A Children?s Oncology Group study has shown that survivors of childhood cancer who carry particular variants of the CBR gene and who received low doses of anthracycline chemotherapy were much more likely to develop heart disease than those without this form of the gene who received low doses.

This finding may guide a more personalized approach to preventing toxicities associated with anthracycline chemotherapy among a specific subset of children with cancer. Prior to treatment, oncologists may be able to screen patients for these specific gene variants, and based on these results, to choose non-cardiotoxic alternatives.

?Although we depend heavily on anthracyclines for treating children with cancer, we are fully aware of their toxic effects to the heart. We also know that some patients – despite being exposed to higher doses – don?t develop heart problems, while others with little exposure have considerable cardiac damage,? said senior author Smita Bhatia, MD, MPH, professor and chair of the department of population sciences at the City of Hope National Medical Center in Duarte, CA. ?Our results are a good example of how understanding a cancer patient?s genetic makeup can help us better tailor individual therapies.?

Nearly 80% of children treated for cancer survive, but many have health effects from treatment later in life. A major late effect of some chemotherapy drugs, such as commonly used anthracyclines, is cardiomyopathy, where the heart cannot pump efficiently. CBRs, or carbonyl reductases, are enzymes that help metabolize anthracyclines into substances that can damage the heart. Variants in two CBR producing genes, CBR1 and CBR3, are known to affect CBR activity. The researchers examined the potential effects of the CBR1 and CBR3 variants on cardiomyopathy risk.

In this case-control study, Dr. Bhatia and her colleagues compared 165 childhood cancer survivors who developed cardiomyopathy (the largest cohort of documented childhood cancer-related cardiomyopathy) and 323 cancer survivor controls with no heart disease. The participants were diagnosed between 1966 and 2008, with approximately 80% treated beginning after 1981. The children?s median age at diagnosis was 7.5 years.

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The researchers found that among those with cardiomyopathy who had been treated with high doses (greater than 250 mg/m2) of anthracyclines, the CBR genes had little effect on heart disease risk, since the risk was already high because of the large dose of drug. But among those who developed cardiomyopathy and received low drug doses (less than 250 mg/m2), both CBR1 and CBR3 variants increased the cardiomyopathy risk. Those carrying the CBR1 variant had a 5.3-fold increased risk for cardiomyopathy compared to those carrying the low-risk variant; those with the CBR3 variant had a 3.1-fold increased risk.

The researchers believe that at the lower doses, anthracycline cardiotoxicity is dependent on CBR gene metabolism, whereas at higher doses, toxicity is likely mediated by other mechanisms driven by high doses of unmetabolized anthracyclines.

Oral Abstract Session: Pediatric Oncology II
Study Author: Smita Bhatia, MD, MPH, City of Hope National Medical Center, Duarte, CA
Presentation: Monday, June 7, 2010, 9:30-9:45 AM CDT, Room S504
Abstract: 9512
Title: Anthracycline-related cardiomyopathy in childhood cancer survivors and association with polymorphisms in the carbonyl reductase genes: A Children?s Oncology Group study.
Authors: J. G. Blanco, C. Sun, W. Landier, L. Chen, K. C. Oeffinger, M. M. Hudson, J. P. Neglia, A. K.
Ritchey, M. V. Relling, S. Bhatia

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