UGT2B17, exemestane metabolism, and their association with physical health-related quality of life in Caucasian postmenopausal women participating in the Mammary Prevention.3 Trial
Background: In the Mammary Prevention.3 (MAP.3) trial of exemestane (EXE) for breast cancer prevention, postmenopausal women commonly reported physical menopause-related symptoms, such as joint and muscle pain and fatigue. UGT2B17 contributes to the elimination of EXE-induced activity; however, approximately 10% of Caucasians are carriers of the UGT2B17 homozygous deletion and have impaired elimination of the active EXE metabolite, 17-DHE. This homozygous deletion is hypothesized to have a detrimental effect on physical health-related quality of life (HRQL) in Caucasian postmenopausal women randomized to EXE. Objectives: The objectives of this thesis were to characterize the relationship between the UGT2B17 homozygous deletion and 1) very bothersome prevalent physical HRQL with effect modification by HRT use and 2) meaningful decline in physical HRQL with effect modification by EXE use. This thesis also explored the relationship between glucuronidation of 17-DHE and meaningful decline in physical HRQL. Methods: HRQL data in MAP.3 was collected using the Menopause-Specific Quality of Life Questionnaire (MENQOL) at study entry, and at 6- and 12-month follow-up visits. Multivariate logistic regression and log-binomial regression was used to assess the association the UGT2B17 homozygous deletion and adverse prevalent and incident physical HRQL, respectively. Log-binomial regression was used to investigate the association between glucuronidation of 17-DHE and decline in physical HRQL. Results: The UGT2B17 homozygous deletion was significantly associated with meaningful decline in physical HRQL among women in the EXE arm only (RR=1.30, 95% CI: 1.02-1.67), although effect modification by EXE was not significant (PEM=0.14). Higher glucuronidation of 17-DHE exhibited a significant linear association with meaningful decline in physical HRQL (RR=0.84, 95% CI: 0.74-0.94). There was no statistically significant association between the UGT2B17 homozygous deletion and prevalent very bothersome physical HRQL prior to treatment allocation (RR=0.79 95% CI: 0.39-1.62), nor was there significant effect modification by HRT use (PEM=0.51). Conclusions: The UGT2B17 homozygous deletion appears to have a detrimental effect on physical HRQL among women taking EXE only, but not prior to treatment allocation. Furthermore, higher glucuronidation of the active metabolite, 17-DHE, is protective against meaningful decline among women using EXE. Further research is needed to support the utility of UGT2B17 screening for breast cancer chemoprevention.