Genome-wide interaction study of gemcitabine treatment and genotype on survival in pancreatic cancer.

Abstract

4022 Background: Gemcitabine (gem) is commonly given for all stages of pancreatic adenocarcinoma (PC). However, it is not known a priori which patients will benefit from gem treatment compared to other treatments such as FOLFIRINOX. It is possible that germline variation may influence the efficacy of gem. Therefore, we performed a treatment-benefit interaction study of gem exposure with genome-wide single nucleotide polymorphisms (SNPs) on PC survival. Methods: We performed a two-stage cohort survival study of PC patients from the Mayo Clinic Pancreas Biospecimen Resource from 2000-08. In the first stage, we assessed data on 550,000 SNPs from 413 pts [median age 68, 56% male, 35%/34%/31% resected/locally advanced/metastatic (R/LA/M)] with PC for a Cox regression analysis assessing the interaction of gem treatment (Y/N) and genotype on survival, adjusted for age, stage, sex, and BMI. SNPs were also correlated with treatment toxicity. The 100 most significant SNPs from this first stage were used for a replication study of another 527 pts (median age 65, 53% male, 34%/32%/33% R/LA/M). Survival was assessed from first diagnosis to death (84% had died), and only patients with complete treatment records were included. Results: Nine SNPs interact with the same direction of effect (Table), including genes affecting apoptosis, reactive oxygen species, and other genes. PYCARD and MAPRE2 were strongly significant in both stages. MAPRE2, EPHB1, and NOX4 expression have previously been reported to affect chemosensitivity in pancreatic cancer cells in vitro. Conclusions: In a two-stage study, multiple SNPs appear to be predictive of the efficacy of gem therapy. No effects on gem toxicity were identified. SNP Gene Adjusted p value for interaction variable of genotype and gem exposure on survival Stage I (N=413) Stage II (N=527) Combined (N=940) rs6507115 MAPRE2 1.81 x 10-6 1.5 x 10-3 4.8 x 10-9 rs497279 NOX4 1.6 x 10-5 0.02 5.8 x 10-8 rs8056505 PYCARD 6.1 x 10-5 9.1 x 10-4 1.97 x 10-7 rs4889426 PLCG2 4.0 x 10-6 0.04 3.1 x 10-7 rs1021584 LOC100131418 4.5 x 10-5 0.03 5.9 x 10-7 rs7243052 PARD6G 2.5 x 10-4 0.01 2.7 x 10-6 rs1457784 KCNQ3 2.4 x 10-6 0.03 4.0 x 10-6 rs11130399 CACNA2D3 1.9 x 10-5 0.02 5.5 x 10-6 rs36064 EPHB1 3.6 x 10-4 0.04 1.5 x 10-5