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

  • Epidemiology
  • Published:
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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.

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Acknowledgements

We thank the 4560 women who agreed to participate in this study; the trial committee; the many investigators, pharmacists, and clinical research associates involved in the trial; the Central Office staff of the Canadian Clinical Trials Group who contributed to the conduct of the main trial and Pfizer Pharmaceuticals for support and for providing exemestane and placebo. We also thank the entire Mammary Prevention 3 (MAP.3) investigator group. Finally, we thank the Mass Spectrometry Core facility and the Genomic Core facility at Washington State University-Spokane for their help with UPLC-MS and genotyping, respectively. We are also very grateful to Zuping Xia in the Department of Pharmaceutical Sciences at Washington State University for providing 17β-DHE as a standard for these studies.

Author information

Author notes

  1. Vikki Ho and Romain Pasquet Shared first authorship.

  2. Vikki Ho and Romain Pasquet are contributed equally to this work.

Authors and Affiliations

  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

    Vikki Ho & Romain Pasquet

  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

    Vikki Ho

  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

    Shaman Luo, Gang Chen & Philip Lazarus

  4. Harvard Medical School, MGH Cancer Center, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA

    Paul Goss

  5. Division Canadian Cancer Trials Group, Queen’s University, 10 Stuart Street, Kingston, ON, K7L 3N6, Canada

    Dongsheng Tu

  6. Department of Public Health Sciences, Cancer Research Institute, Queen’s University, 10 Stuart Street, Kingston, ON, K7L 3N6, Canada

    Dongsheng Tu

  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

    Harriet Richardson

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Consortia

on behalf of the MAP3 Investigators

Contributions

PG, HR and the MAP3 Investigators directed the MAP.3 trial. Each author has directly participated in the planning, execution, or analysis of the current study. VH, RP, PL and HR designed the study’s analytic strategy and interpreted the results. DT and HR provided advice on study design or data analysis. VH, RP and HR drafted the manuscript. All authors critically revised and commented on the manuscript.

Corresponding author

Correspondence to Harriet Richardson.

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Conflicts of interest

This study was funded by a grant (RO1-CA164366) from the National Cancer Institute at the National Institutes of Health to P. Lazarus (PI) and H. Richardson (Sub-award PI). Employment or Leadership Position: None; Consultant or Advisory Role: None; Stock Ownership: None; Honoraria: None; Expert Testimony: None; Patents, Royalties, and Licenses: None; Other Remuneration: None. Research Funding from company: Harriet Richardson and the CCTG held an IIR grant from Pfizer for the MAP.3 trial (2004–2016); Vikki Ho holds a Sex and Gender Science Chair in Cancer Research from the Canadian Institutes for Health Research and is currently supported by the Cancer Research Society, Fonds de recherche du Québec – Santé (FRQS) and Ministère de l'Économie, de la Science et de l'Innovation du Québec (MESI). Shaman Luo received a China Scholarship Council grant (File No. 201406600026). Romain Pasque declares that he has no conflict of interest. Gang Chen declares that he has no conflict of interest. Paul Goss declares that he has no conflict of interest. Dongsheng Tu declares that he has no conflict of interest. Philip Lazarus declares that he has no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study and only those that also consented to genetic testing were included in the analyses presented in this paper.

Research involving human participants

All procedures performed in this study were in accordance with the ethical standards of the Queens’s Health Sciences Research Ethics Board and with the 1964 Helsinki declaration on medical research in human subjects and the Canadian Tri-Council Policy Statement on the Ethical Conduct for Research Involving Humans (TCPS).

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Ho, V., Pasquet, R., Luo, S. et al. Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial. Breast Cancer Res Treat 183, 705–716 (2020). https://doi.org/10.1007/s10549-020-05812-1

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  • DOI: https://doi.org/10.1007/s10549-020-05812-1

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