June 1, 2013 | by Nicole White
Anthracyclines have successfully treated many childhood cancers, including leukemia and lymphoma. But although the drugs have led to a growing number of childhood cancer survivors, patients treated with these drugs face a high risk of developing heart failure.
Of the 350,000 childhood cancer survivors in the U.S., about two-thirds were treated with anthracyclines. Of those, two-thirds have developed heart abnormalities that could progress to heart failure. The common method for screening these patients is with an echocardiogram, but by the time the damage can be picked up by this test, it's irreversible.
Two City of Hope studies seek to mitigate the risk of heart failure in such patients. One has identified a potential gene variant that could indicate which children are more susceptible to developing heart failure if treated with anthracyclines; another identifies methods to catch heart problems early, when intervention is still an option.
Gene variant linked to risk of cardiomyopathy
Because cardiomyopathy – a deterioration in the function of the heart muscle – occurs only in some patients treated with anthracylines, researchers suspected the existence of a genetic link. After examining 10,000 genetic variations in 2,100 genes, researchers homed in on variations in the HAS3 gene.
Childhood cancer survivors from 121 institutions participated in the study. During routine clinic visits, 93 patients with cardiomyopathy and 194 with healthy hearts were asked to donate blood samples. Researchers found that for individuals with one variant of the HAS3 gene, exposure to anthracyclines at any dose was not associated with cardiomyopathy risk. However, those with a different variant had an 8.5-fold increased risk for developing heart deterioration.
The findings were replicated in a group of 76 City of Hope patients with anthracycline-related cardiomyopathy. They too showed similarly elevated odds for developing the disease based on the gene variants.
If the findings are corroborated with a larger population of patients, the gene could become a tool to help physicians determine what dose of the drug is appropriate – or if another drug should be considered instead, said Smita Bhatia, M.D., M.P.H., professor and Ruth Ziegler Chair in Population Sciences.
“We want to take this to a large cohort with samples before and after treatment, and look at who develops heart failure,” she said. “We will see if there is a predictability test we can use.”
Catching signs of heart failure earlier
Anthracyclines are also associated with left ventricular dysfunction in childhood cancer survivors, which almost inevitably leads to congestive heart failure. A common measure of how well the left ventricle – the heart’s main pumping chamber – is functioning is to use an echocardiogram. That test assesses the ejection fraction, that is, the percentage of blood leaving the heart with each contraction. However, by the time the ejection fraction drops, the patient is already nearing congestive heart failure.
Using a combination of advanced echocariographic techniques and testing for certain blood biomarkers, City of Hope researchers found a potential means of early detection that could lead to targeted interventions for childhood cancer survivors at highest risk of heart failure.
In a study of 150 patients, a team led by Saro Armenian, D.O. M.P.H., assistant professor in the Division of Outcomes Research/Intervention at City of Hope, established that the thickness and stress on the wall of the left ventricle is an indicator of damage to the heart. In addition, the team found, certain blood markers are common among those at highest risk of heart failure.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number K12 CA001727. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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