Abstract
PurposeTamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy. Three endoxifen thresholds have been suggested (5.9 ng/ml, 5.2 ng/ml and 3.3 ng/ml) for therapeutic drug monitoring (TDM). Our aim was to validate these thresholds and to examine endoxifen exposure with clinical outcome in early-breast cancer patients using tamoxifen.MethodsData from 667 patients from the CYPTAM study (NTR1509) were available. Patients were stratified (above or below), according to the endoxifen threshold values for tamoxifen efficacy and tested by Cox regression. Logistic regressions to estimate the probability of relapse and tamoxifen discontinuation were performed.ResultsNone of the thresholds showed a statistically significant difference in relapse-free survival: 5.2 ng/ml threshold: hazard ratio (HR): 2.545, 95% confidence interval (CI) 0.912–7.096, p value: 0.074; 3.3 ng/ml threshold: HR: 0.728; 95% CI 0.421–1.258, p value: 0.255. Logistic regression did not show a statistically significant association between the risk of relapse (odds ratio (OR): 0.971 (95% CI 0.923–1.021, p value: 0.248) and the risk for tamoxifen discontinuation (OR: 1.006 95% CI 0.961–1.053, p value: 0.798) with endoxifen concentrations.ConclusionOur findings do not confirm the endoxifen threshold values for TDM nor does it allow definition of a novel threshold. These findings indicate a limited value of TDM to guide tamoxifen efficacy.
Highlights
In the therapy of breast cancer, tamoxifen has been successfully prescribed for more than 40 years as adjuvant endocrine therapy in early-breast cancer patients [1]
Patients were categorized in the different groups depending on their endoxifen serum concentration according to the different proposed endoxifen thresholds (5.9 ng/ml, 5.2 ng/ml, 3.3 ng/ml and median (10.3 ng/ml)
In this large cohort of early-breast cancer patients receiving tamoxifen, logistic regression analyses suggest a minor exposure–response relation with a slightly decreased risk of relapse and a small increased risk for tamoxifen discontinuation at higher endoxifen concentrations. These observations indicates the existence of a concentration–effect relationship for endoxifen concentrations and the probability of breast cancer relapse (RFSt) the clinical relevance seems limited
Summary
In the therapy of breast cancer, tamoxifen has been successfully prescribed for more than 40 years as adjuvant endocrine therapy in early-breast cancer patients [1]. In the current clinical guidelines, tamoxifen is recommended for premenopausal female patients as a 5-year monotherapy [2, 3], whereas for postmenopausal women a switch to an aromatase inhibitor is advised after two of 3 years of tamoxifen treatment [2, 3]. Tamoxifen is a selective estrogen receptor modulator that is characterised by a complex metabolism. 4-hydroyx-tamoxifen and endoxifen are recognized as the active metabolites of tamoxifen.
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