Cardiomyopathy in childhood cancer survivors associated with CBR gene, anthracycline dose

2010 ASCO Annual Meeting

Researchers with the Children's Oncology Group have refined the dose-response association between anthracycline-based chemotherapy and cardiomyopathy in childhood cancer survivors. Specifically, they demonstrated a significantly increased risk beyond 250 mg/m2 of cumulative anthracycline exposure. More importantly, they describe an association between the high risk variants of the CBR1 and CBR3 gene and anthracycline-related cardiomyopathy. However, this association is confined to patients exposed to low doses of anthracyclines, and not observed among those exposed to higher doses.

If these results are confirmed, physicians would be able to screen for these gene variants and chose non-cardiotoxic alternatives depending on the results, said Smita Bhatia, MD, MPH, chair of the department of Population Sciences at the City of Hope National Medical Center in Duarte, Calif. She discussed the results during a press conference in advance of the 2010 ASCO Annual Meeting.

“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,” she said. “Our results are a good example of how understanding a cancer patient’s genetic makeup can help us better tailor individual therapies.”

Bhatia and colleagues compared 165 survivors of childhood cancer who developed cardiomyopathy with 323 survivor controls who did not have heart disease. Participants were diagnosed between 1966 and 2008, and roughly 80% began treatment after 1981. Median age at diagnosis was 7.5 years and median time to cardiomyopathy was 7.1 years.

Patients who developed heart disease received a median anthracycline dose of 300 mg/m² vs. 140 mg/m² for controls.

Among those who received a dose of 250 mg/m² or less, patients carrying the CBR1 GG variant had a 5.3-fold increased risk for cardiomyopathy, while patients carrying the CBR3 GG variant were at a 3.1-fold increased risk for anthracycline-related cardiomyopathy.

“The effect of the CBR1 and CBR3 genotypes on the anthracycline-related cardiomyopathy risk is observed primarily among those who are exposed to the lower doses [of anthracyclines],” Bhatia said. “We believe that at these doses, the conversion to the highly cardiotoxic metabolite of the anthracyclines becomes critical in the induction of cardiomyopathy.”

She said that in patients who received the highest doses of anthracyclines, greater then 250 mg/m2, CBR gene variants played a less critical role in the risk for developing heart disease because high doses of unmetabolized anthracyclines are known to exert cardiotoxic effect through alternative mechanisms.

"We don't observe the association with these genotypes with higher doses of anthracyclines primarily because we believe that cardiotoxicity is likely to be dominated by other mechanisms such as oxidative stress generated by unmetabolized anthracycline." – by Jason Harris

This trial emphasizes the importance of employing new technologies to look at old problems. These are very old drugs; they’ve been around for 30 years or more. We are, just now, with modern technology, able to get a handle on some of these complications. Therapeutic individualization involves the host, as well as the tumor. Looking at host metabolism is going to be crucial to understanding how to give these agents safely. This study is a first step to leading to safer and perhaps more effective approaches to treating our younger cancer patients.

– George W. Sledge Jr, MD
Ballve-Lantero Professor of Oncology, Professor of Pathology and Laboratory Medicine, Indiana University School of Medicine

For more information:

Blanco JG. #9512. Presented ahead of: the 2010 ASCO Annual Meeting; June 4-8; Chicago.

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