Abstract
PurposeTamoxifen is a key therapeutic option for breast cancer treatment. Understanding its complex metabolism and pharmacokinetics is important for dose optimization. We examined the possibility of utilizing archival formalin-fixed paraffin-embedded (FFPE) tissue as an alternative sample source for quantification since well-annotated retrospective samples were always limited.MethodsSix 15 μm sections of FFPE tissues were deparaffinized with xylene and purified using solid-phase extraction. Tamoxifen and its metabolites were separated and detected by liquid chromatography–tandem mass spectrometry using multiple-reaction monitoring.ResultsThis method was linear between 0.4 and 200 ng/g for 4-hydroxy-tamoxifen and endoxifen, and 4–2,000 ng/g for tamoxifen and N-desmethyl-tamoxifen. Inter- and intra-assay precisions were <9 %, and mean accuracies ranged from 81 to 106 %. Extraction recoveries were between 83 and 88 %. The validated method was applied to FFPE tissues from two groups of patients, who received 20 mg/day of tamoxifen for >6 months, and were classified into breast tumor recurrence and non-recurrence. Our preliminary data show that levels of tamoxifen metabolites were significantly lower in patients with recurrent cancer, suggesting that inter-individual variability in tamoxifen metabolism might partly account for the development of cancer recurrence. Nevertheless, other causes such as non-compliance or stopping therapy of tamoxifen could possibly lead to the concentration differences.ConclusionsThe ability to successfully study tamoxifen metabolism in such tissue samples will rapidly increase our knowledge of how tamoxifen’s action, metabolism and tissue distribution contribute to breast cancer control. However, larger population studies are required to understand the underlying mechanism of tamoxifen metabolism for optimization of its treatment.
Highlights
Tamoxifen (TAM) has an important role in breast cancer treatment and prevention
The multiple-reaction monitoring (MRM) technique used in our LC–MS/MS assay provides a high degree of sensitivity and specificity
Limit of detection (LOD) of the assay was obtained based on the concentrations that produced a signal-to-noise (S/N) ratio of ≥3 to deduce the presence of the analytes in formalinfixed paraffin-embedded (FFPE) tissue
Summary
Tamoxifen (TAM) has an important role in breast cancer treatment and prevention. This drug inhibits breast cancer by competing with endogenous estrogens for binding to estrogen receptors (ERs) in tumor tissue. Despite the proven anti-cancer effects of TAM, numerous studies have shown that the properties of this drug may cause detrimental effects such as increased risk of endometrial cancer and thromboembolic diseases [1,2,3,4]. Many patients develop resistance to TAM therapy after several years of treatment and eventually experience cancer recurrence [5,6,7]. The therapeutic and adverse effects of TAM have stimulated interest in understanding the biological activity of this drug. There is a growing body of evidence indicating that the anti-proliferative
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