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

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.

Value of therapeutic drug monitoring of endoxifen in Egyptian premenopausal patients with breast cancer given tamoxifen adjuvant therapy: A pilot study

“…The study concluded that reduced plasma level of END (≤ 14.72 nM) after 3 months of TAM treatment could be a predictor of early cancer recurrence in patients under adjuvant TAM therapy (P = 0.041) and a longer follow-up and a larger cohort may be needed to confirm the END cutoff value that is a predictor of long-term recurrence. 51 A study proposed that the increased risk of cancer recurrence at lower concentrations of END is estrogendependent whereas a stimulatory effect of low-END levels may lead to disease growth. However, contradictory observations of increased risk of cancer relapse at high levels of END concentrations (> 70 ng/mL) had no explanation and needed to be validated.…”

“…The study concluded that reduced plasma level of END (≤ 14.72 nM) after 3 months of TAM treatment could be a predictor of early cancer recurrence in patients under adjuvant TAM therapy ( P = 0.041) and a longer follow-up and a larger cohort may be needed to confirm the END cutoff value that is a predictor of long-term recurrence. 51…”

Endoxifen Concentration is Associated with Recurrence-Free Survival in Hormone-Sensitive Breast Cancer Patients

“…Survival analysis was conducted with the Kaplan-Meier estimator, and the statistical significance of the difference between the two groups was determined with a log-rank test. Along with the presumed cutoff, endoxifen cutoffs suggested in previous studies [10][11][12][13][14] were evaluated with our cohort. The evaluated cutoffs from the literature were as follows: 1) 3.36 ng/mL (9.00 nM) [10], 2) 5.29 ng/mL (14.15 nM) [11], 3) 5.60 ng/mL (15.00 nM) [12], 4) 5.97 ng/mL (15.98 nM) [13], and 5) 10.30 ng/mL (27.58 nM) [14].…”

“…Along with the presumed cutoff, endoxifen cutoffs suggested in previous studies [10][11][12][13][14] were evaluated with our cohort. The evaluated cutoffs from the literature were as follows: 1) 3.36 ng/mL (9.00 nM) [10], 2) 5.29 ng/mL (14.15 nM) [11], 3) 5.60 ng/mL (15.00 nM) [12], 4) 5.97 ng/mL (15.98 nM) [13], and 5) 10.30 ng/mL (27.58 nM) [14].…”

“…Therapeutic drug monitoring (TDM) of endoxifen concentration could be beneficial for breast cancer patients if endoxifen concentration correlates with prognosis. However, there is no consensus on the cutoff for endoxifen to distinguish prognosis, with multiple studies proposing different cutoff values [10][11][12][13][14]. While a previous study also attempted to elucidate the prognostic significance of endoxifen using various previously reported cutoffs ranging from 3.3 ng/mL to 10.3 ng/mL, none of these cutoffs were significant in the survival analysis [14].…”