Background: The difference in prostate cancer incidence and survival between European American (EuAm) and African American (AfAm) men is an important health disparity. Vitamin D (VitD) has been linked to key carcinogenesis-related processes and there is strong evidence of cross talk between the androgen and VitD signaling pathways. AfAm men are more likely to be VitD deficient compared to EuAm men which could be one reason for the health disparity. The current study examined genetic variability in the VitD pathway in relation to prostate cancer risk and investigated whether finasteride, a 5α-reductase inhibitor that blocks the metabolism of testosterone, influenced the relationship of cancer risk in EA and AfAm men with VitD-related polymorphisms.

Materials and Methods: This nested case-control study included 2,356 men (EuAm: 1,091 cases and 1,088 controls; AfAm: 47 cases, 130 controls) from the Prostate Cancer Prevention Trial, a randomized double-blind, placebo-controlled trial of finasteride for the primary prevention of prostate cancer. In EuAm men, controls were frequency matched to cases on distributions of age, first degree family history of prostate cancer and treatment arm. Due to smaller numbers, all available AfAm men were selected. Participants underwent for-cause or end of study prostate biopies with central pathology review to determine case or control status. Twenty-nine SNPs from 14 genes identified from previous studies as being associated with VitD levels and/or prostate cancer were genotyped from buffy coats using the Illumina VeraCode GoldenGate assay (Illumina Inc; San Diego, CA). Odds ratios were calculated to determine associations of SNP genotypes with prostate cancer risk. Interaction was ermined by adding an interaction term to the logistic models. All statistical tests are 2-sided with p<0.05 considered statistically significant. SAS (ver 9.2, Cary NC) and R (2.15.1, Vienna Austria) were used for all analyses.

Results: Three SNPs (C1orf88 rs6599638, CYP24A1 rs6013897, HSD3B1 rs1856888) showed significant interaction by treatment group (finasteride vs. placebo) in AfAm men only (p-interaction for rs6599638, rs6013897, rs1856888 was 0.01, 0.02 and 0.02, respectively). None of the SNPs were associated with cancer in EuAm men and there was no evidence of interaction by treatment group in EuAm men. SNPs rs6599638 and rs6013897 were not associated with cancer in AfAm men in the placebo group. In AfAm men taking finasteride, however, the odds ratios (OR) were significant [rs6599638 AA genotype (7 cases/ 5 controls) compared to AG/GG (12 cases/77 controls) OR= 10.84, 95%CI: 2.77, 45.5; p=0.001; for rs6013897 AA/AT genotypes (13 cases/31 controls) compared to TT (7 cases/51 controls) OR= 3.08, 95%CI: 1.10, 8.60; p=0. 03]. For the rs1856888 SNP, the GG/AG genotypes were protective in the AfAm placebo group [GG/AG (11 cases/33 controls) compared to AA (16 cases/17 controls) OR=0.31, 95%CI: 0.11, 0.84, p= 0.02] but the OR increased to 1.98 in the AfAm finasteride group (p=0.23). The potential impact is limited for rs6599638 as only 10% of AfAm controls have the AA genotype. The impact is larger for rs6013897 and rs1856888 with 41% and 62% of controls with the AA/AT and GG/AG genotypes, respectively. Numbers were too small to examine associations by Gleason grade.

Conclusions: There appears to be differential response to finasteride by race and genotype in three of the 29 VitD pathway SNPs examined in the current study. In these three SNPs in the presence of finasteride, the risk genotypes were associated with an increased odds for cancer in AfAm men and not EuAm men. This implies that finasteride may need to be prescribed with caution to some AfAm men. These results should be confirmed in a larger sample size.

Citation Format: Kathleen C. Torkko, Cathee Till, Phyllis J. Goodman, Catherine M. Tangen, Adrie van Bokhoven, M. Scott Lucia, Ian M. Thompson, Jr., Ulrike Peters, Marian L. Neuhouser. Interactions between finasteride and vitamin D-related polymorphisms is associated with prostate cancer risk in African American men. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B18.