360 The Association of Chemotherapy-induced Thrombocytopaenia with CYP2C19 and ALDH2 Genetic Polymorphisms in Chinese Breast Cancer Patients

Abstract

Background: Chemotherapy (CT) is one of the treatments for patients with breast cancer. However, associated adverse events (AEs) are common, amongst which myelosuppression (neutropaenia and thrombocytopaenia) is one of the most severe toxicities. In this study, we examined the potential effect of genetic variations at rs671 of the ALDH2 (Aldehyde dehydrogenase 2 family mitochondrial) gene, as well as rs4244285 and rs4986893 of the CYP2C19 (Cytochrome P450 2C19) gene, on clinically significant CT-induced thrombocytopenia in breast cancer patients. Materials and Methods: 205 Chinese females with early stage breast cancer underwent AC CT as part of the standard adjuvant therapy; AC consists of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 given 3-weekly for 4 cycles. Patients were monitored for AEs including thrombocytopaenia throughout the 4 cycles of AC. Toxicities were graded according NCI CTC criteria (v. 3). DNA was extracted from the peripheral blood samples obtained from each patient at the start of AC. Genotypes of the 3 SNPs were determined using allele-specific Tm-shift PCR and melting analysis. Cochran-Armitage test for trend was used to examine for association between thrombocytopaenia in patients and the 3 SNPs. Results: Patients were categorized into 'non-thrombocytopaenic' group if there was no thrombocytopaenia throughout AC (83%), or 'thrombocytopenic' if they suffered thrombocytopenia of grade I or above during any AC cycle (17%). The genotype frequency distributions of all 3 SNPs were significantly different between the non-thrombocytopaenic and thrombocytopaenic groups (P = 1.8E-7 for rs671, P = 3.69E-9 for rs4244285, and P = 1.54E-40 for rs4986893). The odds of developing thrombocytopaenia in patients carrying the risk allele at each SNP (A-allele for all three SNPs) was 4.3-fold higher for rs671 (P = 4.74E-8), 5.6-fold higher for rs4244285 (P = 6.36E-10), and 923.7-fold higher for rs4986893 (P = 4.68E-72). Conclusion: In this study, we detected a strong association between ALDH2 and CYP2C19 genes variations and the risk of developing thrombocytopaenia in breast cancer patients undergoing AC. Our results suggest that the 3 SNPs on these 2 genes might be good pharmacogenetic markers for the prediction of thrombocytopaenia during AC. Detection of these genetic polymorphisms may contribute to the development of personalized medicine that could minimize thrombocytopaenia in cancer patients receiving CT.