Abstract 1438: Organic anion transporter(SLCO)genotype and prostate cancer progression: Prospective cohort study and meta-analysis

Abstract Background: Organic anion-transporting polypeptides, encoded by SLCO genes, have multiple substrates, including androgens. Genotype and protein levels moderate the uptake of androgens into prostate cells, a process competitively inhibited in vitro by statin medications. Single-nucleotide polymorphisms (SNPs) in SLCO2B1 influence SLCO1B2 expression and efficacy of androgen uptake in vitro. Methods: Among men of self-reported European ancestry diagnosed with prostate cancer during prospective follow-up of the Health Professionals Follow-up Study (HPFS, diagnosed 1986-2017) and the Physicians’ Health Study (PHS, 1982-2010) combined, we evaluated four SLCO2B1 SNPs identified in prior studies and time from diagnosis to lethal disease (metastases/prostate cancer-specific death), adjusting for age, calendar year of diagnosis, and principal components of genetic variation to account for local ancestry. We also conducted a systematic review and harmonized allele coding in prior studies for a two-stage dose-response meta-analysis with additive allele coding. Results: Of the 3208 men in the prospective cohort study, 96% were diagnosed with clinically localized (T1/T2) prostate cancer. Most were treated with radical prostatectomy (47%) or radiation (36%); 33% ever received androgen deprivation therapy (ADT). Over up to 32 years of follow-up (median, 14.4 years), 382 lethal events occurred. The intronic SNP rs1077858 had the strongest association with lethal disease (hazard ratio [HR] per minor allele 1.14, 95% confidence interval [CI] 0.98-1.33). Data were suggestive of potential differences for the four SNPs by use of statins and ADT but were not conclusive. The systematic review identified 2 additional population-based studies of primary disease and 4 hospital-based studies of advanced disease, none of which studied effect modification by statins or ADT. Among these 2377 men, 1088 events of recurrence, metastasis, or prostate cancer death occurred. In a meta-analysis of all 7 studies, the genotype of the exonic SNP rs12422149 (minor allele frequency 15%) that results in lower androgen uptake was associated with better outcomes (HR per minor allele 0.80, 95% CI 0.69-0.93), with little between-study heterogeneity (I2 0.27). For the intronic SNP rs1077858, the genotype with higher SLCO2B1 mRNA expression was associated with worse outcomes (HR per minor allele 1.14, 95% CI 0.99-1.31, 3 studies with I2 0.68). Conclusion: These results are compatible with the hypothesis that inherited genetic variation in SLCO2B1 influences androgen uptake and prostate cancer prognosis. These and other genetic variants, together with clinical features, may have potential utility as predictive biomarkers for identifying men with prostate cancer who might benefit from early therapy beyond ADT. Whether adjuvant statin therapy could mitigate the inherited risk requires further study. Citation Format: Konrad H. Stopsack, Harisha Rajanala, Anna Plym, Jane B. Vaselkiv, Konstantina Matsoukas, Ericka M. Ebot, Sarah C. Markt, Kathryn L. Penney, Gwo-Shu M. Lee, Lorelei A. Mucci, Philip W. Kantoff. Organic anion transporter(SLCO)genotype and prostate cancer progression: Prospective cohort study and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1438.