City of Hope researchers and national colleagues have identified a large subset of children at high risk for developing congestive heart failure after taking anthracycline chemotherapy for pediatric cancer.

Smita Bhatia found why some children are at high risk of a treatment-related heart disease. (Photo by Darrin S. Joy)

The findings, reported online Nov. 28 in the Journal of Clinical Oncology, bring scientists a step closer to genetic tests that might reduce cancer patients’ risk of cardiomyopathy, a life-threatening weakening of the heart muscle.

“Anthracyclines are very powerful drugs that help us fight leukemia, lymphoma and other cancers in children, as well as diseases like breast cancers in adults,” said Smita Bhatia, M.D., M.P.H., Ruth Ziegler Chair in Population Sciences and senior author on the study. “Unfortunately, these drugs can cause cardiomyopathy, and we know that the higher the anthracycline dose patients receive, the greater their risk for heart damage.

“But we observed that some children tolerated high doses of anthracyclines, while others experienced cardiomyopathy even after low doses — so we began to investigate why.”

The study’s lead authors were Javier G. Blanco, Ph.D., of the State University of New York at Buffalo, and Can-Lan Sun, M.D., Ph.D., of City of Hope’s Department of Popu-lation Sciences.

Physicians at 130 institutions in the Children’s Oncology Group enrolled 170 teens and young adults who were diagnosed with cardiomyopathy in the years after treatment for pediatric cancer — the largest such study reported in medical literature. They also enrolled 317 other childhood cancer survivors who did not develop cardiomyopathy, for comparison, allowing the researchers to study genetic factors contributing to the increased risk of anthracycline-related cardiomyopathy.

Laboratory work has indicated that variations in two genes, CBR1 and CBR3, influence risk for drug-related cardiomyopathy. CBR is short for carbonyl reductase, an enzyme in the body that breaks down anthracyclines into a form of alcohol that damages the heart. Certain variations in these genes cause more of the alcohol to be produced.

The latest findings take the team’s work a significant step further. Now they have found one genetic group, in particular, that faces the greatest risk.

As Bhatia explained, each person carries two copies, or alleles, of each gene in their DNA blueprint. For CBR3, a few slight genetic variations mean the difference between someone having two “A” alleles, two “G” alleles or one of each. These variations are called polymorphisms.

The scientists found that children who had the same, specific polymorphism — the “G” version — in both copies of their CBR3 gene faced a high likelihood of developing heart damage even after minimal doses of anthracycline drugs.

“This isn’t a negligible group,” Bhatia said. “About 50 percent of blacks and 30 percent of whites carry this double allele.” (Data on other ethnic groups are not available yet.)

And considering that about 50 percent of today’s frontline cancer regimens include anthracyclines, Bhatia said, anthracycline-related cardiomyopathy is a significant health problem among cancer survivors.

They plan further studies to follow more patients and are conducting genome-wide studies to look for other genes that play a part. At the same time, they hope to help develop tests that physicians could use to determine patients’ CBR3 status.

With that information, physicians could either prescribe different drug regimens to high-risk cancer patients or give patients additional drugs that could protect the heart.

“The science is really coming together in this area,” Bhatia said, “and it’s exciting for us to be finding answers to a significant problem.”

Funding came from the National Cancer Institute, Lance Armstrong Foundation, National Institute of General Medical Sciences (NIGMS), The Leukemia & Lymphoma Society, National Institutes of Health/NIGMS Pharmacogenomics Research Network and American Lebanese Syrian Associated Charities.