Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial. Article

Ho, Vikki, Pasquet, Romain, Luo, Shaman et al. (2020). Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial. . 183(3), 705-716. 10.1007/s10549-020-05812-1

cited authors

  • Ho, Vikki; Pasquet, Romain; Luo, Shaman; Chen, Gang; Goss, Paul; Tu, Dongsheng; Lazarus, Philip; Richardson, Harriet; MAP3 Investigators

fiu authors

abstract

  • Purpose

    To examine associations between the UGT2B17 gene deletion and exemestane metabolites, and commonly reported side effects (fatigue, hot flashes, and joint pain) among postmenopausal women participating in the MAP.3 chemoprevention trial.

    Methods

    The analytical samples for the UGT2B17 analysis comprised 1752 women on exemestane and 1721 women on placebo; the exemestane metabolite analysis included 1360 women on exemestane with one-year serum samples. Both the UGT2B17 gene deletion and metabolites were measured in blood. The metabolites were conceptualized as a ratio (17-DHE-Gluc:17-DHE). Symptoms were assessed using the CTCAE v4.0 at approximately 1-year intervals. Log-binomial regression was used to examine the associations between UGT2B17 deletion, exemestane metabolites and each side effect at 1 and up to 5-year follow-up, adjusting for potential confounders.

    Results

    Among individuals on exemestane with the UGT2B17 gene deletion (i.e., lower detoxification), a higher risk of severe fatigue (RR = 2.59 95% CI: 1.14-5.89) was observed at up to 5-year follow-up. Among individuals on placebo, those with the UGT2B17 gene deletion had a higher risk of any fatigue (RR = 1.39, 95% CI: 1.02-1.89) at year 1. A lower metabolite ratio (poor detoxification) was associated with a higher risk of any fatigue, hot flashes and joint pain at year 1 (fatigue: RR = 1.89, 95% CI: 1.16-3.09; hot flashes: RR = 1.77, 95% CI: 1.40-2.24; joint pain: RR = 2.05, 95% CI: 1.35-3.12); similar associations were observed at 5-year follow-up.

    Conclusion

    Variation in the metabolism of exemestane through the UGT2B17-mediated pathway is associated with subsequent risk of commonly reported symptoms in MAP.3.

publication date

  • October 1, 2020

keywords

  • Androstadienes
  • Breast Neoplasms
  • Female
  • Genotype
  • Glucuronosyltransferase
  • Humans
  • MAP3 Investigators
  • Menopause
  • Minor Histocompatibility Antigens

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 705

end page

  • 716

volume

  • 183

issue

  • 3