Clinical Newswire, June 8, 2010 (Chicago, IL) - Survivors of childhood cancer treated with low doses of anthracycline chemotherapy are more likely to develop heart disease if they carry particular variants of the CBR gene than those without this form of the gene, according to the results of a Children’s Oncology Group study presented at the 2010 Annual Meeting of the American Society of Clinical Oncology (ASCO).
Anthracyclines are used in 50-60% of children with cancer, however exposure to them is associated with cardiomyopathy and congestive heart failure (CHF). “Although we depend heavily on anthracyclines for treating children with cancer, we are fully aware of their toxic effect to the heart,” said senior study author Smita Bhatia, MD, MPH (City of Hope National Medical Center, Duarte, CA, USA). Up to 60% of patients treated with anthracyclines show preclinical abnormalities in cardiac structure and function and up to 30% of those exposed to more than 500mg/m2 risk overt, clinically symptomatic CHF which is associated with poor prognosis.
Risk factors for anthracycline-associated CHF include younger age at exposure, total cumulative dose of anthracyclines, chest radiation exposure and female sex, however there is a significant variability between individuals in tolerance to cumulative anthracycline exposure. While some patients don’t develop heart problems despite exposure to higher doses, others have considerable cardiac damage despite little exposure, possibly due to genetic susceptibility.
Carbonyl reductases (CBR) are enzymes which catalyze the reduction of anthracyclines to cardiotoxic alcohol metabolites. The researchers looked at the role of genetic polymorphisms in the CBR3 and CBR1 genes on CBR activity and their potential effect on cardiomyopathy risk.
In this case-control study Dr. Bhatia and colleagues compared 165 childhood cancer survivors (median age at study participation 16.5 years) who developed cardiomyopathy (the largest cohort of documented childhood cancer-related cardiomyopathy) and 323 cancer survivor controls (median age at study participation 18.6 years) without heart disease. The children's median age at diagnosis was 7.5 years.
The researchers found a clear dose-dependent relationship with anthracycline exposure, with a significantly increased cardiomyopathy risk beyond 250 mg/m2 of cumulative exposure. The CBR1 and CBR3 genotype status had an impact on anthracycline-related cardiomyopathy risk among those exposed to lower doses of anthracyclines (less than 250 mg/m2), but not among those exposed to higher doses (greater than 250 mg/m2). With cumulative exposure doses less than 250 mg/m2, patients carrying the high-risk CBR1 variant had a 5.3 times greater risk for developing cardiomyopathy than those carrying the low-risk variant, those with the high-risk CBR3 variant had a 3.1-fold increased risk.
The findings suggest that at lower doses anthracycline cardiotoxicity is dependent on CBR metabolism, while at higher doses toxicity may be mediated by other mechanisms such as oxidative stress and apoptosis caused by high doses of unmetabolized anthracyclines.
The researchers suggest that in childhood cancer patients requiring cumulative doses of anthracyclines less than 250 mg/m2, such as acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) patients, therapy can be individualized by using non-cardiotoxic alternatives and accounting for CBR1 and CBR3 status. For patients requiring cumulative doses of anthracyclines more than 250 mg/m2, such as acute myeloid leukemia (AML) and sarcoma patients, emphasis should shift towards secondary prevention of cardiomyopathy, possibly by using cardioprotection, risk-based surveillance and pharmacologic intervention. According to Dr. Bhatia, “Our results are a good example of how understanding a cancer patient’s genetic makeup can help us better tailor individual therapies.”
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