Tamoxifen metabolism and efficacy in breast cancer- a prospective multicentre trial

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifenefficacy by serum endoxifenlevels and the tamoxifenactivity score (TAS). Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor–positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifenlevels after 3 months. Endpoints were also related to other tamoxifenmetabolites and to TAS. Results: Endoxifenlevels were available for 247 of all 297 patients (83%), of which 209 with target lesions(85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per μg/L increase in endoxifen(95% confidence interval, 0.971–1.046; P = 0.56 ). In general, none of the endpoints was associated with endoxifenlevels, tamoxifenmetabolites, or TAS. Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoringof endoxifento be of clinical value in postmenopausal women treated with tamoxifenfor breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312–8. ©2018 AACR .