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

by Selleckchem | Oct 06 2023

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.

Comments:

Summary: The study aimed to investigate the pharmacokinetics and pharmacodynamics of tamoxifen in older women with non-metastatic breast cancer. The researchers analyzed data from the CYPTAM study, which included 668 patients stratified by age groups (<65 and 65 and older). They measured steady-state trough concentrations of tamoxifen and its metabolites and assessed CYP2D6 and CYP3A4 phenotypes through genotyping. Multiple linear regression models were used to analyze the variability of tamoxifen and endoxifen concentrations. The outcome measures included recurrence-free survival at the time of tamoxifen discontinuation (RFSt) and overall survival (OS).

The results showed that older patients (65 and older) had significantly higher concentrations of tamoxifen and endoxifen compared to younger patients, regardless of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained a small portion of the variability in tamoxifen and endoxifen concentrations. Older patients also had worse RFSt and OS compared to younger patients, but these differences were not related to endoxifen concentration or CYP polymorphisms.

The researchers concluded that serum concentrations of tamoxifen and its metabolites are higher in older patients, possibly due to a higher bioavailability of tamoxifen. However, they noted that the clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients.

Overall, this study suggests that age may influence the pharmacokinetics of tamoxifen in older women with breast cancer, but further research is needed to fully understand the clinical implications of these findings.