CHICAGO—In another step toward personalized cancer care, researchers report that they have homed in on gene variants that increase the risk that some young cancer patients will suffer cardiotoxic effects from anthracyclines.
Childhood cancer patients who are carriers of a variant in the CBR1 and CBR3 genotype are at increased risk of cardiac damage from low-dose anthracycline use, said Smita Bhatia, MD, MPH, Chair of the Department of Population Sciences at City of Hope National Medical Center.
At higher doses, the gene variants no longer appear to affect outcomes, she said at a teleconference briefing in advance of the ASCO Annual Meeting.
Anthracyclines form the backbone of childhood cancer treatment, used in about 50% of pediatric treatment regimens, and cardiotoxicity, especially congestive heart failure, is a well-known side effect of the anthracyclines, and fewer than half of patients who develop heart failure survive two years, Dr. Bhatia said.
But some children exposed to high dosages never develop cardiac problems, while others exposed to low doses suffer significant heart damage. This significant inter-individual variability in tolerance to cumulative anthracycline exposure indicates a role for genetic susceptibility, she said, which indeed proved to be the case.
Dr. Bhatia and her colleagues hypothesized that functional genetic polymorphisms in carbonyl reductases (CBRs), enzymes involved in the metabolism of anthracyclines into highly cardiotoxic C-13 alcohol metabolites, may play a role in the risk of anthracycline-related cardiomyopathy.
Largest Case Series of Documented Cardiomyopathy
The study, which the researchers called the largest case series of documented cardiomyopathy, involved 165 cases of childhood cancer survivors who were prospectively genotyped at diagnosis with cardiomyopathy. They were compared with 323 control subjects with no documented cardiomyopathy, matched by primary diagnosis, follow-up, and ethnicity.
The median age at diagnosis was 7.5 years, with anthracyclines used to treat acute leukemia, lymphoma, sarcoma, and a variety of other cancers.
The study covered the period from 1966 to 2008, with the majority of children treated after 1981. Cardiomyopathy developed a median of 7.1 years after treatment.
Results showed a clear dose-response relationship between anthracycline use and cardiomyopathy, Dr. Bhatia reported.
Multivariate analysis adjusted for age at diagnosis, gender, radiation to the heart, race/ethnicity, years of diagnosis, primary diagnosis, and follow-up showed that compared with children with no anthracycline exposure, the risk of cardiomyopathy in children exposed to anthracyclines was:
* 2.02-fold higher at 1 to 100 mg/m2.
* 3.56-fold higher at 101 to 200 mg/m2.
* 11.43-fold higher at 201 to 300 mg/m2.
* 22.32-fold higher at 301 mg/m2 and higher.
Further analysis showed that after low-dose anthracycline exposure, children who carried two copies of the CBR1 and CBR3 alleles were at increased risk of cardiomayopathy compared with those with only one or no copies.
Specifically, the odds ratios were:
* 2.64 vs 1.19 at 1 to 100 mg/m2.
* 5.78 vs 1.59 at 101 to 200 mg/m2.
* 12.65 vs 8.69 at 201 to 300 mg/m2.
Once the dose of anthracyclines was above 300 mg/m2, however, the relationship no longer held. That is, there is a high risk for cardiomyopathy, regardless of the genotype, as the heart becomes overwhelmed by cumulative oxidative damage from all the unmetabolized anthracycline, Dr. Bhatia said.
“These data identify a definable subset of patients who may benefit from cardioprotection, surveillance, or pharmacologic interventions,” she reported.
If validated, the results suggest that patients with these gene variants undergoing low-dose anthracycline therapy should be offered alternative noncardiotoxic chemotherapy, she said.
Children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma are typically given lower doses of anthracyclines. Children with bone tumors, sarcomas, and acute myeloid leukemia typically receive higher doses of anthracyclines, and therefore face an increased risk of cardiomyopathy regardless of gene status.
With these children, “the focus would be shifted to other things, such as more aggressive surveillance, pharmacological intervention, and then cardioprotection with agents such as [dexrazoxane],” she said.
Although the study did not involve adults, Dr. Bhatia said it is likely that the findings likely apply to them as well, and that that is something her team plans to study.
ASCO 2010-2011 President George W. Sledge Jr., MD, the Ballvé Professor of Oncology at Indiana University School of Medicine, called the findings another example of personalized medicine and an important step toward safer treatment of pediatric cancer patients.
“We're just now, with modern technology, being able to get a handle on some of these complications,” he said.
The gene variants “are relatively easy and cheap to measure. Doing this could help avoid a lot of anthracycline toxicities and let us tailor the right dose to the right patients.”