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

Souwer, E.T.D.; Sanchez-Spitman, A.; Moes, D.J.A.R.; Gelderblom, H.; Swen, J.J.; Portielje, J.E.A.; ... ; Gelder, T. van (2023)

Article / Letter to editor

BackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData 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).Results668 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, R-2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R-2 = 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.ConclusionSerum 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.

• Breast cancer
• Adjuvant treatment
• Tamoxifen
• Therapeutic drug monitoring
• Pharmacokinetics
• Pharmacodynamic

• All authors: Souwer, E.T.D.; Sanchez-Spitman, A.; Moes, D.J.A.R.; Gelderblom, H.; Swen, J.J.; Portielje, J.E.A.; Guchelaar, H.J.; Gelder, T. van
• Date: 2023-04-17
• Journal: Breast Cancer Research and Treatment
• Volume: 199
• Pages: 471 - 478
• DOI: doi:10.1007/s10549-023-06925-z
• Link: https://link.springer.com/article/10.1007/s10549-023-06925-z