Cancer Res Treat.  2025 Jan;57(1):140-149. 10.4143/crt.2023.1285.

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

• Lee B
• Nam SJ
• Kim SW
• Yu J
• Chae BJ
• Lee SK
• Ryu JM
• Lee JE
• Lee SY

• KMID: 2564588
• DOI: http://doi.org/10.4143/crt.2023.1285

Abstract

Purpose
The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dose. However, the clinical significance of endoxifen for the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication.
Materials and Methods
The study included 478 breast cancer patients. Tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry. An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff.
Results
An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and the high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% confidence interval [CI], 77.0 to 89.9) and 88.3% (95% CI, 83.3 to 93.5) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor associated with prognosis.
Conclusion
Endoxifen could serve as a marker for appropriate tamoxifen treatment with a cutoff of 21.00 ng/mL. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying suboptimal endoxifen concentrations.

Keyword

Breast neoplasms; Endoxifen; Prognosis; Recurrence-free survival; Tamoxifen

Figure

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  Fig. 1. Study design.

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  Fig. 2. (A) Distribution of endoxifen concentration in our study population. Kaplan-Meier curve of RFSt (B) and RFSc (C) probability of breast cancer patients according to an endoxifen cutoff of 21.00 ng/mL. RFSc, complete recurrence-free survival; RFSt, recurrence-free survival censored following tamoxifen discontinuation.

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  Fig. 3. Kaplan-Meier curve of RFSt (A, C) and RFSc (B, D) probability of breast cancer patients according to an endoxifen cutoff of 5.97 ng/mL (15.98 nM) (A, B) and 10.30 ng/mL (27.58 nM) (C, D). RFSc, complete recurrence-free survival; RFSt, recurrence-free survival censored following tamoxifen discontinuation.

Reference

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