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Clinical Trial
. 2025 Feb;209(3):595-602.
doi: 10.1007/s10549-024-07519-z. Epub 2024 Oct 21.

CYP2D6 activity in patients with metastatic breast cancer treated with single agent tamoxifen: results from ECOG-ACRIN E3108

Vered Stearns  1   2 , Anne ONeill  3 , Bryan P Schneider  4 , Todd C Skaar  4 , Minetta C Liu  5   6 , Caroline Lohrisch  7 , Matthew P Goetz  8 , Carlos S Vallejos  9 , Joseph A Sparano  10   11 , Diego Villa  7 , Paula Silverman  12 , Puneet S Cheema  13 , Dennis F Moore Jr  14 , George W Sledge Jr  4   15
Affiliations
Clinical Trial

CYP2D6 activity in patients with metastatic breast cancer treated with single agent tamoxifen: results from ECOG-ACRIN E3108

Vered Stearns et al. Breast Cancer Res Treat. 2025 Feb.

Abstract

Purpose: In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. We assessed the impact of reduced CYP2D6 activity and circulating endoxifen concentrations on breast cancer outcomes.

Patients and methods: Patients with locally advanced or stage IV hormone receptor-positive breast cancer were enrolled in this single arm phase II trial and received open label tamoxifen 20 mg PO daily. The primary objective was to assess CYP2D6 poor metabolizer (PM) vs intermediate and normal metabolizer status (IM + NM) with progression-free survival (PFS). CYP2D6 phenotype was determined from whole blood samples (Roche Amplichip), and secondary endpoint evaluated endoxifen concentrations determined from 3 month post registration plasma samples (Quest Diagnostics).

Results: From September 2010 to June 2013, 113 of planned 204 patients were registered to the trial and began protocol treatment. Accrual to the trial closed early due to lower-than-expected rate of CYP2D6 poor metabolizers. Median age was 62, 86% (97/113) were white, 33% (30/113) Hispanic, 83% (92/113) postmenopausal. Samples were evaluable for CYP2D6 in 75% (85/113) of patients (2/85 PM, 27/85 IM, and 56/85 NM). Median PFS for PM and IM + NM was 12.9 months and 6.9 months, respectively. Median PFS was 11.1 and 13.8 months respectively for patients with low (≤ 15.5) and high (> 15.5) endoxifen concentrations (ng/ml).

Conclusion: We did not observe significant associations between CYP2D6 metabolizer status or endoxifen with PFS. Small sample sizes and barriers to adequate samples in this trial prohibited determination of relationship between these markers and PFS.

Trial id: NCT01124695 (registered May 14, 2010).

Keywords: CYP2D6; Endoxifen; Pharmacogenetics; Tamoxifen.

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Conflict of interest statement

Declarations. Competing interests: The authors report the following competing interests, all outside the submitted work. VS: Received research grants to institution from Abbvie, Biocept, Pfizer, Novartis, Puma Biotechnology, and QUE Oncology; In kind clinical trial assays from Foundation Medicine; Advisory board: Novartis. Chair, Data Safety Monitoring Board, AstraZeneca, all outside the submitted work. AO: None. BPS: Research support (drug only) from Genentech and Pfizer. Research support (testing support only) from Foundation Medicine and Epic Sciences, all outside the submitted work. TCS: None. MCL: Received research grants to institution from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Honoraria from Astra Zeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax to institution. Travel support from AstraZeneca, Genomic Health, Ionis; Employment and stock options Natera Inc., all outside the submitted work. CL: In kind clinical trial research support from Veracyte (formerly Nanostring). Advisory board: Novartis. Data safety monitoring board: SBI ALApharma, all outside the submitted work. MPG: MPG is the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D. and reports personal fees for CME activities from Research to Practice, Clinical Education Alliance, Medscape, and MJH Life Sciences; personal fees serving as a panelist for a panel discussion from Total Health Conferencing and personal fees for serving as a moderator for Curio Science; consulting fees to Mayo Clinic from ARC Therapeutics, AstraZeneca, Biotheranostics, Blueprint Medicines, Lilly, Rna Diagnostics, Sanofi Genzyme, Seattle Genetics and Engage Health Media; and grant funding to Mayo Clinic from Lilly, Pfizer, Sermonix, Loxo, AstraZeneca and ATOSSA Therapeutics. He is an inventor on a patent application entitled “Degrading PKCb1 to Treat Cancer.” CSV: None. JAS: None. DV: Honoraria and advisory boards from Janssen, AstraZeneca, BeiGene, Abbvie, Roche, Kite/Gilead, BMS/Celgene, Zetagen, Merck, Incyte. Research funding (to the institution): Roche, AstraZeneca, all outside the submitted work. PS: None. PSC: None. DFM: None. GWS: Employment Caris Life Sciences, all outside the submitted work. The authors declare no competing interests. Ethical approval: E3108 received approval from each of the participating sites. Consent to participate: A written informed consent was obtained from all individuals included in E3108 for participation and publication.

References

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