Abstract
The CYP2D6 enzyme is crucial for the metabolism of tamoxifen. The CYP2D6 gene is highly polymorphic, and individuals can be extensive, intermediate, or poor tamoxifen metabolizers. The aim of this study was to determine the frequencies of the CYP2D6 *3, *4, and *10 alleles in women with breast cancer who were treated with tamoxifen and analyze the association of enzyme activity with prognostic factors and disease-free survival. We observed a high frequency of CYP2D6 *10, with an allelic frequency of 0.14 (14.4%). The *3 allele was not present in the studied population, and *4 had an allelic frequency of 0.13 (13.8%). We conclude that patients with reduced CYP2D6 activity did not present worse tumor characteristics or decreased disease-free survival than women with normal enzyme activity, as the difference was not statistically significant. We also observed a high frequency of CYP2D6 *10, which had not been previously described in this specific population. This study is the first in north-northeastern Brazil that aimed to contribute to the knowledge of the Brazilian regional profile for CYP2D6 polymorphisms and their phenotypes. These findings add to the knowledge of the distribution of different polymorphic CYP2D6 alleles and the potential role of CYP2D6 genotyping in clinical practice prior to choosing therapeutic protocols.
Highlights
Cytochrome P450 is involved in the metabolism of many drugs, including antidepressants, b-blockers, antiarrhythmics, antihypertensives, opioids, antipsychotics, and antineoplastics [1]
The aim of this study was to determine the frequencies of the CYP2D6 *3, *4, and *10 alleles in women with breast cancer who were treated with tamoxifen and analyze the association of enzyme activity with prognostic factors and disease-free survival
These studies indicate that women with breast cancer (BC) who are carriers of one or more alleles that result in decreased CYP2D6 function, or those who use potent enzyme inhibitors, such as fluoxetine and paroxetine, have inferior therapy outcomes than women with normal CYP2D6 enzyme function
Summary
Cytochrome P450 is involved in the metabolism of many drugs, including antidepressants, b-blockers, antiarrhythmics, antihypertensives, opioids, antipsychotics, and antineoplastics [1]. Tamoxifen (TMX), a selective modulator of the estrogen receptor (ER), has been considered the gold standard endocrine treatment of breast cancer (BC) for more than three decades [2]. It is used as an adjuvant endocrine therapy in women with ER-positive breast tumors for treatment of pre- and post-menopausal women with metastatic BC, chemoprevention in high-risk women, and treatment of women with in situ ductal carcinoma [3]. The clinical outcomes resulting from TMX treatment are influenced by several factors, including activity of the cytochrome P450 enzyme, patient adherence to treatment, use of comedications that can inhibit conversion of TMX into active metabolites, and other mechanisms of molecular resistance [4].
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