Genome-wide association study of survival in small cell lung cancer patients treated with irinotecan and cisplatin chemotherapy.

Abstract

7089 Background: The prognosis of patients with extensive-disease small-cell lung cancer (ED-SCLC) remains poor. Despite a high initial response rate to chemotherapy, most patients die from rapid recurrence. We conducted a genome-wide analysis study (GWAS) to examine whether germline genetic variations are prognostic factors in ED-SCLC patients treated with irinotecan and cisplatin (IP) chemotherapy. Methods: We prospectively collected blood samples from 139 patients who participated in two phase II studies of IP chemotherapy as first-line therapy and conducted a GWAS using overall survival (OS) as the endpoint. Germline DNA was genotyped using the Affymetrix 5.0 or 6.0 array sets. Associations between OS and single nucleotide polymorphisms (SNPs) were investigated using multivariate Cox regression analysis. Adjustments for age, performance status (PS) and gender were made. We selected most promising SNPs with p<1×10−6 in the GWAS allelic association analyses. Results: A total of 426,019 SNPs were genotyped and 343,530 SNPs passed quality control (HWE, p<10-7, minor allele frequency>1%). We found 7 SNPs showing a significant association with OS. Patients harboring rs16950650 CT, rs7186128 AG or GG, rs17574269 AG, rs8020368 CC, rs4655567 CC, rs2166219 TT and rs2018683 TT genotypes showed shorter OS compared to patients with control alleles. Hazards ratios of death for each risk variants were 30.2 (95% CI, 8.3-109.0, p=2.1X10-7), 2.5 (95% CI, 1.7-3.5, p=3.8X10-7), 7.6 (95% CI, 3.4-16.6, p=4.5X10-7), 3.4 (95% CI, 2.1-5.5, p=3.5X10-7), 4.9 (95% CI, 2.7-9.0, p=3.1X10-7), 5.8 (95% CI, 2.9-11.7, p=8.4X10-7) and 7.8 (95% CI, 3.4-17.7, p=8.0X10-7), respectively. Among these SNPs, rs4655567, rs8020368, rs2018683 and rs17574269 were significantly associated with a refractory relapse. In multivariate logistic analysis including age, gender and PS, rs8020368 CC genotype showed higher risk of refractory relapse than patients with TT or TC genotype (HR=14.9 [95% CI, 1.9-114.8], p=0.010). Conclusions: This exploratory GWAS identified several candidate SNPs that might predictive for the outcome of patients with ED-SCLC receiving IP chemotherapy.