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

被引：51

作者：

Neven, Patrick ^{[1
,2
]}

Jongen, Lynn ^{[1
]}

Lintermans, Anneleen ^{[1
]}

Van Asten, Kathleen ^{[1
]}

Blomme, Chantal ^{[2
]}

Lambrechts, Diether ^{[3
,4
]}

Poppe, An ^{[2
]}

Wildiers, Hans ^{[1
,5
]}

Dieudonne, Anne-Sophie ^{[1
]}

Brouckaert, Olivier ^{[2
]}

Decloedt, Jan ^{[6
]}

Berteloot, Patrick ^{[7
]}

Verhoeven, Didier ^{[8
]}

Joerger, Markus ^{[9
]}

Vuylsteke, Peter ^{[10
]}

Wynendaele, Wim ^{[11
]}

Casteels, Minne ^{[12
]}

Van Huffel, Sabine ^{[13
,14
]}

Lybaert, Willem ^{[15
]}

Van Ginderachter, Johan ^{[16
]}

Paridaens, Robert ^{[1
,5
]}

Vergote, Ignace ^{[1
,2
]}

Dezentje, Vincent Olaf ^{[17
,18
]}

Van Calster, Ben ^{[19
,20
]}

Guchelaar, Henk-Jan ^{[17
]}

机构：

[1] Univ Leuven, KU Leuven, Dept Oncol, Herestr 49, B-3000 Leuven, Belgium

[2] Univ Hosp Leuven, Dept Gynaecol & Obstet, Leuven, Belgium

[3] Univ Leuven, Dept Human Genet, Lab Translat Genet, KU Leuven, Leuven, Belgium

[4] VIB Vesalius Res Ctr, Lab Translat Genet, Leuven, Belgium

[5] Univ Hosp Leuven, Dept Med Oncol, Leuven, Belgium

[6] Algemeen Ziekenhuis Sint Blasius, Dept Gynaecol & Obstet, Dendermonde, Belgium

[7] Algemeen Ziekenhuis Sint Maarten, Dept Gynaecol & Obstet, Duffel, Belgium

[8] Algemeen Ziekenhuis Klina, Dept Med Oncol, Brasschaat, Belgium

[9] Cantonal Hosp, Dept Med Oncol & Hematol, St Gallen, Switzerland

[10] Univ Catholic Louvain, CHU UCL, Dept Med Oncol, Namur Site St Elisabeth, Namur, Belgium

[11] Imelda Ziekenhuis, Dept Med Oncol, Bonheiden, Belgium

[12] Univ Leuven, KU Leuven, Dept Clin Pharmacol & Pharmacotherapy, Leuven, Belgium

[13] Univ Leuven, KU Leuven, Dept Elect Engn, Leuven, Belgium

[14] Imec, Leuven, Belgium

[15] Algemeen Ziekenhuis Nikolaas, Dept Med Oncol, St Niklaas, Belgium

[16] Algemeen Ziekenhuis Maria Middelares, Dept Gynaecol & Obstet, Ghent, Belgium

[17] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands

[18] Netherlands Canc Inst Antoni van Leeuwenhoek, Dept Med Oncol, Amsterdam, Netherlands

[19] Univ Leuven, KU Leuven, Dept Dev & Regenerat, Leuven, Belgium

[20] Leiden Univ, Dept Biomed Data Sci, Med Ctr, Leiden, Netherlands

来源：

CLINICAL CANCER RESEARCH | 2018年 / 24卷 / 10期

基金：

美国国家卫生研究院;

关键词：

CYP2D6 ACTIVITY SCORE; ADJUVANT TAMOXIFEN; POSTMENOPAUSAL WOMEN; DOSE-ESCALATION; GENOTYPE; THERAPY; Z-4-HYDROXY-TAMOXIFEN; BIOTRANSFORMATION; RECURRENCE; INHIBITORS;

D O I：

10.1158/1078-0432.CCR-17-3028

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: 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). 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 (PIS), 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. Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for HS 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 mu g/L increase in endoxifen (95% confidence interval, 0.971-1.046;P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: 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. (C) 2018 AACR.

引用

页码：2312 / 2318

页数：7

共 37 条

[1] Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism:: Implication for optimization of breast cancer treatment [J].

