Effects of <em>CYP2D6 </em>and <em>CYP3A5 </em>polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

Abstract

PurposeThis study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations.Patients and methodsOne hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal–Wallis or Mann–Whitney U test, including the simple main effects analysis.ResultsThe patients had stage 0–IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype.ConclusionCYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group.

Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer

“…CYP3A5 *3 (rs776746) is a loss of function allele that is more common in African Americans (MAF = 0.13) than Caucasians (MAF = 0.01) [ 115 ]. Clinical studies have not reported any effect of CYP3A5 *3 on endoxifen levels [ 84 , 90 , 112 , 113 , 115 , 116 , 117 ], even in large studies that conducted subgroup analyses stratified by CYP2D6 and CYP2C9/19 phenotype [ 73 ].…”

Tamoxifen and oxidative stress: an overlooked connection

“…Confirming with previous studies CYP2C19*2 was associated with better efficacy of tamoxifen. CYP3A5 and CYP2C19 plays a minor role compared to CYP2D6 enzyme [69][70][71][72][73][74]. Therefore, researchers concluded there is an association between CYP genotypes and clinical pathology of breast cancer.…”

Effects of Genetic Polymorphisms of Drug Metabolizing Enzymes and co‐Medications on Tamoxifen Metabolism in Black South African Women with Breast Cancer

“…PMs due to CYP2D6 *5/*4 and *4/*5 genotypes have been previously reported to be associated with low and subtherapeutic levels of ENDO 47 and IM genotypes, such as CYP2D6*10 , have also been shown to be associated with low and sometimes subtherapeutic levels of ENDO. 46 , 47 These observations have led to CYP2D6 genotype dose escalation studies in Asians 37 and mixed populations 38 that have demonstrated that increasing the dose of TAM can raise ENDO to therapeutic levels. Our finding that patients carrying CYP2D6*17 and CYP2D6*29 diplotypes have ENDO concentrations below the therapeutic range implies that such patients might benefit from dose adjustments, as has been done for patients carrying the CYP2D6*10 in Asian populations 37 and in patients with diplotypes predictive of IMs in other populations.…”

“…The PM and IM genotypes were expected to have lower ENDO due to effects on the NDM to ENDO pathway catalyzed by CYP2D6. PMs due to CYP2D6 *5/*4 and *4/*5 genotypes have been previously reported to be associated with low and subtherapeutic levels of ENDO 47 and IM genotypes, such as CYP2D6*10 , have also been shown to be associated with low and sometimes subtherapeutic levels of ENDO 46,47 . These observations have led to CYP2D6 genotype dose escalation studies in Asians 37 and mixed populations 38 that have demonstrated that increasing the dose of TAM can raise ENDO to therapeutic levels.…”