Abstract P6-04-05: Tamoxifen dose escalation based on endoxifen level: a prospective trial with genotyping, phenotyping and pharmacokinetics over 4 months.
Authors: K Zaman, E Dahmane, L Perey, A Bodmer, S Anchisi, A Wolfer, M Galmiche, A Stravodimou, T Buclin, C Eap, L Decosterd, C Csajka, S Leyvraz
Journal: Cancer Research (2012)

Abstract Background: Retrospective studies assessing the impact of tamoxifen (Tam) metabolism and its active metabolite, endoxifen, on the efficacy of the treatment produced conflicting results. The prospective CYPTAM-BRUT 2 trial is ongoing1. In the present study we assessed if the level of Tam metabolites could be improved by doubling tamoxifen dose in breast cancer patients (pts) with any CYP2D6 genotype, poor (PM), intermediate (IM) and also extensive metabolizer (EM). Patients and methods: This multicenter, prospective, open-label trial included pts treated with Tam for ≥ 4 months. CYP2D6 activity was determined centrally by genotyping and phenotyping (dextromethorphan test). Liquid chromatography-tandem-mass spectrometry was used to measure Tam, N-desmethyltamoxifen (N-DMT), 4-hydroxytamoxifen (4-HT) and endoxifen twice at baseline (Tam 20 mg qd), then at days 30, 90 and 120 after having increased the dose to 20 mg bid. Endoxifen increase and the differences between genotype/phenotype subgroups were analyzed by ANOVA. Results: 76 pts were analyzed. Steady-state concentrations for Tam and its metabolites were reached in 30 days after doubling the dose. A range of 1.6 to 1.8 fold increase was observed. Geometric mean plasma concentrations in ng/ml (CV%) were: at baseline and day 30 respectively 134 (48) and 246 (46) for tamoxifen (p &amp;lt; 0.0001); 246 (53) and 413 (48) for N-DMT (p &amp;lt; 0.0001); 2.3 (44) and 3.7 (51) for 4HT (p &amp;lt; 0.0001); 18.7 (89) and 31.1 (92) for endoxifen (p = 0.005). The level of endoxifen increased 1.4 to 1.7 folds in all genotype subgroups with geometric mean plasma concentrations in ng/ml (CV%): 6.9 (36) to 9.7 (24) in PMs (p = 0.7); 14.2 (69) to 20.7 (76) in IMs (p &amp;lt; 0.0001); and 22.6 (76) to 38.7 (85) in EMs (p &amp;lt; 0.0001). Similar results were obtained while considering phenotype subgroups. Genotypes and phenotypes explained less than 30% of the variability in endoxifen levels. The occurrence of hot flashes and night sweating were followed prospectively. Endoxifen levels did not predict an increase in HF/NS events' overall occurrence (OR = 1.01, CI95% 0.78–1.31 for HF and 1.01, CI95% 0.79–1.29 for NS). Twelve pts received CYP2D6 inhibitors. Nine pts did not complete the planned 4 months with tamoxifen 20 mg bid. The main reasons were mood disorders, hot flashes, headache and nausea. Self-reported treatment compliance assessed by monthly anonymous questionnaire was ≥ 95%, except 80–95% in 4 pts. Conclusions: This is the first trial reporting the impact of the increase of tamoxifen dose in all CYP2D6 genotypes, including EMs. Dose escalation of tamoxifen increased significantly the plasma level of endoxifen by similar ratio in all genotype subgroups. Because of a huge inter-individual variability genotyping and phenotyping are not adequate surrogate markers of endoxifen level. Very low endoxifen levels are observed even in pts classified as EM. Future trials aiming to improve the plasma level of endoxifen should consider direct measurement of the metabolite in plasma and adjust tamoxifen dose according to the initial level of the metabolite independently of the genotype. Reference 1. A. Dieudonné, Journal of Clinical Oncology, 2011; vol 29, No 15, suppl (May 20, 2011): TPS 140 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-05.