Tamoxifen Pharmacokinetics and Pharmacodynamics in Older Patients with Non-metastatic Breast Cancer

Overview

Journal Breast Cancer Res Treat

Specialty Oncology

Date 2023 Apr 17

PMID 37067610

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

Affiliations

Soon will be listed here.

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, R = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R = 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.

Citing Articles

Effects of tamoxifen on cognitive function in patients with primary breast cancer.

Luijendijk M, Buijs S, Jager A, Koolen S, van der Wall E, Schagen S Br J Cancer. 2024; 132(2):180-187.

PMID: 39592740 PMC: 11747089. DOI: 10.1038/s41416-024-02914-1.

References

Sanchez-Spitman A, Swen J, Dezentje V, Moes D, Gelderblom H, Guchelaar H . Effect of CYP2C19 genotypes on tamoxifen metabolism and early-breast cancer relapse. Sci Rep. 2021; 11(1):415. PMC: 7801676. DOI: 10.1038/s41598-020-79972-x. View

Sanchez Spitman A, Moes D, Gelderblom H, Dezentje V, Swen J, Guchelaar H . Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. Eur J Clin Pharmacol. 2017; 73(12):1589-1598. PMC: 5684327. DOI: 10.1007/s00228-017-2323-2. View

Sanchez-Spitman A, Moes D, Swen J, Dezentje V, Lambrechts D, Neven P . Exposure-response analysis of endoxifen serum concentrations in early-breast cancer. Cancer Chemother Pharmacol. 2020; 85(6):1141-1152. PMC: 7305085. DOI: 10.1007/s00280-020-04089-x. View

Sanchez-Spitman A, Swen J, Dezentje V, Moes D, Gelderblom H, Guchelaar H . Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. Expert Rev Clin Pharmacol. 2019; 12(6):523-536. DOI: 10.1080/17512433.2019.1610390. View

Baxter S, Teft W, Choi Y, Winquist E, Kim R . Tamoxifen-associated hot flash severity is inversely correlated with endoxifen concentration and CYP3A4*22. Breast Cancer Res Treat. 2014; 145(2):419-28. DOI: 10.1007/s10549-014-2963-1. View

Rae J, Drury S, Hayes D, Stearns V, Thibert J, Haynes B . CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012; 104(6):452-60. PMC: 3611934. DOI: 10.1093/jnci/djs126. View

Caudle K, Sangkuhl K, Whirl-Carrillo M, Swen J, Haidar C, Klein T . Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci. 2019; 13(1):116-124. PMC: 6951851. DOI: 10.1111/cts.12692. View

Lien E, Soiland H, Lundgren S, Aas T, Steen V, Mellgren G . Serum concentrations of tamoxifen and its metabolites increase with age during steady-state treatment. Breast Cancer Res Treat. 2013; 141(2):243-8. PMC: 3785179. DOI: 10.1007/s10549-013-2677-9. View

Fotoohi A, Karim H, Lafolie P, Pohanka A, Ostervall J, Hatschek T . Pronounced Interindividual But Not Intraindividual Variation in Tamoxifen and Metabolite Levels in Plasma During Adjuvant Treatment of Women With Early Breast Cancer. Ther Drug Monit. 2015; 38(2):239-45. DOI: 10.1097/FTD.0000000000000257. View

10.

Braal C, Jager A, Oomen-de Hoop E, Westenberg J, Lommen K, de Bruijn P . Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer. Clin Pharmacokinet. 2021; 61(4):527-537. PMC: 8975771. DOI: 10.1007/s40262-021-01077-z. View

11.

Tamura K, Imamura C, Takano T, Saji S, Yamanaka T, Yonemori K . Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study. J Clin Oncol. 2019; 38(6):558-566. PMC: 7030889. DOI: 10.1200/JCO.19.01412. View

12.

Braal C, Beijnen J, Koolen S, Oomen-de Hoop E, Steeghs N, Jager A . Relevance of Endoxifen Concentrations: Absence of Evidence Is Not Evidence of Absence. J Clin Oncol. 2019; 37(22):1980-1981. DOI: 10.1200/JCO.19.00418. View

13.

Hertz D, Kidwell K, Hilsenbeck S, Oesterreich S, Osborne C, Philips S . CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. Breast Cancer Res Treat. 2017; 166(1):277-287. PMC: 6028015. DOI: 10.1007/s10549-017-4400-8. View

14.

Sheth H, Lord G, Tkaczuk K, Danton M, Lewis L, Langenberg P . Aging may be associated with concentrations of tamoxifen and its metabolites in breast cancer patients. J Womens Health (Larchmt). 2003; 12(8):799-808. DOI: 10.1089/154099903322447765. View

15.

Province M, Goetz M, Brauch H, Flockhart D, Hebert J, Whaley R . CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther. 2013; 95(2):216-27. PMC: 3904554. DOI: 10.1038/clpt.2013.186. View

16.

Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt S . Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011; 89(5):718-25. PMC: 3081375. DOI: 10.1038/clpt.2011.32. View

17.

Sanchez-Spitman A, Dezentje V, Swen J, Moes D, Bohringer S, Batman E . Tamoxifen Pharmacogenetics and Metabolism: Results From the Prospective CYPTAM Study. J Clin Oncol. 2019; 37(8):636-646. DOI: 10.1200/JCO.18.00307. View

18.

Helland T, Henne N, Bifulco E, Naume B, Borgen E, Kristensen V . Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients. Breast Cancer Res. 2017; 19(1):125. PMC: 5706168. DOI: 10.1186/s13058-017-0916-4. View

19.

Peyrade F, Frenay M, Etienne M, Ruch F, Guillemare C, Francois E . Age-related difference in tamoxifen disposition. Clin Pharmacol Ther. 1996; 59(4):401-10. DOI: 10.1016/S0009-9236(96)90108-3. View

20.

Sanchez-Spitman A, Moes D, Gelderblom H, Dezentje V, Swen J, Guchelaar H . The effect of rs5758550 on CYP2D6*2 phenotype and formation of endoxifen in breast cancer patients using tamoxifen. Pharmacogenomics. 2017; 18(12):1125-1132. DOI: 10.2217/pgs-2017-0080. View