort 1 (n = 263) to determine the impact of CTRB2ex6 deletion status on chemotherapy response.

[RESULTS] CTRB2ex6 deletions were found in 20% of patients in both cohorts combined (19% in Cohort 1, and 21% in Cohort 2). No significant difference was observed in OS by CTRB2 deletion status in either cohort (Cohort 1: HR = 0.95, p = 0.60; Cohort 2: HR = 1.04, p = 0.43). Among chemotherapy-treated patients in Cohort 1, CTRB2 deletion carriers had a longer median TTP (20.4 vs. 12 months), though this was not statistically significant (p = 0.49). Homozygous deletion carriers had the longest TTP (70 months).

[DISCUSSION] No clinical impact on chemotherapy response or OS was observed by CTRB2 deletion status. Further studies are needed to identify reliable biomarkers of therapy response in PDAC.