Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer.

Abstract

OBJECTIVES:

Vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer.

METHODS:

Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes.

RESULTS:

Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele.

CONCLUSION:

UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat, and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen.

• Authors: Nan-Soon Wong, Elaine Zh Seah, Ling-Zhi Wang, Wee-Lee Yeo, Hui-Ling Yap, Benjamin Chuah, Yi-Wan Lim, Peter Cs Ang, Bee-Choo Tai, Robert Lim, Boon-Cher Goh, Soo-Chin Lee
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 21 Issue 11 Pg. 760-8 (Nov 2011) ISSN: 1744-6880 [Electronic] United States
• PMID: 21849928 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hydroxamic Acids
• Minor Histocompatibility Antigens
• Vorinostat
• Glucuronosyltransferase
• UGT2B17 protein, human

Topics

• Adult
• Antineoplastic Agents (adverse effects, metabolism, pharmacokinetics, therapeutic use)
• Asian People (genetics)
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Demography
• Disease-Free Survival
• Female
• Genotype
• Glucuronosyltransferase (genetics)
• Humans
• Hydroxamic Acids (adverse effects, metabolism, pharmacokinetics, therapeutic use)
• Middle Aged
• Minor Histocompatibility Antigens
• Neoplasm Metastasis
• Time Factors
• Treatment Outcome
• Vorinostat