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

Abstract

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the inde-pendent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; P ¼ 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line abiraterone acetate in men with mCRPC. a P values are comparisons across the three genotypes. Hahn et al. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.

Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy—Modulators of Cellular Entry or Pharmacokinetics?

“…pathologic response after radical prostatectomy as compared to lower tissue abiraterone concentrations [40]. In agreement, Hahn et al [41] corroborated that patients heterozygous for SLCO2B1 rs12422149 with metastatic castration-resistant prostate cancer receiving first-line abiraterone acetate had improved progression-free survival as compared to homozygous wildtype carriers (GG) (Figure 1). It remains to be determined whether genetic variants of SLCO2B1 can be used as biomarkers for the response to abiraterone treatment in advanced prostate cancer.…”

“…(D) Ct-OATP1B3-specific chemotherapeutic substrates to enhance tumor cell accumulation sparing healthy tissue expressing lt-OATP1B3 [129]. (E) Identification of genetic variants exhibiting superior transport capacity as compared to the wildtype that could allow personalized medication and dose finding [41]. (F) Inhibition of an SLC transporter in healthy tissue such as the kidney in order to reduce toxic side effects [130].…”

Organic Anion Transporting Polypeptide 2B1 (OATP2B1) Genetic Variants: In Vitro Functional Characterization and Association With Circulating Concentrations of Endogenous Substrates

“…et al, 2017 ). In prostate cancer patients undergoing androgen deprivation therapy, SLCO2B1 c.935G>A variant carriers were compellingly shown to have shorter time to progression in different cohorts ( Yang et al, 2011 ; Fujimoto et al, 2013 ; Wang et al, 2016 ; Hahn et al, 2019 ).…”

The Role of Genetic Polymorphisms in the Diagnosis and Management of Prostate Cancer: An Update

“…abiraterone acetate for metastatic castration-resistant prostate cancer (mCRPC), who carry the heterozygous rs12422149 variant, had a significant improvement in progression free survival (PFS) compared with the homozygous wild-type group (32). The mutation rs12422149 is a polymorphism located in SLCO2B1 gene that encodes for a transporter protein involved in cellular uptake of different hormones such as testosterone, DHEA sulfate and abiraterone acetate (32).…”

“…abiraterone acetate for metastatic castration-resistant prostate cancer (mCRPC), who carry the heterozygous rs12422149 variant, had a significant improvement in progression free survival (PFS) compared with the homozygous wild-type group (32). The mutation rs12422149 is a polymorphism located in SLCO2B1 gene that encodes for a transporter protein involved in cellular uptake of different hormones such as testosterone, DHEA sulfate and abiraterone acetate (32). Finally, it has been described that the polymorphism rs11549465, localized in the hypoxia inducible factor 1 alpha (HIF1A) gene, is associated with a greater risk for developing distant metastasis and resistance to ADT (33).…”