Supplementation of Tamoxifen with low-dose Endoxifen in breast cancer patients with impaired tamoxifen metabolism (TAMENDOX): a randomized controlled phase 1/2 trial
Thomas E. Mürdter, Werner Schroth, Matthew P. Goetz, Roman Tremmel, Svitlana Igel, Elke Schaeffeler, Simon Jäger, Sibylle Loibl, Andreas Gerteis, Lena Pfaff, Christina Bechtner, Denise Wrobel, Ilka Bernhöft, Imma Fischer, Christoph Meisner, Michael Block, Hiltrud Brauch, Matthias Schwab
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引用次数: 0
Abstract
Purpose: Tamoxifen undergoes bioactivation to its active metabolite (Z)-endoxifen, which blocks estrogen-dependent breast tumor growth at high potency. We tested the feasibility and safety of supplementing standard tamoxifen therapy with low-dose (Z)-endoxifen in breast cancer patients with compromised tamoxifen bioactivation. Patients and Methods: We conducted a prospective, interventional, three group randomized trial including 235 hormone receptor-positive breast cancer patients who received standard tamoxifen therapy (20mg/day). Patients were stratified by CYP2D6 genotype (n=78), defining poor (PM), intermediate (IM) and normal metabolizers (NM), or by baseline (Z)-endoxifen plasma concentration (n=78), defining ≤15 nM, 15-25 nM and ≥25 nM. Co-treatment with (Z)-endoxifen 3, 1.5 mg/day or placebo was performed, respectively. A control group (n=79) received placebo regardless of metabolizer phenotype. The primary endpoint was the number of patients with (Z)-endoxifen levels >32 nM after six weeks treatment. Adverse events were continuously monitored. Results: A higher proportion of patients in both intervention groups achieved target concentrations >32 nM compared to control (P < 0.0001). At 3 mg (Z)-endoxifen supplementation, 92.3% of CYP2D6 PM patients and all patients with baseline (Z)-endoxifen ≤15 nM achieved the target concentration. At 1.5 mg (Z)-endoxifen supplementation, 88% of CYP2D6 IM patients and 95% of patients with 15-25 nM baseline (Z)-endoxifen levels achieved the target concentration. Similar proportions of patients receiving (Z)-endoxifen (6/80, 7.5%) or placebo (8/155, 5.2%) experienced Grade 3 adverse events. Conclusion: Adding low-dose (Z)-endoxifen to standard tamoxifen is safe and provides a new approach to personalized anti-estrogen treatment for patients with low endoxifen plasma levels.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.