Genetic variants of the organic anion transporter SLCO2B1 as pharmacogenomic determinants of response to androgen deprivation therapy (ADT) for prostate cancer.

Abstract

137 Background: Genotypes at three SNPs (rs12422149; rs1789693; rs1077858) within SLCO2B1 were associated with time to progression (TTP) on ADT in the Dana-Farber Cancer Institute (DFCI) Prostate CRIS ADT cohort (J Clin Oncol. 2011 29(18): 2565). Variation at exonic SNP rs12422149 (Gln to Arg) allows more efficient import of DHEAS, enhances AR signaling and cell growth, and as a result, is associated with shorter TTP on ADT. We further externally validated the association of SLCO2B1 variants with TTP on ADT in an independent ADT cohort and estimate their association with overall survival (OS) in both cohorts. Methods: An independent ADT cohort (N=616) was established for validation. TTP was defined using the same criteria as for the original cohort. The associations of genetic variants with TTP on ADT and OS were estimated from multivariable Cox regression and adjusted by known prognostic factors. Effects of one intronic SNP rs1077858 on SLCO2B1 and DHEAS uptake activity were characterized in cell cultures. Results: Association between genotype at rs12422149 and TTP on ADT was confirmed in univariable (P= 0.0187) and multivariable (adjusted HR= 1.31 for GG vs AA/AG, P= 0.0489) analyses. The Median OS from ADT initiation was 6.5 years in all patients (N= 1094, original plus validation cohort). The intronic SNP rs1077858 was significantly associated with the OS from ADT initiation in both univariable (P= 0.0091) and multivariable (adjusted HR= 1.34 for GG vs AA/AG, P= 0.014) analyses. The difference of median OS was 18 months. SLCO2B1 expression in normal prostate tissue carrying the major allele of SNP rs1077858 (AA) was significantly lower than those carrying the risk allele (GG) (Ptrend= 0.0193), suggesting that the association of the SNP rs1077858 with the OS on ADT may be due to its impact on the SLCO2B1 expression. SLCO2B1 knockdown in vitro decreased DHEAS uptake and diminished DHEAS-induced prostate cancer cell growth. Conclusions: Germline variants within SLCO2B1 modulate function or expression of SLCO2B1, subsequently affecting the uptake of androgen precursors and affecting TTP or OS in prostate cancer patients.