Tamoxifen pharmacokinetics and pharmacodynamics in older patients with non-metastatic breast cancer

• DOI: 10.1007/s10549-023-06925-z
• Publication Date: 2023-04-17T12:02:41Z
• Authors: E. T. D. Souwer; A. Sanchez-Spitman; D. J. A. R. Moes; H. Gelderblom; J. J. Swen; J. E. A. Portielje; H. J. Guchelaar; T. van Gelder
• Keywords: Pharmacodynamic; Antineoplastic Agents, Hormonal; Genotype; Breast Neoplasms; Adjuvant treatment; Therapeutic drug monitoring; Clinical Trial; 3. Good health; Tamoxifen; Breast cancer; Cytochrome P-450 CYP2D6; Humans; Cytochrome P-450 CYP3A; Pharmacokinetics; Female

Abstract Background We aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.

Methods Data for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS).

Results 668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96–1.04, p = 0.84) or CYP polymorphisms.

Conclusion Serum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients.