Finasteride concentrations and prostate cancer risk: results from the Prostate Cancer Prevention Trial

Abstract

Objective: In the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%, even though high-grade prostate cancer was more common in the finasteride group. However, it remains to be determined whether finasteride concentrations may affect prostate cancer risk. In this study, we examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations.

Methods: Data for this nested case-control study are from the PCPT. Cases were drawn from men with biopsy-proven prostate cancer and matched controls. Finasteride concentrations were measured using a liquid chromatography-mass spectrometry validated assay. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. We also examine whether polymorphisms in the enzyme target and metabolism genes of finasteride are related to drug concentrations using linear regression.

Results and conclusions: Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway.

Trial registration: ClinicalTrials.gov NCT00288106.

Fig 1. Linkage disequilibrium (LD) pattern and haplotype architecture for (A) CYP3A4 & CYP3A5; (B) SRD5A2; and (C) SRD5A2L/SRD5A3 genes.

The haplotype block structure, as exhibited by Haploview is shown. LD was measured using data from all white subjects in the present study. The haplotype blocks were determined using the criteria described by Gabriel et al. The physical position of each SNP is presented in the upper diagram. Each diamond contains the level of LD measured by Hedrick's multiallelic D′ between pairs of single nucleotide polymorphisms. Shading shows the magnitude and significance of pairwise LD, with darker shades representing stronger LD; the diamond without a number corresponds to D′ = 1. Haplotypes for the variations and their population frequency (light gray color) are shown below each haplotype block of the corresponding genes. The SNP numbers across the top of the haplotypes correspond to those in the Haploview plot. D′ indicates the level of recombination between two blocks and is shown in the crossing area. The connection from one block to the next block is displayed through frequency corresponding to the thickness of the line.