415 Genetic Variability in Multi Drug Resistance Protein 1 (ABCC1/MRP1) and UDP-Glucuronosyltransferase-2B7 (UGT2B7) Are Highly Correlated with Severe Haematological Toxicity of Adjuvant FEC in Breast Cancer

Abstract

Background: We assessed the impact on hematological chemotherapy toxicity of single nucleotide polymorphisms (SNP) in germline DNA in a panel of potential genes of interest through high throughput sequencing. First aim was to validate the predictive value of certain SNP that have previously been shown to correlate with toxicity/outcome in small patient groups receiving at least one of the FEC compounds (ABCBI/MDRI, ABCC1/MRP1, ABCC2/MRP2, ABCG2, ALDH3A1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A5, DPYD, GSTP1, MTHFR, NQ01, TYMS, XPD/ERCC2, XRCC1). Secondly we investigated previously not studied genes known to be involved in epirubicin metabolisation (UGT1A1, UGT1A6, UGT2B7). Material and Methods: We identified 1089 breast cancer patients treated in a single centre with 3 to 6 cycles of (neo-)adjuvant FEC (fluorouracil 500, epirubicin 100, cyclophosphamide 500 mg/m2) from 2000-2010 for whom germline DNA is available. All patients were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint), febrile neutropenia first cycle, prolonged grade 4 or deep (<100/ml) neutropenia, anemia grade 3-4 and thrombocytopenia grade 3-4. For statistical evaluation, correction was made for number of planned cycles, primary growth factor use, age and body mass index. Because of multiple testing the false discovery rate (FDR) was calculated. Results: Variant genotypes for rs45511401 (GT/TT, 12%) in the Multi Drug Resistance Protein 1 gene (MRP1/ABCC1), compared to the wild-type (GG, 88%) were associated with febrile neutropenia, febrile neutropenia in first cycle and thrombocytopenia (respectively 26.5 vs 15.8%, 17.1 vs 9.7% and 3.4 vs 0.3%; p-value 0.007, 0.027 and 0.005, FDR 0.3, 0.79 and 0.19). Variant genotypes for rs7668282 (CC/CT, 1.5%) in the UDP-Glucuronosyltransferase 2B7 gene (UGT2B7) compared to the wild-type (TT, 98.5%) genotype were associated with febrile neutropenia and prolonged or deep neutropenia (respectively 6.7 vs 17.2% and 6.7 vs 35.3%, p value 0.024 and 0.001, FDR 0.53 and 0.04). More details on other endpoints and other SNP will be presented, although in general no important association was found for other SNP mentioned. Conclusions: Genetic variation in the MRP1 and UGT2B7 gene was highly associated with severe haematologic toxicity of FEC, while other previously described SNP were not validated. This is by far the largest breast cancer cohort in which the impact of genetic variability on toxicity was investigated.