Anthracyclines are among the most frequently used agents for treating cancer. They serve as the cornerstone for chemotherapy regimens commonly used to treat hematological and solid organ malignancies. Despite their efficacy, their utility is limited by a dose-dependent cardiomyopathy, also known as anthracycline-associated cardiotoxicity (ACT). ACT is commonly detected by imaging studies and may present as anthracycline-associated heart failure. It is estimated that one in ten children exposed to cumulative anthracycline doses >300 mg/m² develop anthracycline-induced heart failure (1), and childhood cancer survivors are at a 5–10-fold increased risk of cardiac dysfunction compared to the general population (1, 2). Despite established risk factors such as older age and pre-existing cardiovascular comorbidities, there remains significant inter-individual variability in the development of cardiac toxicity. Some patients tolerate high doses without adverse effects, whereas others develop ACT at relatively low doses. The variable predisposition to ACT between patients suggests that genetic susceptibility may play a role in the development of ACT. Candidate genes with potential contributions to ACT pathophysiology have traditionally been nominated based on mechanistic studies in preclinical models, such as zebrafish and mice. While these models can provide valuable mechanistic data in the setting of in vivo treatment, conservation of the pathway and/or specific genetic variant of interest across species remains an important consideration in translating observations to human patients. Cell lines derived directly from human tissues, such as patient-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), offer a unique opportunity to identify genetic variation that may contribute to ACT risk in specific patients. Both animal models and hiPSC-CMs provide mechanistic information that is often complementary to discovery – omics studies in patients.

This review will address the current knowledge of specific genetic associations with ACT, current practice of genetic testing and interpretation in the cardiology clinic and the potential management implications of genetic testing, particularly related to overlap between ACT and other cardiomyopathies.

Efforts to identify genetic variants associated with ACT have been conducted in several studies in pediatric and adult cohorts. Candidate gene approaches and genome wide association studies (GWAS) have yielded several single nucleotide polymorphisms (SNPs) of potential interest. In general, genetic studies in this patient population have been limited by their small sample size and the lack of consensus for clinical or echocardiographic diagnosis of ACT.

Surveillance protocols to detect ACT, as well as the definition of ACT, have not been standardized across studies. As a result, the incidence and timeline of diagnosis of ACT varies considerably in the literature. Clinically, ACT has been identified as new onset heart failure/cardiomyopathy in patients who were treated with anthracyclines. Left ventricular ejection fraction (LVEF) is commonly used in the detection of ACT, but echocardiography surveillance protocols vary considerably from one center to another, and asymptomatic cardiomyopathy is likely underdiagnosed. In addition, LVEF is influenced by preload, afterload and adrenergic state, leading to subjectivity and interpretive variation. A consensus definition of ACT lead by the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) defines ACT as a decrease in the LVEF >10% to an absolute value of <53% (3).

Several genetic modifiers have been identified as potentially contributing to ACT, which we will review here according to their proposed pathophysiologic mechanism (summarized in Table 1).

The interaction between environmental factors (such as the anthracycline dose) and underlying genetic variation may affect the phenotypic expression of ACT. To date, most studies have not been designed to address this question in detail.

Overlap in genetic variants between DCM and ACT represents a particularly interesting avenue of investigation (Figure 1). Garcia-Pavia et al. (14) demonstrated an increased prevalence of DCM-associated gene variants in the ACT patient population, where 12.2% of patients with ACT were found to have a cardiomyopathy variant. Titin-truncating variants (TTNtv) were identified in 16 of 213 ACT cases (7.5%) and were associated with more heart failure, hospitalizations, and atrial fibrillation, as occurs in patients with DCM caused by TTNtv (42, 43). Other genes associated with DCM such as BAG3, LMNA, and MYH7 have been poorly characterized in patients with ACT (14). As highlighted by the findings of Garcia-Pavia et al. (14), genetic modifiers of ACT overlapping with DCM genes may represent a distinct risk profile in addition to genes specific to ACT pathophysiology, a concept that will be important to consider as genetic testing is integrated into the clinical care of cardio-oncology patients.

Different types of genetic test are available to analyze changes in genes. At present, commercially available genetic tests do not include most of the genetic modifiers associated with ACT. Here we will focus on molecular testing that might be relevant to ACT gene testing in the future.

There is no consensus on the clinical application of genetic testing in the management of patients receiving anthracyclines. With growing data to support genetic predisposition as a key factor in ACT, one might envision future risk assessment tools based on both genetic testing and clinical risk factors. For example, patients with the RARG rs2229774 risk variant and the UGT1A6*4 rs17863783 risk variant may be considered at increased risk of ACT beyond what would be estimated from clinical risk factors alone. This could prompt closer cardiovascular follow-up and echocardiographic imaging during and post-treatment, as well as more aggressive risk factor management.

