Supplementation of Tamoxifen with low-dose Endoxifen in breast cancer patients with impaired tamoxifen metabolism (TAMENDOX): a randomized controlled phase 1/2 trial

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.