Researchers in the Department of Pediatrics and BC Children’s Hospital have found a genetic variation that brings a five times higher risk of heart damage for cancer patients treated with a type of chemotherapy drug called anthracyclines.
Anthracyclines are prescribed to over 900,000 patients worldwide each year for leukemia, bone tumours and other cancers in children and adults, but can cause permanent heart damage that leads to heart failure. The damage can be immediate or develop years after treatment, and may require a heart transplant.
“Anthracycline cardiotoxicity is a devastating problem,” says Professor of Pediatrics Bruce Carleton, the co-lead investigator of the study, published this month in Nature Genetics. “These drugs are responsible in part for dramatically improving the survivability of many cancers, but tragically in some patients they are also responsible for heart failure. In some cases heart transplants can save patient lives – but heart transplantation is not the best outcome for cancer patients.”
The researchers’ previous work identified two genes linked to anthracycline-related heart problems. Their new discovery of a variation in the RARG gene allows for more precise genetic testing to identify patients at risk of these toxic side effects.
Doctors at BC Children’s Hospital are now leading new research that combines genetic testing with patient clinical information to personalize treatment for children with many common types of cancer. For cancer patients at high risk of anthracyline-induced cardiac damage, physicians and the patient (or in the case of children, the patient’s family) could opt to use an alternative chemotherapy drug, or could decide to use the drug but under much closer monitoring for any sign of adverse effects, at which point the therapy might be curtailed.
“Now that we’ve identified this new gene, it opens the door to administering a rapid predictive test to identify patients at the highest risk of anthracycline cardiotoxicity, before the drug is administered, helping quantify the drug’s benefit and risk in a specific patient,” said co-lead investigator Colin Ross, an Assistant Professor of Pediatrics and CFRI Scientist. “With this new knowledge, we are also working to develop new protective strategies to prevent this toxicity from occurring in the future.”
There were 456 children who joined the study between 2005 and 2011, including 280 children from cancer units across Canada, 128 children from the Netherlands and 164 children from California. All of the children had normal heart function before receiving anthracyclines for their cancers. The researchers analyzed the children’s genomes including genes involved in drug biotransformation. This allowed them to identity the RARG gene and its effects on the development of anthracycline-induced heart damage. The genetic analysis was done at the Canadian Pharmacogenomics Network for Drug Safety core facility at CFRI.
“The genetic testing provides real-time genetic results that allow us to carefully consider modifying treatment for kids who are at high risk of heart damage,” said Clinical Assistant Professor of Pediatrics Rod Rassek, a co-author. “We must weigh the risks of drug toxicity against cure rate and involve families in decision-making to personalize treatment for their child.”