Genotypes Linked With Time to Progression, Overall Survival in Prostate Cancer Treated With ADT

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Decreased overall survival in patients with prostate cancer could be a result of differential SLCO2B1 expression.
Decreased overall survival in patients with prostate cancer could be a result of differential SLCO2B1 expression.

Decreased overall survival in patients with prostate cancer could be a result of differential SLCO2B1 expression, which ultimately may cause resistance to androgen-deprivation therapy.1

Investigators led by Philip W. Kantoff, MD, of the Dana-Farber Cancer Institute, Harvard Medical School in Boston MA, sought to determine the association of 3 previously demonstrated SLCO2B1 germline variants with time-to-progression (TTP) in patients receiving androgen-deprivation therapy and determine if the SLCO2B1 genetic variants affect overall survival in patients with prostate cancer.

To determine the associations, investigators genotyped 3 single nucleotide polymorphisms (SNPs): exonic SNP rs12422149, intronic SNPs rs1789693, and rs1077858 in an independent validation cohort of 616 patients with prostate cancer who were treated with androgen-deprivation therapy at the Dana-Farber Cancer Institute between 1996 and 2013. Known prognostic factors were adjusted for by using the multivariable Cox proportional hazards regression model and the association of these variants with TTP and overall survival analyzed.

Prostatectomy samples were examined for SLCO2B1. Its effect on dehydroepiandrosterone sulfate (DHEAS) uptake was evaluated in cell lines.

Multivariate and univariate analyses confirmed an association between exonic SNP rs12422149 and TTP in patients treated with androgen-deprivation therapy.

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Overall survival was examined in the combined initial and validation cohorts (N = 1094). Results showed that the intronic SNP rs1077858 was associated with overall survival (univariable analysis: P = .009; Bonferroni's method adjusted P = .027; multivariable analyses: adjusted hazard ratio, 1.35; 95% CI, 1.07 - 1.71 for GG v AA/AG; P = .012). SLCO2B1 in normal prostate tissue and in 22RV1 cells with the major allele of SNP rs1077858 was lower than in cells carrying the risk allele.

“We show in vitro that SLCO2B1 expression levels correlated with DHEAS uptake by PC cells,” the authors concluded.

Reference

  1. Wang X, Harshman LC, Xie W, et al. Association of SLCO2B1 genotypes with time to progression and overall survival in patients receiving androgen-deprivation therapy for prostate cancer [published online ahead of print December 14, 2015]. J Clin Oncol. doi: 10.1200/JCO.2015.62.5988.

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