PURPOSE: Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen. PATIENTS AND METHODS: From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis. RESULTS: A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799). CONCLUSION: This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.
PURPOSE:Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen. PATIENTS AND METHODS: From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis. RESULTS: A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799). CONCLUSION: This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.
Authors: Matthew P Goetz; Vera J Suman; Yusuke Nakamura; Kazuma Kiyotani; V Craig Jordan; James N Ingle Journal: J Clin Oncol Date: 2019-06-18 Impact factor: 44.544
Authors: Thomas P Ahern; Lindsay J Collin; James W Baurley; Anders Kjærsgaard; Rebecca Nash; Maret L Maliniak; Per Damkier; Michael E Zwick; R Benjamin Isett; Peer M Christiansen; Bent Ejlertsen; Kristina L Lauridsen; Kristina B Christensen; Rebecca A Silliman; Henrik Toft Sørensen; Trine Tramm; Stephen Hamilton-Dutoit; Timothy L Lash; Deirdre Cronin-Fenton Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-01-13 Impact factor: 4.254
Authors: Neeltje Steeghs; Alwin D R Huitema; Stefanie L Groenland; Remy B Verheijen; Markus Joerger; Ron H J Mathijssen; Alex Sparreboom; Jos H Beijnen; Jan H Beumer Journal: Clin Cancer Res Date: 2021-09-21 Impact factor: 12.531
Authors: Jasmine A Luzum; Natasha Petry; Annette K Taylor; Sara L Van Driest; Henry M Dunnenberger; Larisa H Cavallari Journal: Clin Pharmacol Ther Date: 2021-07-07 Impact factor: 6.903
Authors: Anna Mueller-Schoell; Robin Michelet; Lena Klopp-Schulze; Madelé van Dyk; Thomas E Mürdter; Matthias Schwab; Markus Joerger; Wilhelm Huisinga; Gerd Mikus; Charlotte Kloft Journal: Cancers (Basel) Date: 2021-05-18 Impact factor: 6.639
Authors: Anabel Beatriz Sanchez-Spitman; Dirk-Jan A R Moes; Jesse J Swen; Vincent O Dezentjé; Diether Lambrechts; Patrick Neven; Hans Gelderblom; Henk-Jan Guchelaar Journal: Cancer Chemother Pharmacol Date: 2020-05-29 Impact factor: 3.333