Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial
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EPIDEMIOLOGY
Variation in the UGT2B17 genotype, exemestane metabolism and menopause‑related toxicities in the CCTG MAP.3 trial Vikki Ho1,2 · Romain Pasquet1 · Shaman Luo3 · Gang Chen3 · Paul Goss4 · Dongsheng Tu5,6 · Philip Lazarus3 · Harriet Richardson7 · on behalf of the MAP3 Investigators Received: 17 April 2020 / Accepted: 15 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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-DHEGluc: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. Keywords Exemestane · Chemoprevention · Randomized clinical trial · Menopausal symptoms · Metabolism · Pharmacogenetics
Introduction
Vikki Ho and Romain Pasquet Shared first authorship. Vikki Ho and Romain Pasquet are contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10549-020-05812-1) contains supplementary material, which is available to authorized users. * Vikki Ho [email protected] Extended author information available on the last page of the article
Exemestane is an aromatase inhibitor (AI) with demonstrated efficacy in reducing the incidence or recurrence of breast cancer in postmenopausal women [1–3]. However, menopause-related side effects due to estrogen suppression from exemestane can limit uptake and adherence. Variation in exemestane metabolism may provide valuable insights about treatment efficacy, side effects and
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