CYP2D6 GENOTYPE AND PHENOTYPE CHARACTERIZATION IN A BRAZILIAN BREAST CANCER POPULATION

Jeanine Marie Nardin, Thais Abreu de Almeida, Angela Dasenbrock, Elisa Gaio, Raquel Skrsypcsak, Roberto Pecoit Filho, Hiltrud Brauch, Jose Claudio Casali da Rocha

Institution: PUC-PR e Hospital Erasto Gaertner – LPCC

Breast cancer is the most frequent cancer among women and despite the efforts to identify subsets of patients, different outcomes and response patterns are observed. This biological variability raises questions about the factors that may be relevant to the different answers. Tamoxifen is standard-of-care for the treatment of ER-positive breast cancer therefore, the CYP2D6 tamoxifen pharmacogenetic relationship is relevant and the clinical outcome of tamoxifen-treated patients may be influenced by it. Tamoxifen undergoes a hepatic biotransformation and the formation of the major active metabolite strongly depends on the activity of the drug-metabolizing enzyme cytochrome P450(CYP)2D6. CYP2D6 is highly polymorphic and presents with variable functional activities (phenotypes): from absent (PM), reduced (IM), normal (EM), to increased (UM) enzyme function. The main objective of this study was to determine the frequencies of genotypes at CYP2D6. For that 188 subjects with breast cancer were recruited from April to December/2014 and CYP2D6 genotyping was performed for 9 alleles using MALDI-TOF and Taqman. The median age of patients was 54 years, average BMI was 28,56 Kg/m2. The most common histological subtype was invasive carcinoma (87,7%) and the immunohistochemical analysis was ER-positive for 69,9% cases, (18,7% positive for HER2 and 18,3% triple-negative). The current pharmacogenetic investigation includes 188 patients: 73% whites, 3,2% blacks, 23% pardo/mulato, 0,5% yellow, and 0,5% indians. With the exception of CYP2D6*7 and *8 all genotyped CYP2D6 alleles were present. Genotypes did not deviate from Hardy-Weinberg equilibrium. The minor allele frequencies for the major CYP2D6*4 allele was 13,1% as compared to 21% in Europeans. A comparison of CYP2D6 activity scores with European patients showed lower frequencies of CYP2D6 PM patients (1.6% vs 6-8%) and a higher frequency of EM patients (46% vs 37%) which may be explained by population admixture and must be addressed in an extended analysis considering additional CYP2D6 alleles.

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