Forschung & Innovation
Publikationen
Supplementation of Tamoxifen with Low-Dose Endoxifen in Patients with Breast Cancer with Impaired Tamoxifen Metabolism (TAMENDOX)
PMU Autor*in
Simon Jager
Alle Autor*innen
Thomas E. Murdter, Werner Schroth, Matthew P. Goetz, Roman Tremmel, Svitlana Igel, Elke Schaeffeler, Simon Jager, Sibylle Loibl, Andreas Gerteis, Lena Pfaff, Christina Bechtner, Denise Wrobel, Ilka Bernhoft, Imma Fischer, Christoph Meisner, Michael Block, Hiltrud Brauch, Matthias Schwab,
Fachzeitschrift
CLINICAL CANCER RESEARCH
Kurzfassung
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 patients with breast cancer with compromised tamoxifen bioactivation. Patients and Methods :We conducted a prospective, interventional, three group randomized trial including 235 patients with hormone receptor-positive breast cancer who received standard tamoxifen therapy (20 mg/day). Patients were stratified by CYP2D6 genotype (n = 78), defining poor, intermediate, and normal metabolizers, or by baseline (Z)-endoxifen plasma concentration (n = 78), defining <= 15, 15 to 25, and >= 25 nmol/L. Co-treatment with (Z)-endoxifen 3 and 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 nmol/L after 6 weeks of treatment. Adverse events were continuously monitored. Results: A higher proportion of patients in both intervention groups achieved target concentrations >32 nmol/L compared with control (P < 0.0001). At 3 mg (Z)-endoxifen supplementation, 92.3% of CYP2D6 poor metabolizer patients and all patients with baseline (Z)-endoxifen <= 15 nmol/L achieved the target concentration. At 1.5 mg (Z)-endoxifen supplementation, 88% of CYP2D6 intermediate metabolizer patients and 95% of patients with 15 to 25 nmol/L 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. Conclusions: Adding low-dose (Z)-endoxifen to standard tamoxifen is safe and provides a new approach to personalized antiestrogen treatment for patients with low endoxifen plasma levels.
Keywords
WOMEN, Estrogen-receptor, Active metabolite, Cyp2d6 genotype