Abstract P6-13-05: Association between the UGT2B17 gene deletion, exemestane metabolites and vasomotor QOL in women participating on the MAP3 prevention trial

Abstract

Abstract Background: The aromatase inhibitor Exemestane (EXE) reduces the risk of breast cancer in postmenopausal women. However, participants have varied responses to EXE treatment in terms of efficacy and toxicity, possibly due to differences in EXE metabolism. One of the main elimination pathways for EXE is through glucuronidation by UGT2B17. Aims: This project examined the relationship between the UGT2B17 gene deletion, EXE metabolites and menopause-related quality of life (QOL) in postmenopausal women. Hypothesis: Glucuronidation of the main EXE metabolite, 17-dihydroexemestane (17-DHE), is reduced in women with the UGT2B17 double gene deletion, leading to increased circulating 17-DHE and potential toxicity. Methods: This study included 3576 women nested within the CCTG MAP.3 trial, who were allocated to EXE or placebo treatment groups. Genotyping analysis was conducted with baseline blood cell DNA using real-time PCR and allelic discrimination. Women who were homozygous null were considered “exposed”. In addition to EXE, EXE metabolites including 17-DHE and glucuronidated 17-DHE (17 DHE-Gluc) were analyzed from serum by UPLC/MS. Ratios of the main metabolites (17-DHE/EXE) and glucuronidated metabolites (17-DHE-Gluc/17-DHE) were standardized, using an autoscaling method. Metabolite levels that were below the detection limit were replaced by “half the detection limit for that metabolite”. Women had the outcome if they experienced a clinically meaningful (>10%) worsening in vasomotor QOL from baseline within the first year. Modified Poisson regression models were used to calculate the relative risks for both the (1) UGT2B17 gene deletion and (2) metabolite ratios and vasomotor QOL. Results: Ten percent of participants exhibited the homozygous UGT2B17 deletion genotype. There was no significant relationship between the UGT2B17 deletion polymorphism and worsened vasomotor QOL (RR= 1.04, 95% CI: 0.93, 1.17), adjusted for age, race and treatment. Among women with no vasomotor symptoms at baseline but extremely bothersome symptoms at follow-up (incident vasomotor symptoms), there was a suggestive but non-significant protective effect of the UGT2B17 deletion (RR=0.61, 95% CI: 0.32-1.19). This effect was more extreme in the placebo arm (RR=0.20) than in the EXE arm (RR=0.78; p-interaction=0.17). Among women on EXE, levels of EXE and 17-DHE were not different between UGT2B17 genotypes, but levels of 17-DHE-Gluc were significantly lower for the UGT2B17 deletion genotype (p=<0.0001). An increasing ratio of 17-DHE-Gluc/17-DHE [per standard deviation (SD) increase] had a borderline protective effect against worsened vasomotor QOL (RR=0.94, p=0.049), adjusted for age and race. In contrast, an increasing ratio of 17-DHE /EXE (per SD increase) was associated with a small but significant increased risk of worsened vasomotor QOL (RR=1.02, p=0.01). The effect observed for the 17-DHE/EXE ratio was stronger for very bothersome incident vasomotor symptoms at follow-up, but this did not reach statistical significance [17-DHE/EXE (per SD increase): RR=1.36, p=0.12]. Conclusion: EXE metabolite levels could potentially be used as a biomarker for extreme vasomotor QOL changes in breast cancer chemoprevention settings using EXE. Citation Format: Richardson H, Knight B, Chen G, Luo S, Massey T, Goss PE, Lazarus P. Association between the UGT2B17 gene deletion, exemestane metabolites and vasomotor QOL in women participating on the MAP3 prevention trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-05.