Individual Genetic Variability Highly Correlated with Hematologic Toxicity

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(ChemotherapyAdvisor) – Genetic variation in multidrug resistance protein 1 (ABCC1/MRP1) and UDP glucuronosyltransferase-2B7 (UGT2B7) was found to be highly correlated with severe hematologic toxicity among patients receiving adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) for breast cancer, a study presented during the 8th European Breast Cancer Conference in Vienna, Austria, March 23, has shown.

“This is by far the largest breast cancer cohort in which the impact of genetic variability on toxicity was investigated,” said Christof Vulsteke, MD, of Catholic University of Leuven, Belgium, and colleagues. “Our research has brought us one step closer towards prescribing personalized chemotherapy treatment with a minimum of side effects.”

They assessed impact on hematological toxicity of single nucleotide polymorphisms (SNPs) in germline DNA in a panel of potential genes of interest using high throughput sequencing, including those previously correlated with toxicity/outcome among patients receiving at least one of the FEC compounds. Also investigated were unstudied genes known to be involved in epirubicin metabolism.

Germline DNA was available for 1,089 patients with breast cancer treated with three to six cycles of fluorouracil 500mg/m2, epirubicin 100mg/m2, cyclophosphamide 500mg/m2 from 2000 to 2010. Retrospective electronic chart review provided data on febrile neutropenia, the primary end point; first cycle febrile neutropenia; prolonged grade 4 or deep (<100/μl) neutropenia; grade 3–4 anemia; and grade 3–4 thrombocytopenia.

Variant genotypes for rs45511401 (GT/TT, 12%) in the MRP1/ABCC1 gene vs. wild-type (GG, 88%) were associated with febrile neutropenia (26.5% vs. 15.8%; P=0.007), febrile neutropenia in first cycle (17.1% vs. 9.7%; P=0.027) and thrombocytopenia (3.4% vs. 0.3%; P=0.005).

Variant genotypes for rs7668282 (CC/CT, 1.5%) in the UGT2B7 gene vs. wild-type (TT, 98.5%) genotype were associated with febrile neutropenia (6.7% vs. 17.2%; P=0.024) and prolonged or deep neutropenia (6.7% vs. 35.3%, and P=0.001). In general, no important association for other SNPs was found.

“We found that genetic variation in one gene was highly correlated with chemotherapy side effects,” said Dr. Vulsteke. “Investigating this gene before starting chemotherapy would allow us to support the patient with either growth factors to increase the patient's immunity, or dose modifications, or a different chemotherapy regimen better adapted to the patient, or a combination of these.”

Abstract (Enter "Vulsteke” in the author box to search for Abstract #413)

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