SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

Abstract

A B S T R A C T PurposeAndrogen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. Patients and MethodsA cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. ResultsThree SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P Ͻ .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (P interaction ϭ .041). ConclusionGenetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer.

SLCO Transport Genes in Prostate Cancer—Response

“…Consistent with findings reported by Hamada and colleagues (2), Sharifi and colleagues (3), and Yang and colleagues (4) in studies of men with advanced prostate cancer receiving androgen deprivation therapy (ADT), we show that a high-testosterone import allele of SLCO1B3 SNP rs4149117 is also associated with an increased risk of prostate cancer-specific mortality (PCSM) in a population-based study of incident prostate cancer cases. Although the associated HRs in each study are small, the consistency of the observation is striking given the differences in the prostate cancer populations under evaluation.…”

“…As discussed by Figg and colleagues in their letter, our work and the work by Yang and colleagues (4) reported different findings for the SLCO2B1 SNP rs12422149 [which encodes for a dehydroepiandrosterone (DHEA) sulfate (DHEAS) transporter]. Whereas Yang and colleagues observed a more rapid time to progression on ADT in men bearing a high-DHEAS import allele of SLCO2B1 SNP rs12422149, we observed an increased risk of PCSM in men bearing the lowimport allele.…”

Androgens and androgen receptor signaling in prostate tumorigenesis

“…Recent studies have suggested that functional genetic polymorphisms in the CYP19A1 gene may modify serum and/or intratumoral sex hormone levels and therefore influence prostate cancer risk and survival (Latil et al 2001, Suzuki et al 2003, Tsuchiya et al 2006, Kanda et al 2015. The androgen transporter gene SLCO2B1 also has a polymorphism that has been associated with prostate cancer risk and outcome (Yang et al 2011). While none of these associations are incredibly strong, taken together, these findings suggest androgen pathway genes likely influence prostate cancer risk, suggesting that androgens are involved in tumorigenesis.…”

Molecular Markers in Key Steroidogenic Pathways, Circulating Steroid Levels, and Prostate Cancer Progression

“…In advanced disease state, studies have shown the impact of HSD17B4 genetic variations (13) and expression (14) relative to disease progression, and germline variations in SLCO2B1 and SLCO1B3 in response to palliative ADT therapy (15). However, there is still a lack of molecular markers better defining aggressive and lethal prostate cancer.…”