Borges, Silvana ;

Desta, Zeruesenay ;

Li, Lang ;

Skaar, Todd C. ;

Ward, Bryan A. ;

Nguyen, Anne ;

Jin, Yan ;

Storniolo, Anna Maria ;

Nikoloff, D. Michele ;

Wu, Lin ;

Hillman, Grant ;

Hayes, Daniel F. ;

Stearns, Vered ;

Flockhart, David A. .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2006, 80 (01) :61-74

[2] Composite Functional Genetic and Comedication CYP2D6 Activity Score in Predicting Tamoxifen Drug Exposure Among Breast Cancer Patients [J].

Borges, Silvana ;

Desta, Zeruesenay ;

Jin, Yan ;

Faouzi, Azzouz ;

Robarge, Jason D. ;

Philip, Santosh ;

Nguyen, Anne ;

Stearns, Vered ;

Hayes, Daniel ;

Rae, James M. ;

Skaar, Todd C. ;

Flockhart, David A. ;

Li, Lang .

JOURNAL OF CLINICAL PHARMACOLOGY, 2010, 50 (04) :450-458

[3] Oxidative metabolism of tamoxifen to Z-4-hydroxy-tamoxifen by cytochrome P450 isoforms:: An appraisal of in vitro studies [J].

Coller, JK .

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2003, 30 (11) :845-848

[4] The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver [J].

Coller, JK ;

Krebsfaenger, N ;

Klein, K ;

Endrizzi, K ;

Wolbold, R ;

Lang, T ;

Nüssler, A ;

Neuhaus, P ;

Zanger, UM ;

Eichelbaum, M ;

Mürdter, TE .

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2002, 54 (02) :157-167

[5] A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers [J].

Decensi, A ;

Robertson, C ;

Viale, G ;

Pigatto, F ;

Johansson, H ;

Kisanga, ER ;

Veronesi, P ;

Torrisi, R ;

Cazzaniga, M ;

Mora, S ;

Sandri, MT ;

Pelosi, G ;

Luini, A ;

Goldhirsch, A ;

Lien, EA ;

Veronesi, U .

JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2003, 95 (11) :779-790

[6] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6 [J].

Desta, Z ;

Ward, BA ;

Soukhova, NV ;

Flockhart, DA .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 310 (03) :1062-1075

[7] CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects [J].

Dezentje, V. O. ;

Opdam, F. L. ;

Gelderblom, H. ;

den Hartigh, J. ;

Van der Straaten, T. ;

Vree, R. ;

Maartense, E. ;

Smorenburg, C. H. ;

Putter, H. ;

Dieudonne, A. S. ;

Neven, P. ;

Van de Velde, C. J. H. ;

Nortier, J. W. R. ;

Guchelaar, H. -J. .

BREAST CANCER RESEARCH AND TREATMENT, 2015, 153 (03) :583-590

[8] CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial [J].

Dezentje, V. O. ;

van Schaik, R. H. N. ;

Vletter-Bogaartz, J. M. ;

van der Straaten, T. ;

Wessels, J. A. M. ;

Kranenbarg, E. M. -K. ;

Berns, E. M. ;

Seynaeve, C. ;

Putter, H. ;

van de Velde, C. J. H. ;

Nortier, J. W. R. ;

Gelderblom, H. ;

Guchelaar, H. -J. .

BREAST CANCER RESEARCH AND TREATMENT, 2013, 140 (02) :363-373

[9] Clinical Implications of CYP2D6 Genotyping in Tamoxifen Treatment for Breast Cancer [J].

Dezentje, Vincent O. ;

Guchelaar, Henk-Jan ;

Nortier, Johan W. R. ;

van de Velde, Cornelis J. H. ;

Gelderblom, Hans .

CLINICAL CANCER RESEARCH, 2009, 15 (01) :15-21

[10] Prevalent breast cancer patients with a homozygous mutant status for CYP2D6 4: Response and biomarkers in tamoxifen users [J].

Dieudonné A.S. ;

Lambrechts D. ;

Claes B. ;

Vandorpe T. ;

Wildiers H. ;

Timmerman D. ;

Billen J. ;

Leunen K. ;

Amant F. ;

Berteloot P. ;

Smeets A. ;

Paridaens R. ;

Weltens C. ;

Van Limbergen E. ;

Van Den Bogaert W. ;

Vergote I. ;

Van Huffel S. ;

Christiaens M.R. ;

Neven P. .

Breast Cancer Research and Treatment, 2009, 118 (3) :531-538

← 1 2 3 4 →