At present, genetic evaluation has no clinical application in ACT evaluation, unless there is a family history of cardiomyopathy or sudden cardiac death that warrants further investigation. As more data emerge regarding genetic risk factors for ACT, clinicians could consider personalized approaches to cardioprotection as follows:

In patients with established ACT, treatment is similar to that recommended by standard heart failure management guidelines. The use of neurohormonal blockade as the cornerstone of management is consistent with data demonstrating cardiac reverse remodeling and improved survival in heart failure in general. There has been interest in identifying which patients respond favorably to neurohormonal blockade. Outside the context of ACT, differences in individual response to beta-blockers are thought to be due to genetic polymorphisms in the gene encoding the beta-adrenergic receptor. In the WOSCOPS trial and MERIT-HF trial (54), these polymorphisms were not associated with a change in morbidity or mortality. Similarly, genes encoding angiotensin II and the associated receptors demonstrated polymorphisms associated with different response to therapy. For instance, a homozygous DD genotype for the ACE gene with a polymorphism of AGTR1 might cause higher levels of renin–angiotensin–aldosterone system activation, resulting in worse prognosis despite treatment with ACEI (55) and lower survival (56). The routine use of genetic testing for gene polymorphisms lacks clinical validation at present, but individualized medical therapy holds promise to improve outcomes in patient with ACT.

Most genetic studies of ACT have attempted to identify candidate genes and/or genetic modifiers by evaluating the cumulative burden of gene variants to determine which genes were overrepresented for genetic variation in a cohort of patients with ACT. This approach differs from that used for other inherited cardiac diseases in clinical practice, such as DCM, where the evidence for pathogenicity includes the evaluation of individuals SNPs based on prior reported associations for the SNP or location of SNPs in gene mutation “hotspots”. To achieve this level of evidence for individual SNPs in ACT will require utilization of genome editing tools such as CRISPR as well as patient-derived in vitro models such as hiPSC-CM, as well as accumulating evidence for genetic variants in ACT in clinical practice.

Furthermore, in other types of cardiomyopathy, the evaluation of variant pathogenicity is directed toward a monogenic variant that is otherwise absent (or of very low frequency) in the general population. However, reported variants associated with ACT have typically been common in the general population, with an allele frequency reaching up to 6% (e.g., ABCC2). These genetic modifiers may contribute to the risk of cardiomyopathy, but they likely have a low penetrance for disease in the general population and may require an environmental interaction (such as exposure to anthracycline) as a second hit to produce the clinical ACT phenotype. The uncertainty surrounding genetic testing will necessitate close collaboration with genetic counselors who can help navigate the implications of testing results as genetics is integrated into the cardio-oncology clinic.

There continue to be several limitations to the use of genetics in routine clinical care. Above all, the identification of disease causing variants remains challenging. Some genetic variants might be necessary but not sufficient to predispose to ACT, and how these variants interact with other unidentified genetic factors remains to be explored. More studies are needed to identify high risk genetic variants with clinical validation. Recent data suggest that patient derived hiPSC-CM may provide a platform for validation of genes/variants identified through GWAS and to clarify the associated molecular mechanisms predisposing to cardiotoxicity. Ultimately, this approach may allow for tailored doses of chemotherapeutics based on patient genotype (57).

There has also been an increasing interest in understanding the role of complementary approaches, such as epigenetics, proteomics, and metabolomics in the development of cardiomyopathy. An integrated-omics approach has the potential to improve our understanding of ACT. Artificial intelligence methods could be applied to large populations to further improve the diagnosis, prognosis, and treatment of ACT. With improved understanding of genetic predisposition for ACT, a risk assessment model that incorporates genetics and conventional clinical risk factors may be better suited to classify an individual patient’s risk.

Anthracycline-induced cardiomyopathy is a complex adverse drug reaction that is associated with morbidity, mortality, and increased social and economic burden for patients, their families, and the healthcare system. Recent advances in the field of genetics have led to an improved understanding of ACT, although significant limitations to clinical applicability remain.

AA: conceptualization. TA-O: analysis and data collection. TA-O and BW: writing original manuscript draft. AA and UT: review and editing manuscript. All authors reviewed the results and approved the final version of the manuscript.

AA has consulted for Sanofi and AstraZeneca, serves as an advisory board member for Cytokinetics, and serves as the principal investigator for a sponsored research agreement with Genentech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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