The Association between the UGT2B17 Gene Deletion and Menopause-Related Quality of Life in Postmenopausal Women in the CCTG MAP.3 Breast Cancer Chemoprevention Trial
Background: Mammary Prevention.3 (MAP.3) was a randomized placebo controlled trial of exemestane for breast cancer prevention. Participants commonly experienced vasomotor symptoms, such as hot flashes. Exemestane is ultimately eliminated through glucuronidation activity by UGT2B17; approximately 10% of Caucasians are homozygous null for the UGT2B17 gene. The UGT2B17 deletion is hypothesized to be associated with worsened vasomotor health-related quality of life (HRQL) in women randomized to exemestane. Objective: The thesis objectives examine the relationship between UGT2B17 genotype and 1) worsened vasomotor HRQL and 2) incident adverse vasomotor HRQL. This thesis also explores whether UGT2B17 genotype modifies the relationship between incident adverse vasomotor symptoms and early treatment discontinuation. Methods: MAP.3 participants completed the Menopause-Specific Quality of Life Questionnaire (MENQOL) at study entry, and at 6- and 12-month follow-up visits. Multivariable modified Poisson regression and logistic regression were used to assess the association between UGT2B17 genotype and worsened vasomotor HRQL and incident adverse vasomotor HRQL, respectively. The relationship between UGT2B17 genotype, incident adverse vasomotor HRQL and early discontinuation was investigated with modified Poisson regression. Results: Of the 3576 MAP.3 participants, 46% experienced worsened vasomotor HRQL within 12 months. 11% of participants had the UGT2B17 homozygous deletion. The UGT2B17 deletion polymorphism was not significantly associated with worsened vasomotor HRQL (RR=1.03; 95% CI: 0.96-1.11). Additionally, there was no statistically significant association between UGT2B17 status and incident adverse vasomotor HRQL (OR=0.61; 95% CI: 0.32-1.19) or interaction with treatment (p-valueinteraction = 0.17), although the association trended towards a protective effect, particularly in the placebo group (OR=0.17; 95% CI: 0.02-1.29). Incident adverse vasomotor HRQL was significantly associated with early treatment discontinuation (RR=3.05; 95% CI: 2.28-4.07) but the UGT2B17 deletion did not modify this relationship (p-valueinteraction = 0.30). Conclusions: In contrast to the study hypothesis, it appears the UGT2B17 deletion polymorphism is not associated with worsened vasomotor HRQL in women randomized to exemestane. The lack of UGT2B17 activity may attenuate the effects of exemestane-induced estrogen depletion on vasomotor symptoms, via a sex steroid metabolic pathway. Further research on the UGT2B17 deletion could help clarify its role with respect to endogenous estrogen availability in women with menopause-related symptoms.