Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer

Abstract

Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer (PCa) outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo SLCO-mediated transport and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.<br /><br />Experimental Design: Steroid and abiraterone levels were measured by mass spectrometry in serum and tissue from 58 men with localized PCa in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 single nucleotide polymorphisms (SNPS) in 6 SLCO genes.<br /><br /> <p>Results:Abiraterone levels spanned a broad range (serum median 28ng/ml, 108nM; tissue median 77ng/ml, 271nM) and were correlated (r=0.355, p=0.001). Levels correlated positivey with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable vs detectable tissue abiraterone at prostatectomy (median 0.10 vs 0.03ng/dl, p=0.02; 1.28 vs 0.44cc, p=0.09, respectively).  SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, p=0.0008; rs12422149, p=0.03) and higher rates of minimal residual disease (tumor volume <0.5cc; rs1789693, 67% vs 27%, p=0.009; rs1077858, 46% vs 0%, p=0.03). LNCaP cells expressing SLCO2B1 showed 2-4 fold higher abiraterone levels compared to vector controls (p<0.05).</p> <p>Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized PCa. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.