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25-03-2012 | Genetics | Article

Gene polymorphisms predict toxic effects of breast cancer chemotherapy


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MedWire News: Research presented at the 8th European Breast Cancer Conference in Vienna, Austria shows that DNA testing can identify those breast cancer patients who are most likely to suffer serious side effects of chemotherapy.

Christof Vulsteke (University Hospitals Leuven, Belgium) and colleagues examined germline DNA samples from 1089 breast cancer patients who were treated between 2000 and 2010 with at least one of fluorouracil, epirubicin, or cyclophoshamide - collectively known as FEC chemotherapy.

The researchers investigated whether single nucleotide polymorphisms (SNPs) in 20 genes involved in metabolizing these three chemotherapeutic drugs were associated with hematologic toxicity, which is a serious and often common side effect of chemotherapy.

"We found that genetic variation in one gene was highly correlated with chemotherapy side effects," said Vulsteke in a statement to the press. "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."

The gene in question was the Multi Drug Resistance Protein 1 gene (MRP1/ABCC1). Patients who were carriers of the T allele of the rs45511401 SNP (GT/TT, 12%) in this gene were significantly more likely to experience febrile neutropenia than those homozygous for the 'wild-type' GG genotype (88%), at 26.5% versus 15.8%.

Febrile neutropenia in the first cycle and grade 3-4 thrombocytopenia were also significantly more common in patients with variant rs45511401 than in those with the wild-type, at 17.1% versus 9.7% and 3.4 versus 0.3%, respectively.

A second SNP, rs7668282 (CC/CT, 1.5%) in the UDP-Glucuronosyltransferase 2B7 gene (UGT2B7) was also associated with febrile neutropenia, with 17.2% of patients who were carriers of the C allele experiencing the side effect compared with 6.7% of patients with the wild-type TT genotype.

Carriers of the rs7668282 SNP were also more likely to develop prolonged grade 4 or deep (<100 cells/µL) neutropenia compared with patients with the wild-type allele, at 6.7% versus 35.3%.

Vulsteke said that his team now intend to look for data from other European countries in order to further validate their results. They will also continue to follow up their own patients; currently the patients have an average of 5 years of follow-up data.

"In 2016 we will have a very accurate assessment of the impact of genetic variation on breast cancer survival and recurrence," Vulsteke remarked. "Our future research will focus on other genes involved in processing the chemotherapeutic drugs that we studied, and we will also enlarge the scope of the research by including other chemotherapeutic drugs where we can hypothesise that genetic variability plays an equally important role," he concluded.

Conference Chair David Cameron, from the University of Edinburgh in the UK, told reporters: "In the search for ways to 'personalize' anti-cancer treatments, much of the focus has been on matching the treatment to the cancer. However it should not be forgotten that we also need to ensure the treatment is 'matched' to the patient, and this study is an important step in this direction, potentially allowing us to ensure that standard chemotherapy can be delivered with either less severe toxicity, or perhaps to have the dose adjusted to give maximal benefit.

"Further studies will be needed to demonstrate that improvements in patient survival can be achieved by tailoring the actual doses along the lines that this study suggests could be possible."

By Laura Cowen

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