Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial
- 1 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Breast Cancer Research and Treatment
- Vol. 183 (3), 705-716
- https://doi.org/10.1007/s10549-020-05812-1
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.Keywords
Funding Information
- Foundation for the National Institutes of Health (RO1-CA164366)
This publication has 30 references indexed in Scilit:
- Patient-Reported Discontinuation of Endocrine Therapy and Related Adverse Effects Among Women With Early-Stage Breast CancerJournal of Oncology Practice, 2012
- Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast CancerJournal of Clinical Oncology, 2012
- Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogeneticsPharmacogenetics and Genomics, 2010
- Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancerBreast Cancer Research and Treatment, 2010
- Improving compliance and persistence to adjuvant tamoxifen and aromatase inhibitor therapyCritical Reviews in Oncology/Hematology, 2010
- Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen and aromatase inhibitorsDrug Metabolism Reviews, 2009
- Genome-wide Copy-Number-Variation Study Identified a Susceptibility Gene, UGT2B17, for OsteoporosisAmerican Journal of Human Genetics, 2008
- Adherence to Initial Adjuvant Anastrozole Therapy Among Women With Early-Stage Breast CancerJournal of Clinical Oncology, 2008
- Early discontinuation of tamoxifenCancer, 2007
- Analysis and interpretation of health-related quality-of-life data from clinical trials: basic approach of The National Cancer Institute of Canada Clinical Trials GroupEuropean Journal of Cancer, 2005