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Article

(Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study

by
Thais Almeida
1,2,
Werner Schroth
3,
Jeanine Nardin
4,5,
Thomas E. Mürdter
3,
Stefan Winter
3,
Solane Picolotto
6,
Reiner Hoppe
3,
Jenifer Kogin
5,
Elisa Gaio
1,
Angela Dasenbrock
1,
Raquel Cristina Skrsypcsak
1,
Lucia de Noronha
2,
Matthias Schwab
3,7,8,9,10,
Hiltrud Brauch
3,7,8,† and
José Claudio Casali-da-Rocha
2,11,12,*,†
1
Clinical Oncology Department, Erasto Gaertner Hospital, Curitiba 81520-060, Brazil
2
Post Graduation Department, Pontifical Catholic University of Parana, Curitiba 80215-901, Brazil
3
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tuebingen, 70376 Tuebingen, Germany
4
Clinical Research Department, Erasto Gaertner Hospital, Curitiba 81520-060, Brazil
5
School of Health Science, UniBrasil, Curitiba 82820-540, Brazil
6
Pharmacy Department, Erasto Gaertner Hospital, Curitiba 81520-060, Brazil
7
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, 69120 Tuebingen, Germany
8
Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, 69120 Tuebingen, Germany
9
Department of Clinical Pharmacology, University of Tübingen, 69120 Tuebingen, Germany
10
Department of Biochemistry and Pharmacy, University of Tübingen, 69120 Tuebingen, Germany
11
Department of Oncogenetics, Erasto Gaertner Hospital, Curitiba 81520-060, Brazil
12
Department of Oncogenetics, A. C. Camargo Cancer Center, São Paulo 01525-001, Brazil
 
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*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Pers. Med. 2022, 12(4), 511; https://doi.org/10.3390/jpm12040511
Submission received: 24 February 2022 / Revised: 12 March 2022 / Accepted: 19 March 2022 / Published: 22 March 2022
(This article belongs to the Special Issue Genome Research and Personalized Medicine in Breast Cancer)
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Abstract

Adherence to treatment and use of co-medication, but also molecular factors such as CYP2D6 genotype, affect tamoxifen metabolism, with consequences for early breast cancer prognosis. In a prospective study of 149 tamoxifen-treated early-stage breast cancer patients from Brazil followed up for 5 years, we investigated the association between the active tamoxifen metabolite (Z)-endoxifen at 3 months and event-free survival (EFS) adjusted for clinico-pathological factors. Twenty-five patients (16.8%) had recurred or died at a median follow-up of 52.3 months. When we applied a putative 15 nM threshold used in previous independent studies, (Z)-endoxifen levels below the threshold showed an association with shorter EFS in univariate analysis (p = 0.045) and after adjustment for stage (HR 2.52; 95% CI 1.13–5.65; p = 0.024). However, modeling of plasma concentrations with splines instead of dichotomization did not verify a significant association with EFS (univariate analysis: p = 0.158; adjusted for stage: p = 0.117). Hence, in our small exploratory study, the link between impaired tamoxifen metabolism and early breast cancer recurrence could not be unanimously demonstrated. This inconsistency justifies larger modeling studies backed up by mechanistic pharmacodynamic analyses to shed new light on this suspected association and the stipulation of an appropriate predictive (Z)-endoxifen threshold.
Keywords: breast cancer; CYP2D6; tamoxifen; (Z)-endoxifen; early recurrence; survival; Brazil breast cancer; CYP2D6; tamoxifen; (Z)-endoxifen; early recurrence; survival; Brazil
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MDPI and ACS Style

Almeida, T.; Schroth, W.; Nardin, J.; Mürdter, T.E.; Winter, S.; Picolotto, S.; Hoppe, R.; Kogin, J.; Gaio, E.; Dasenbrock, A.; et al. (Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study. J. Pers. Med. 2022, 12, 511. https://doi.org/10.3390/jpm12040511

AMA Style

Almeida T, Schroth W, Nardin J, Mürdter TE, Winter S, Picolotto S, Hoppe R, Kogin J, Gaio E, Dasenbrock A, et al. (Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study. Journal of Personalized Medicine. 2022; 12(4):511. https://doi.org/10.3390/jpm12040511

Chicago/Turabian Style

Almeida, Thais, Werner Schroth, Jeanine Nardin, Thomas E. Mürdter, Stefan Winter, Solane Picolotto, Reiner Hoppe, Jenifer Kogin, Elisa Gaio, Angela Dasenbrock, and et al. 2022. "(Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study" Journal of Personalized Medicine 12, no. 4: 511. https://doi.org/10.3390/jpm12040511

APA Style

Almeida, T., Schroth, W., Nardin, J., Mürdter, T. E., Winter, S., Picolotto, S., Hoppe, R., Kogin, J., Gaio, E., Dasenbrock, A., Skrsypcsak, R. C., de Noronha, L., Schwab, M., Brauch, H., & Casali-da-Rocha, J. C. (2022). (Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study. Journal of Personalized Medicine, 12(4), 511. https://doi.org/10.3390/jpm12040511

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