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Genetics of cancer therapy-associated cardiotoxicity.

ABSTRACT: As the number of cancer survivors has increased significantly over the last decades due to aging of population and development of effective cancer therapies, side effects from cancer therapies have been increasingly recognized. High-dose anthracyclines, immunotherapies, and concurrent radiation, as well as traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidemia, and obesity increase risks for unintended cardiovascular toxicity. However, these factors do not fully explain why only a subset of patients develop adverse cardiovascular sequelae from cancer therapies. Recent studies demonstrate that genetics play a substantial role in susceptibility to development of cardiovascular toxicities from cancer therapies. Common single nucleotide polymorphisms in multiple genes involved in various cellular pathways including membrane transport, stress response, and sarcomeres are recognized to increase risks for these toxicities. Pathogenic variants in the genes encoding proteins that comprise sarcomeres also contribute to cardiomyopathy following cancer therapies. Furthermore, genetic manipulations of model systems indicate mechanisms by which cardiotoxicities emerge following cancer immunomodulatory therapies. Continued efforts are needed to enable insights into cardiovascular responsiveness to these multi-targeted therapies, improve risk stratification of patients, and enable therapeutic interventions that limit these unintended adverse consequences from life-saving cancer treatments.

SUBMITTER: Kim Y

PROVIDER: S-EPMC9107514 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Genetics of cancer therapy-associated cardiotoxicity.

Kim Yuri Y Seidman Jonathan G JG Seidman Christine E CE

Journal of molecular and cellular cardiology 20220328

As the number of cancer survivors has increased significantly over the last decades due to aging of population and development of effective cancer therapies, side effects from cancer therapies have been increasingly recognized. High-dose anthracyclines, immunotherapies, and concurrent radiation, as well as traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidemia, and obesity increase risks for unintended cardiovascular toxicity. However, these factors do no ...[more]

PMID: 35358500

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Project description:Targeted drugs have revolutionized the treatment of advanced non‑small cell lung cancer (NSCLC). However, the understanding of how cardiac comorbidity and toxicity affect the clinical outcomes of patients following targeted therapy remains limited. In a 14‑year cohort, cardiac comorbidities and toxicities among patients with stage‑IV NSCLC treated with targeted therapy were identified. The cardiotoxicities were compared in three patient groups: Cardiac, other and no comorbidities. Survival analysis employed Cox Proportional Hazard Models. In the prospectively followed 3,767 patients with stage‑IV NSCLC, 701 received targeted therapy; of which 133 (19.0%) had cardiac comorbidity, 504 (71.9%) had other comorbidities and 64 (9.1%) had none. In total, 15 patients (2.1%) developed cardiotoxicity after taking drugs targeting epidermal growth factor receptor, anaplastic lymphoma kinase (ALK), c‑ros oncogene 1 (ROS1) or vascular endothelial growth factor/receptor (VEGF)/VEGFR, and all 15 had comorbidities: 10 cardiac and 5 other comorbidities. Cardiac comorbidity was associated with a 7.5‑fold higher risk of targeted therapy‑related cardiotoxicity than other comorbidities (7.5 vs. 1.0%; P<0.001). Patients with or without cardiotoxicity had a median survival time of 4.7 or 1.9 years, respectively, and patients with cardiotoxicity had a lower risk of death (hazard ratio, 0.45; 95% confidence interval, 0.25‑0.81) than those without (P=0.003), when adjusting for comorbidities. In the 164 patients that received osimertinib, 32 (19.5%) had cardiac comorbidity and a 1.7‑fold higher risk of death than the 121 (73.8%) patients with other comorbidities. In the 74 patients treated with ALK/ROS1 inhibitors, cardiotoxicity was 14 times more common in patients with heart disease (30.0%) than those without (2.1%) (P=0.001). Cardiotoxicity was uncommon in patients with targeted drug‑treated stage‑IV NSCLC but was more prevalent in those with cardiac comorbidity and appeared to be a protector for longer survival. However, in osimertinib‑treated patients, cardiac comorbidity increased mortality.

Dataset Information

Genetics of cancer therapy-associated cardiotoxicity.

Publications

Genetics of cancer therapy-associated cardiotoxicity.

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