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

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.

Recent Contributions of Mass Spectrometry-Based “Omics” in the Studies of Breast Cancer

“…192 Significant effects of genetic polymorphisms of CYP2D6 and CYP3A4 enzymes have been observed to affect the metabolism of TMX and the concentrations of endoxifen. The most active metabolite is lowered with some polymorphisms which require dose adjustments 193,194 13. CONCLUSION "Omic" data in any cancer is generated as a continuum representing the aberrant cellular activities rather than the "omic" terminologies on central dogma which restricts omic in terms of genomic, transcriptomic, proteomics, and metabolomic.…”

“…Significant effects of genetic polymorphisms of CYP2D6 and CYP3A4 enzymes have been observed to affect the metabolism of TMX and the concentrations of endoxifen. The most active metabolite is lowered with some polymorphisms which require dose adjustments , …”