NEW YORK (GenomeWeb) – Cancer patients with a certain rare genetic variant may be more susceptible to developing treatment-induced cardiomyopathy, according to a new study.
While new cancer treatments have led to improved survival for many patients, they often come with side effects. Anthracyclines, which are used to treat both solid and hematological cancers, are linked to an increased risk of cardiotoxicity, for example, especially when combined with other drugs likes trastuzumab.
As individual susceptibility to developing cancer therapy-induced cardiomyopathy varies, a team led by researchers at Harvard Medical School examined whether rare variants in genes linked to familial cardiomyopathy were also associated with cardiomyopathy risk among treated cancer patients. As they reported today in the journal Circulation, they found that variants resulting in a truncated titin protein were common among patients who experienced cancer therapy-induced cardiomyopathy (CCM).
"We believe that identification of cancer patients with high CCM risk based on genetic testing will enable healthcare providers to tailor their cardiovascular and oncological monitoring and treatment regimen, which will ultimately improve patients' cardiovascular and oncological prognosis," first author Yuri Kim, a cardiology fellow at Harvard, said in a statement.
In their study, the researchers focused on nine genes that are commonly mutated in patients with dilated cardiomyopathy, including BAG3, LMNA, MYH7, TCAP, TNNT2, and TTN.
They sequenced these genes in three cohorts of cancer patients who developed cardiomyopathy: 99 adults with diverse cancers who were retrospectively recruited, 73 adults with breast cancer who were prospectively phenotyped, and 41 prospectively phenotyped children with acute myeloid leukemia. Ninety percent of these 213 patients were treated with anthracyclines and were diagnosed with CCM a median three years after treatment for the retrospectively gathered cohort and a median 0.3 years to 0.7 years after treatment for the other cohorts.
The researchers compared the prevalence of rare variants in these nine genes in the three cohorts to 2,053 individuals from The Cancer Genome Atlas and 445 healthy volunteers.
Overall, CCM patients harbored more rare variants in the cardiomyopathy-linked genes than the other groups. In particular, titin-truncating variants were present among 7.5 percent of CCM patient, as compared to 1.1 percent of TCGA participants, 0.7 percent of healthy volunteers, and 0.6 percent of a reference population. The researchers noted, though, that many TCGA participants were likely treated with anthracyclines and some may have developed CCM.
Clinical outcomes also varied between the groups, as patients with titin-truncating variants were hospitalized more often with heart failure and atrial fibrillation than those without such variants.
To begin to tease out how these variants might influence cardiomyopathy risk, the researchers exposed wild-type mice and mice with a titin-truncating variant to the anthracycline doxorubicin. After treatment, both groups of mice had depressed left ventricle function. The wild-type mice, though, recovered to baseline by week eight, while the mice with a titin-truncating variant continued to have depressed left ventricle function through week 12.
This suggested to the researchers that cancer patients who have an increased genetic susceptibility to develop cardiomyopathy could be identified and placed on treatments to minimize that risk.
"We believe that identification of cancer patients with high CCM risk based on genetic testing will enable healthcare providers to tailor their cardiovascular and oncological monitoring and treatment regimen, which will ultimately improve patients' cardiovascular and oncological prognosis," said Kim.