Prospective Study of UDP-gluconoryltransferase 2B17 Genotype as a Predictive Marker of Exemestane PK and PD
Status:
Unknown status
Trial end date:
2018-08-01
Target enrollment:
Participant gender:
Summary
Aromatase inhibitors have led to significant improvements in clinical outcomes for women with
postmenopausal hormone receptor-positive advanced breast cancer. However, there is a notable
absence of phase III comparisons among the three agents and therefore no clear indication of
the superiority of one AI over the others. Furthermore, there remains a distinct lack of
predictive biomarkers of AI efficacy and toxicity to inform clinical decisions. The metabolic
pathways of exemestane have recently been delineated and UGT2B17 is the most active hepatic
gluconoryltransferase responsible for the glucuronidation of the crucial active exemestane
metabolite, 17-dihydroxyexemestane. The UGT2B17*2/*2 deletion genotype is associated with
markedly reduced glucuronidation of 17-dihydroxyexemestane in vitro and is found more
commonly in Asians than Caucasians (60-70% vs less than 10%). Our research group recently
demonstrated significant reduction in glucuronidation of vorinostat, a UGT2B17 substrate,
with a trend towards improved clinical benefit rate and progression-free survival in Asian
breast cancer patients who were UGT2B17*2 homozygotes treated with this compound. In-vivo
studies correlating UGT2B17*2 genotype with exemestane pharmacokinetics and pharmacodynamics
are lacking. We hypothesize that individuals with UGT2B17*2/*2 genotype have reduced
glucuronidation of 17-dihydroxyexemestane and therefore have increased exposure to the active
drug, resulting in improved treatment efficacy. We propose a study of exemestane in hormone
receptor positive post-menopausal advanced breast cancer patients with prospective
correlation of treatment outcome by UGT2B17 genotype. The primary endpoint is the correlation
of genotype (UGT2B17*2/*2 vs those with at least one wild-type variant) with clinical benefit
rate, and secondary endpoints include its association with exemestane pharmacokinetics,
progression-free survival, overall survival and musculoskeletal toxicities.