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Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial

Patrick Neven, Lynn Jongen, Anneleen Lintermans, Kathleen Van Asten, Chantal Blomme, Diether Lambrechts, An Poppe, Hans Wildiers, Anne-Sophie Dieudonné, Olivier Brouckaert, Jan Decloedt, Patrick Berteloot, Didier Verhoeven, Markus Joerger, Peter Vuylsteke, Wim Wynendaele, Minne Casteels, Sabine Van Huffel, Willem Lybaert, Johan Van Ginderachter, Robert Paridaens, Ignace Vergote, Vincent Olaf Dezentjé, Ben Van Calster & Henk-Jan Guchelaar

abstract Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). 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 endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Endoxifen levels 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; = ). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. .
   
citation Neven P, Jongen L, Lintermans A, Van Asten K, Blomme C, Lambrechts D, Poppe A, Wildiers H, Dieudonné A S, Brouckaert O, Decloedt J, Berteloot P, Verhoeven D, Joerger M, Vuylsteke P, Wynendaele W, Casteels M, Van Huffel S, Lybaert W, Van Ginderachter J, Paridaens R, Vergote I, Dezentjé V O, Van Calster B, Guchelaar H J. Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial. Clin Cancer Res 2018; 24:2312-2318.
   
type journal paper/review (English)
date of publishing 19-02-2018
journal title Clin Cancer Res (24/10)
ISSN print 1078-0432
pages 2312-2318
PubMed 29459457
DOI 10.1158/1078-0432.CCR-17-3028