Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients

• Type of Material: Article
• Authors: Thomas P. Ahern, University of Vermont; Lindsay J. Collin, Emory University; James W. Baurley, BioRealm; Anders Kjaersgaard, Aarhus University Hospital; Rebecca Nash, Emory University; Maret L. Maliniak, Emory University; Per Damkier, Odense University Hospital; Michael Zwick, Emory University; R. Benjamin Isett, Emory University; Peer M. Christiansen, Randers Regional Hospital; Bent Ejlertsen, Copenhagen University Hospital; Kristina L. Lauridsen, Aarhus University Hospital; Kristina B. Christensen, Aarhus University Hospital; Rebecca A. Silliman, Boston University; Henrik T. Sorensen, Aarhus University Hospital; Trine Tramm, Aarhus University Hospital; Stephen Hamilton-Dutoit, Aarhus University Hospital; Timothy Lash, Emory University; Deirdre Cronin-Fenton, Aarhus University Hospital
• Language: English
• Date: 2020-03-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2020 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1055-9965.EPI-19-0833
• Title of Journal or Parent Work: Cancer Epidemiology Biomarks & Prevention
• Volume: 29
• Issue: 3
• Start Page: 582
• End Page: 590
• Grant/Funding Information: The research also was supported in part by the Emory Integrated Genomics Core Shared Resource of Winship Cancer Institute of Emory University through the US National Cancer Institute (2P30CA138292).; Thomas P. Ahern was supported in part by funding from the National Institute of General Medical Sciences (P20GM103644).; James W. Baurley was supported in part by funding from the US National Institute on Drug Abuse (R43DA041211) and the US National Institute on Alcohol Abuse and Alcoholism (R44AA027675).; This project was also supported by funding from the US National Cancer Institute (R01CA118708) awarded to Timothy L. Lash, the Danish Cancer Society (DP06117) awarded to Stephen Hamilton-Dutoit, the Danish Medical Research Council (DOK 1158869) awarded to Timothy L. Lash, the Karen Elise Jensen Foundation awarded to Henrik Toft Sorensen, and the Program for Clinical Research Infrastructure established by the Lundbeck and the Novo Nordisk Foundations awarded to Henrik Toft Sorensen.; The results reported in this paper correspond to the Specific Aims of R01CA166825 from the US National Cancer Institute awarded to Timothy L. Lash and to the Specific Aims of R167–2013-15861 from the Lundbeck Foundation awarded to Deirdre Cronin-Fenton.; Additional support was provided by the Georgia Clinical & Translational Science Alliance of the US National Institutes of Health under Award Number UL1TR002378.; Research reported in this publication was supported in part by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.
• Keywords: Pharmacogenetics; Life Sciences & Biomedicine; Recurrence; Treatment guidelines; Science & Technology; Primary therapy; Clinical database; Public, Environmental & Occupational Health; CYP2D6 genotype; Cooperative group DBCG; Oncology; Active metabolite; International expert consensus; Concurrent use
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology; Biology, Genetics; Health Sciences, Rehabilitation and Therapy

Abstract

Background Tamoxifen and its metabolites compete with estrogen to occupy the estrogen receptor. The conventional dose of adjuvant tamoxifen overwhelms estrogen in this competition, reducing breast cancer recurrence risk by nearly half. Phase 1 metabolism generates active tamoxifen metabolites and phase 2 metabolism deactivates them. No earlier pharmacogenetic study has comprehensively evaluated the metabolism and transport pathways, and no earlier study has included a large population of premenopausal women. Methods We completed a cohort study of 5959 Danish nonmetastatic premenopausal breast cancer patients, in whom 938 recurrences occurred, and a case-control study of 541 recurrent cases in a cohort of Danish predominantly postmenopausal breast cancer patients, all followed for ten years. We collected formalin-fixed paraffin-embedded tumor blocks and genotyped 32 variants in 15 genes involved in tamoxifen metabolism or transport. We estimated conventional associations for each variant and used prior information about the tamoxifen metabolic path to evaluate the importance of metabolic and transporter pathways. Results No individual variant was notably associated with risk of recurrence in either study population. Both studies showed weak evidence of the importance of phase 1 metabolism in the clinical response to adjuvant tamoxifen therapy. Conclusions Consistent with prior knowledge, our results support the role of phase 1 metabolic capacity in clinical response to tamoxifen. Nonetheless, no individual variant substantially explained the modest phase 1 effect on tamoxifen response. Impact These results are consistent with guidelines recommending against genotype-guided prescribing of tamoxifen, and for the first time provide evidence supporting these guidelines in premenopausal women.