Survivors of childhood cancer who were treated with anthracyclines are likely to develop cardiomyopathy years later, the Children's Oncology Group reported at the 2010 ASCO Annual Meeting. The risk is increased among those who received low doses of anthracyclines, if they carry particular variants of the carbonyl reductase genes (CBR1 and CBR2), said senior author Smita Bhatia, MD, MPH, Professor and Chair of the Department of Population Sciences at the City of Hope National Medical Center, Duarte, California.

"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 exposure to higher doses, don't develop heart problems while others with little exposure have considerable cardiac damage," she said at an ASCO press briefing.

The findings may guide a more personalized approach to preventing cardiac toxicity associated with anthracyclines.

CBRs are enzymes that help metabolize anthracyclines into substances that can damage the heart. Variants in the CBR1 and CBR3 genes are known to affect the enzyme's activity. Dr. Bhatia and colleagues examined the potential effects of the CBR1 and CBR3 variants on cardiomyopathy risk.

Their investigation was a case-control study of 165 childhood cancer survivors who developed cardiomyopathy and 323 cancer survivor controls with no heart disease, constituting the largest case series of documented cardiomyopathy. Participants were diagnosed with cancer between 1966 and 2008, and approximately 80% were treated after 1981. Mean time from the primary diagnosis was 7 years.

Low Doses Associated with High Risk for Certain Genotypes

"There was a clear dose-response relationship when the anthracycline dose was treated as a discrete variable," noted Javier G. Blanco, PhD, who presented the data at the 2010 ASCO Annual Meeting.1 Dr. Blanco is Associate Professor of Pharmaceutical Sciences, State University of New York at Buffalo.

After adjustment for age at diagnosis, gender, radiation to the heart, race, ethnicity and other factors, the investigators calculated the odds of developing cardiomyopathy, based on total cumulative anthracycline exposure compared to no exposure and found odds ratios of:

• 2.02 for 1 to 100 mg/m²
• 3.56 for 101 to 200 mg/m²
• 11.43 for 201 to 300 mg/m²
• 22.32 for 301 mg/m² and higher

More interesting was the effect of CBR genotype on risk. Among children with cardiomyopathy who received anthracyclines in high doses (> 250 mg/m²), the CBR genes had little effect on cardiomyopathy risk since the risk was already high due to the cumulative exposure. But among those who developed cardiomyopathy after receiving low doses (< 250 mg/m²), both CBR1 and CBR3 variants increased the risk for cardiac damage, Dr. Blanco reported at the pediatric oncology session.

When 250 mg/m² was used as the cut-off for high vs low exposure, subjects carrying two copies of the CBR1 and CBR3 variant (GG genotype) had a 6.48-fold increased risk compared to just 1.75 for those with one or no copies (GA or AA genotype). However, at doses higher than 250 mg/m², the high-risk variant carried an odds ratio of 16.76, which was lower than the odds ratio of 22.33 for those without the variant. The trend is consistent across all dose groups.

By variant in an adjusted analysis, the odds ratios were 5.3 for CBR1, 3.1 for CBR3, and 4.8 for CBR1/3 combined, at doses up to 250 mg/m².

"We identified the impact of CBR1 and CBR3 genotype status on anthracycline-related cardiomyopathy, and it occurs only among those exposed to lower cumulative doses," he concluded.

Dr. Blanco said the findings have meaning in terms of possible interventions. "Among patients who need exposures lower than 250 mg/m², such as those treated for acute lymphoblastic leukemia or Hodgkin lymphoma, primary prevention is important, and we could individualize therapy, perhaps using genotyping and noncardiotoxic alternatives. For children requiring higher doses, such as for acute myeloid leukemia or sarcoma, the emphasis would be on secondary prevention, perhaps with cardioprotectants, risk-based surveillance, and pharmacologic interventions to ameliorate the development of cardiotoxicity." ■

Reference

1. Blanco JG, Sun C, Landier W, et al: Anthracycline-related cardiomyopathy in childhood cancer survivors and association with polymorphisms in the carbonyl reductase genes: A Children's Oncology Group study. 2010 ASCO Annual Meeting. Abstract 9512. Presented June 7, 2010.