Identification of novel SNPs associated with risk and prognosis in patients with castration-resistant prostate cancer.

AIM: Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). MATERIALS & METHODS: A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. RESULTS: No relation to risk was found. Three SNPs were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171G>A (p = 0.003; n = 30; hazard ratio [HR]: 0.307), GSTP1 rs1799811C>T (p = 0.001; n = 38; HR: 0.254) and SLC5A6 rs1395 (p = 0.004; n = 35; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387C>T (p = 0.039) and ABCC5 rs939339A>G (p = 0.018). CONCLUSION: This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis.

Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer.

The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800 mg/m(2) /24 h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n = 25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P = .003), and t1/2 increased (P = .0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400 mg/m(2) /24 h. The incidence of grades 3-4 thrombocytopenia (P = .0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses > 400 mg/m(2) /24 h.