Comparative analysis of the CYP2D6 metabolic activity and its effect on its effect on the treatment results of primary breast cancer

Abstract

Background. Standard treatment for hormone receptor-positive breast cancer includes long-term hormone therapy.  However, treatment efficacy varies even in homogeneous groups of patients. Tamoxifen is metabolized in the liver,  resulting in the production of endoxifen, its active metabolite. Cytochromes P450 (CYP2D6, etc.) play a major role  in converting tamoxifen to endoxifen. The CYP2D6 gene is extremely polymorphic and has more than 100 alleles that  can encode normal, high, and low metabolic activity or be inactive. Thus, patients can be divided into three groups according to the presence or absence of CYP2D6 gene polymorphisms, namely slow, intermediate, and rapid metabolizers.  Objective – to analyze the long-term results of complex treatment of patients with early breast cancer depending  on the variability of the polymorphism of the CYP2D6 gene.  Materials and methods. We analyzed the frequency of 3 main polymorphisms in the CYP2D6 gene among 89 patients with  hormone receptor-positive stage I–II breast cancer who received tamoxifen at a dose of 20 mg/day as adjuvant hormone  therapy for 6 months to 9 years. Homozygous carriers of wild-type CYP2D6 allele were assigned to the group of patients  with unchanged (normal) metabolism (Group 1) (wt CYP2D6) (n = 64), whereas homozygous and heterozygous carriers  of non-functional CYP2D6 alleles were included into the group of patients with slow metabolism (Group 2) (n = 25).  Results. Disease progression was observed in 21 (23.6 %) patients with primary operable hormone receptor-positive  breast cancer, including 10 women from Group 1 (15.6 %) and 11 women from Group 2 (44 %); the difference between  them was statistically significant (p <0.05). Disease progression after combination therapy without chemotherapy was  registered in 8 (22.9 %) patients, including 2 (5.8 %) patients with normal metabolism and 6 patients (17.1 %) with  slow metabolism (р <0.05). Ten-year relapse-free survival rate was 85.9 % in Group 1 and 63.6 % in Group 2 (р = 0.02).  We found no significant difference in overall survival rates between the two groups, which confirmed the results  of other studies.  Conclusion. The assessment of metabolic activity and its impact on the efficacy of combination treatment for breast  cancer is a promising method; however, it requires further research in this area.