Vikki Ho1,2, Romain Pasquet1, Shaman Luo3, Gang Chen3, Paul Goss4, Dongsheng Tu5,6, Philip Lazarus3, Harriet Richardson7. 1. Department of Social and Preventive Medicine, University of Montreal, 850 rue Saint-Denis, Tour Saint-Antoine, 3rd Floor, S03.412, Montréal, QC, H2X0A9, Canada. 2. Health Innovation and Evaluation Hub, University of Montreal Hospital Research Centre (CRCHUM), 850 rue Saint-Denis, Tour Saint-Antoine, 3rd Floor, S03.424, Montréal, QC, H2X0A9, Canada. 3. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., PBS 431, Spokane, WA, 99202-2131, USA. 4. Harvard Medical School, MGH Cancer Center, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA. 5. Division Canadian Cancer Trials Group, Queen's University, 10 Stuart Street, Kingston, ON, K7L 3N6, Canada. 6. Department of Public Health Sciences, Cancer Research Institute, Queen's University, 10 Stuart Street, Kingston, ON, K7L 3N6, Canada. 7. Divisions of Canadian Cancer Trials Group and Cancer Care and Epidemiology, Cancer Research Institute, Queen's University, 10 Stuart Street, Room 220, Kingston, ON, K7L 3N6, Canada. hrichardson@ctg.queensu.ca.
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 onplacebo; the exemestane metaboliteanalysis 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.
RCT Entities:
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.
Authors: Landry K Kamdem; Jingyue Xi; Brandi L Clark; Bryana J Gregory; Kelley M Kidwell; Ana-Maria Storniolo; Vered Stearns; Daniel F Hayes; Christina L Gersch; James M Rae; N Lynn Henry; Daniel L Hertz Journal: Breast Cancer Res Treat Date: 2019-02-12 Impact factor: 4.872