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. Patients and Methods Steroid and abiraterone levels were measured 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. 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). 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.

The impact of statin use on the efficacy of abiraterone acetate in patients with castration‐resistant prostate cancer

“…AA may also undergo SLCO‐mediated transport given its steroidal structure. The latter is supported by findings from Mostaghel et al that genetic variation in SLCO genes was associated with intraprostatic AA levels and that LNCaP cells overexpressing SLCO had higher intracellular levels of AA. More efficient transport of AA or of other substrates such as DHEAS may play a role in the acquired resistance to AA that almost all patients experience.…”

“…The antagonistic effect of statins on AA efficacy seen in vitro could be balanced by the decrease in DHEAS uptake and depleted intra‐tumoral androgen pool. Additionally, Mostaghel et al have demonstrated significant variation in intra‐prostatic levels of AA in patients with different SLCO2B1 genotypes. If the mechanism is indeed mediated by SLCO transport, different SLCO SNPs may transport AA, DHEAS or statins with varying efficiency and potentially influence the clinical impact of concurrent AA and statin use .…”

Germline Variant in SLCO2B1 and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC)

“…Cum survival Translational research by Mostaghel and colleagues led to our hypothesis that germline variant alleles in SLCO2B1 SNPs could predict response to first-line abiraterone acetate in mCRPC (6). In their study, Mostaghel and colleagues evaluated the effect of SLCO2B1 genotype on tissue abiraterone acetate levels in a cohort of men with intermediate-or high-risk localized prostate cancer randomized to neoadjuvant ADT or neoadjuvant ADT plus abiraterone acetate.…”

“…SLCO2B1 encodes transporter proteins that mediate cellular uptake of numerous drugs and hormones, including testosterone, DHEA sulfate, and abiraterone acetate (4)(5)(6). Initially, SNPs in SLCO2B1 were shown to be a validated, predictive biomarker of time to progression on androgen deprivation therapy (ADT) in patients with mHSPC and biochemical recurrence (5,7,8).…”

“…Initially, SNPs in SLCO2B1 were shown to be a validated, predictive biomarker of time to progression on androgen deprivation therapy (ADT) in patients with mHSPC and biochemical recurrence (5,7,8). In a more recent translational study, Mostaghel and colleagues found that SNPs in SLCO2B1 were associated with higher abiraterone acetate levels in prostate tissue and higher rates of pathologic minimal residual disease on prostatectomy (6). These findings suggested that SLCO2B1 genotype could predict response to abiraterone acetate for patients with metastatic prostate cancer.…”