Genetic Crosstalk in Cancer-Therapy-Induced Cardiomyopathy

Patrice Wendling

April 18, 2019

Patients with cancer-therapy-induced cardiomyopathy (CCM) have an excess of rare mutations in dilated cardiomyopathy genes, and towering among them is TTN, the gene encoding the massive sarcomere protein titin, new research suggests.

The study showed that 7.5% of 213 adult and pediatric CCM patients had truncating variants in TTN, compared with 1.1% of 2053 unselected breast or lung participants in the Cancer Genome Atlas (P = 7.36e-08) and 0.7% of 445 healthy volunteers in the UK Digital Heart Project (P = 3.42e-06).

Adults with CCM and TTN truncating variants (TTNtv) also had more heart failure hospitalizations and atrial fibrillation (P = .003) and worse cardiac function (P = .03) than those without the variants.

In addition to TTNtv, the analysis identified rare protein-altering variants in five dilated cardiomyopathy (DCM) genes: BAG3, LMNA, MYH7, TNNT2, and TCAP.

"The increased burden of rare variants including TTNtv, indicate that genetics are an important component in CCM susceptibility and adverse outcomes," colead authors Pablo Garcia-Pavia, MD, PhD, Hospital Universitario Puerta de Hierro, Madrid, and Yuri Kim, MD, PhD, Harvard Medical School, Boston, write in their report, published online April 16 in Circulation.

"These data establish a genetic relationship between DCM and CCM," they note. Cardiomyopathy variants were found in 12.2% of patients with CCM and occur in about 40% of patients with familial and sporadic DCM.

"The one thing that we are very excited about with this study is the potential implication of hopefully changing management of patients undergoing cancer therapy," Kim told | Medscape Cardiology.

"Once we identify who is going to be at higher risk, we can more closely monitor them, have more frequent cardiac monitoring, or perhaps take cardioprotective medications to improve the cardiovascular outcomes," she said. "We believe that improving these cardiovascular outcomes will also improve their oncologic outcomes because nowadays, unfortunately, if someone develops cardiotoxicity, their oncologic regimen gets interrupted or just stopped."

At Risk for CCM

Anthracyclines, used in nearly all CCM cases, cause cardiotoxicity in up to 10% of patients with cumulative dosages of 250 mg/m². When combined with other therapies, such as trastuzumab, depressed left ventricular ejection fraction (LVEF) occurs in up to 34% of patients and severe, symptomatic heart failure in 2% to 4%, the authors note. Female sex, older age, and pre-existing cardiac risk factors also contribute to CCM but "even when accounting for these factors, predicting individual susceptibility to CCM remains challenging."

TTN truncating variants are prominent in DCM, occurring in 15% of ambulatory and 25% of end-stage patients but are rarely identified in childhood-onset DCM, according to the researchers. Here, 8.1% of adults and 5.0% of children with CCM harbored these deleterious variants.

Titin is the largest protein in the human body, spanning roughly half of the sarcomeres in cardiac and skeletal muscles, and plays a key role in myocardial stiffness and stress sensitive signaling.

For the study, the researchers zeroed in on nine previously identified cardiomyopathy genes with an excess of rare variants. Next-generation sequencing was performed in three CCM cohorts, including patients with hematologic, breast, or other solid tumor cancers, recruited from European heart failure and transplant clinics (n = 99). The remainder were US cohorts identified through prospective, longitudinal cardiac evaluations during treatment for breast cancer (n = 73) or newly diagnosed pediatric acute myelogenous leukemia (n = 41).

Three-fourths of CCM patients were female, 90% received anthracyclines, and 33% of adults received trastuzumab. The median time to CCM diagnosis after starting cancer treatment was 3.0 years (range, 1–9 years) in the European cohort and 0.3 to 0.7 years in the US cohorts.

Across all cohorts, treatment with a high cumulative dose anthracycline (>400 mg/m²) was not associated with poorer LV function at CCM diagnosis (mean LVEF, 42%), the authors say.

Cardiac recovery was reported in about half of CCM patients from each cohort, but 9% of the European cohort underwent cardiac transplant. Cardiac death occurred in 3% of the European cohort and 5% of the US pediatric cohort.

Additional analyses were performed on 40 other genes implicated in cardiomyopathies but there were no significant differences in the prevalence of all rare protein-altering variants or variants predicted as damaging.

Further Validation

Although the findings are promising, Kim said further studies are needed because of the small size of the study, most patients were white, patients were predominantly treated for breast or pediatric acute myelogenous leukemia, and information was not available on which Cancer Genome Atlas participants developed CCM.

She noted, however, that the contribution of TTNtv to CCM was confirmed in an experimental model, in which three doses of doxorubicin were given at weekly intervals (cumulative dose 45 mg/m²) to wild type and heterozygous mice with a titin A-band truncation.

LV function was similar in mice with and without the titin variant at baseline and comparably depressed after 4 weeks of anthracyclines, according to assessment blinded to genotype and treatment. LV function recovered to baseline at week 8 in wild-type mice but remained depressed through week 12 in mice with the titin variant (P = .004).

Functional analyses in isolated cardiomyocytes also confirmed that LV dysfunction reflected cell autonomous effects of anthracyclines, the authors write.

"One thing we'd like to pursue in the near future is to look at other genes because we believe there will be other genetic contributors to cancer therapy-induced cardiomyopathy," Kim said. "We believe that genes important in drug metabolism will be one of them" and "there are other additional genes that are involved in the signaling pathway that are also very important in cardiomyocytes function."

Funding for the study was provided by Instituto de Salud Carlos III, the Spanish Ministry of Economy and Competitiveness, the John S. LaDue Memorial Fellowship, Wellcome Trust, the Medical Research Council, National Institute for Health Research, the Sir Henry Wellcome Postdoctoral Fellowship, Rosetrees and Stoneygate Imperial College Research Fellowship, Foundation Leducq, British Heart Foundation, Alex's Lemonade Stand Foundation, National Institutes of Health, and the Howard Hughes Medical Institute.

Circulation. Published online April 16, 2019. Full text

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