435 Genetic Variability in the Methylenetetrahydrofolate Reductase (NAD(P)H) Gene (MTHFR) is Associated with Severe Non Hematological Toxicity of Adjuvant FEC in Breast Cancer

Abstract

Background: We assessed the impact on non 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 all related non hematological grade 3-4 events (diarrhea, mucositis, myalgia, allergy, fatigue, nausea and vomiting). For statistical evaluation, correction was made for number of planned cycles, age and body mass index using logistic regression analyses. Because of multiple testing the false discovery rate (FDR) was calculated. Results: Grade 3-4 non hematological events occurred in 43 out of 1089 patients (4%) (diarrhea 7/43, mucositis 8/43, myalgia 2/43, allergy 1/43, fatigue 7/43, nausea and vomiting 20/43). Homozygous (CC, 10%) and heterozygous (AC, 43%) variant genotypes for rs1801131 in the MTHFR gene, compared to the wild-type (AA, 47%) were significantly associated with all related non hematological grade 3-4 events (7.0 vs 4.8 vs 2.4%, p-value 0.033, FDR 0.72). None of the other SNP could show a significant association (more details on other SNP and subcategories of endpoints will be presented at the meeting). Conclusions: Genetic variation in a large set of candidate genes could not predict non hematological severe toxicity. The association found in the MTHFR gene was only moderately and with a high FDR. This is by far the largest breast cancer cohort in which the impact of genetic variability on toxicity was investigated.