Impacts of Cytochrome P450 2D6 (CYP2D6) Genetic Polymorphism in Tamoxifen Therapy for Breast Cancer.

Natanael Da Silva Bezerra Junior,Marcelo Antônio Oliveira Santos-Veloso,Lucas Soares Bezerra,Lucilia Carvalho Da Fonseca,Wivianne Lisley Andrade Sales

doi:10.1055/s-0038-1676303

Abstract

Tamoxifen (TMX) is the main drug used both in pre and postmenopausal women as adjuvant treatment for hormone receptor-positive breast cancer. An important barrier to the use of TMX is the development of drug resistance caused by molecular processes related to genetic and epigenetic mechanisms, such as the actions of cytochrome P450 2D6 (CYP2D6) polymorphisms and of its metabolites. The present study aimed to review recent findings related to the impact of CYP2D6 polymorphisms and how they can affect the results of TMX in breast cancer treatment. The keywords CYP2D6, tamoxifen, and breast cancer were searched in the PubMed, Scopus, The Cochrane Library, Scielo, and Bireme databases. Studies related to other types of neoplasms or based on other isoenzymes from cytochrome P450, but not on CYP2D6, were excluded. The impact of CYP2D6 polymorphisms in the TMX resistance mechanism remains unclear. The CYP2D6 gene seems to contribute to decreasing the efficacy of TMX, while the main mechanism responsible for therapy failure, morbidity, and mortality is the progression of the disease.

Highlights

Breast cancer is the most common neoplasm among women worldwide, except for skin cancers, accounting for 31% of the cancer cases, and is the second leading cause of cancer-related deaths in females.[1,2] Breast cancer is an important cause of mortality and morbidity, due to its propensity to metastasize to distant sites such as the liver, the lungs, the brain, and the bones.[3,4] Many therapies have been studied in the last few years to improve the prognosis and to decrease mortality
The present study aimed to review recent findings related to the impact of Cytochrome P450 2D6 (CYP2D6) polymorphisms and how they can affect the results of TMX in breast cancer treatment
The CYP2D6 gene seems to contribute to decreasing the efficacy of TMX, while the main mechanism responsible for therapy failure, morbidity, and mortality is the progression of the disease

Summary

Introduction

Breast cancer is the most common neoplasm among women worldwide, except for skin cancers, accounting for 31% of the cancer cases, and is the second leading cause of cancer-related deaths in females.[1,2] Breast cancer is an important cause of mortality and morbidity, due to its propensity to metastasize to distant sites such as the liver, the lungs, the brain, and the bones.[3,4] Many therapies have been studied in the last few years to improve the prognosis and to decrease mortality. The highly polymorphic CYP2D6 gene encodes the principal enzyme of TMX biotransformation to its major active metabolite, endoxifen.[18]. Some studies have shown no alterations in the efficacy of TMX in patients with breast cancer carrying the CYP2D6 gene polymorphism in terms of recurrence and overall survival,[12,20,21] while other studies demonstrated that CYP2D6 gene polymorphisms (especially *3, *4, and *6) significantly affected the efficacy of TMX.[22–24] Because of these controversial results, available recommendations do not suggest the use of CYP2D6 genetic testing to select the best endocrine therapy regimen for patients.[18]. Considering previous studies of the role of CYP2D6 polymorphisms in the TMX resistance mechanism and in the pharmacokinetics of its active metabolite, including CYP2D6 allele heterogeneity among different populations, the present study was conducted to analyze how mutations in the CYP2D6 gene affect patients undergoing breast cancer therapy with TMX.[13,25]

Methods

Findings

Conclusion