Almeida Thais, Schroth Werner, Nardin Jeanine, Mürdter Thomas E, Winter Stefan, Picolotto Solane, Hoppe Reiner, Kogin Jenifer, Gaio Elisa, Dasenbrock Angela, Skrsypcsak Raquel Cristina, de Noronha Lucia, Schwab Matthias, Brauch Hiltrud, Casali-da-Rocha José Claudio
Clinical Oncology Department, Erasto Gaertner Hospital, Curitiba 81520-060, Brazil.
Post Graduation Department, Pontifical Catholic University of Parana, Curitiba 80215-901, Brazil.
J Pers Med. 2022 Mar 22;12(4):511. doi: 10.3390/jpm12040511.
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 ( = 0.045) and after adjustment for stage (HR 2.52; 95% CI 1.13-5.65; = 0.024). However, modeling of plasma concentrations with splines instead of dichotomization did not verify a significant association with EFS (univariate analysis: = 0.158; adjusted for stage: = 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.
坚持治疗和联合用药，以及诸如CYP2D6基因型等分子因素，都会影响他莫昔芬的代谢，进而影响早期乳腺癌的预后。在一项对149名来自巴西的接受他莫昔芬治疗的早期乳腺癌患者进行的为期5年的前瞻性研究中，我们调查了3个月时活性他莫昔芬代谢物（Z）-4-羟基他莫昔芬与经临床病理因素调整后的无事件生存期（EFS）之间的关联。25名患者（16.8%）在中位随访52.3个月时复发或死亡。当我们应用先前独立研究中使用的假定15 nM阈值时，在单变量分析中，低于该阈值的（Z）-4-羟基他莫昔芬水平与较短的EFS相关（P = 0.045），在调整分期后也是如此（风险比2.52；95%置信区间1.13 - 5.65；P = 0.024）。然而，用样条函数对血浆浓度进行建模而非二分法处理，并未证实与EFS有显著关联（单变量分析：P = 0.158；调整分期后：P = 0.117）。因此，在我们这项小型探索性研究中，无法一致证明他莫昔芬代谢受损与早期乳腺癌复发之间的联系。这种不一致性说明需要开展更大规模的建模研究，并辅以机制性药效学分析，以便为这种疑似关联以及确定合适的预测性（Z）-4-羟基他莫昔芬阈值提供新的线索。
