CV Biomarkers in Cardio-Oncology: Growing Promise and How to Overcome Limited Delivery

The search for biomarkers seems everlasting and ubiquitous to biomedical fields. In simple terms, biomarkers are measurements that aid clinicians in prediction, diagnosis or treatment of the disease. Their development, however, requires rigorous steps from candidate discovery and assay validation to prospective evaluation in large cohorts which is needed to assure their ability to predict the disease state or outcome of interest. ¹ Successful examples of biomarker utilization in cardiovascular (CV) disease, such as cardiac troponin in the diagnosis of acute myocardial infarction and natriuretic peptides in heart failure, demonstrate their transformative impact on disease management and clinical practice. ^{2, 3} The need for such tools is urgent in the rapidly growing field of cardio-oncology, with explosion of cancer therapeutics capable of affecting CV homeostasis and the increasing number of cancer survivors at risk for development, progression and/or complications of CV disease.

The new AHA scientific statement on Future Perspectives of Cardiovascular (CV) Biomarker Utilization in Cancer Survivors⁴ expands the traditional concept of biomarker as a blood-based measure to broad areas of parameters stemming from multimodality imaging and measures of exercise performance captured by digital technology. The Statement utilizes a 30,000-foot view to highlight major technology advances that have occurred in the recent years and points to their potential as biomarkers of disease processes at the intersection of cancer and cardiovascular disease. In addition to novel cardiac imaging tools (e.g., myocardial strain in echocardiography, parametric imaging in cardiac magnetic resonance, metabolic imaging with cardiac positron emission tomography), high-throughput bioassays offer unprecedented opportunities to investigate genomic, proteomic, metabolomic and other “omic” markers. In the future, the Authors propose, all of these tools may be integrated with bioinformatics and statistical analysis to offer personalized biomarker solutions for diagnosis, prognosis and disease management.

What are the key takeaways?

Three key lists are presented in the Statement: 1) Current professional society recommendations for the use of CV biomarkers at the time of cancer diagnosis, during treatment and survivorship (Table 1), 2) Stages of development of different blood-derived biomarkers including indicators of myocardial injury, wall stress, inflammation, fibrosis, endothelial function and oxidative stress (Table 2), and 3) Registered, prospective, and ongoing clinical studies utilizing biomarkers in diagnosis, monitoring or treatment of CV effects of cancer treatments (Table 3). There is stark contrast between the technological advances and novel molecular and functional measures shown in Tables 2 and 3 and current guideline and statement recommendations that largely include echocardiogram with sporadic endorsement of other imaging techniques, cardiac troponin and natriuretic peptides. Even more concerning is the heterogeneity of definitions of outcome and biomarker measures presented in Table 1.

Even if most societies agree on the use of echocardiogram for cardiac function assessment in patients undergoing cancer treatment, specific echocardiographic parameters need to be identified, ranges of normal established and agreed upon, and prospectively tested in large populations. Among many explanations for the current challenges is the historic, single focus of cardiac imaging in assuring safety of oncology treatments, and its reliance on the left ventricular ejection fraction (LVEF) as a primary, if not sole measure of cardiac function. ⁵ With major advances in cancer therapies, often given in a chronic fashion, and recognition of synergism between cardiovascular risk factors, cancer, and adverse events, our needs have shifted towards measures and predictors of cardiovascular health and overall outcomes. ⁶ Table 2 provides a nice summary of ongoing studies investigating role of different serum biomarkers in various pathophysiologic processes from myocardial injury, oxidative stress, inflammation and fibrosis to protein accumulation in light chain amyloidosis. It is notable that the vast majority of exciting biomarkers remains in the validation phase, with the exception of cardiac troponin, natriuretic peptides, and free light chains which have moved into clinical development. The evolution of cardiac troponins and natriuretic peptides, as key tools in the diagnosis and management of myocardial infarction and heart failure respectively, provide us with key steps that need to be followed in the development of cardio-oncology biomarkers. Step 1 is the definition of outcome and the pathophysiologic process of interest. A significant progress has been made in understanding left ventricular dysfunction and heart failure associated with anthracyclines and HER2-targeted monoclonal antibodies, and a number of ongoing clinical trials summarized in Table 3 examine the role of biomarkers in predicting or early diagnosis of cancer treatment related cardiac dysfunction (CTRCD). Studies to diagnose vascular and endothelial injury, increasingly recognized as a potential side effect of both targeted (e.g., vascular endothelial growth factor [VEGF] inhibitors) and conventional cancer therapeutics including radiation, are challenged by the absence of uniform outcome definitions and consequently, heterogeneity of diagnostic tools.

What are the proposed steps to overcome challenges in biomarker development?

The lack of standardization of cardiovascular toxicity definitions has been the major limiting step in the development of successful cardiovascular biomarkers in oncology patients. On the bright side, we are witnessing increased recognition of the spectrum of cardiovascular effects associated with cancer therapies in both cardiology and oncology professional society guidelines, ^6–10 and the upcoming International Cardio-Oncology Society (IC-OS) Consensus Statement represents a major step forward towards standardized definitions.¹¹ A recent publication on the universal definition of heart failure,³ with central role of imaging and serum biomarkers, illustrates the long and rigorous process from identifying a signal of myocardial wall stress to developing clinical tools that determine heart failure diagnosis and guides therapy. The impact of definitions of outcomes and biomarker cut-offs can also be seen in well-established areas such as the one of myocardial infarction. In the example of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial,¹² the analysis using 2 pre-specified definitions of procedural myocardial infarction showed marked differences in outcome and prognosis depending on the definition chosen.¹² In cardio-oncology, the development of universally accepted outcome definitions faces additional challenges of relatively young field with multidisciplinary stakeholders and sometimes opposing perspectives (oncology treatment effectiveness vs cardiovascular risk). The rapid growth of cancer therapeutics often translates in limited understanding of the pathophysiology behind adverse events and at the same time, urgent need for clinical tools for their diagnosis.

In summary, the path to advancement of biomarkers in cardio-oncology relies on establishment of accepted, standard definitions of specific outcome diagnoses (e.g., heart failure, myocarditis, myocardial infarction, vascular events and vascular function measures, atrial fibrillation burden) and precise exposure measures (e.g., dose and duration of conventional chemotherapeutic, targeted cancer therapeutic, immune-oncology agent etc. ) that will allow validation and comparison of prospective cardiovascular biomarkers across different settings. Adoption of these definitions in oncology clinical trials, registries and clinical practice is another critical step in moving the identified candidate biomarkers to clinical phase and to practice implementation. The potential is immense, and we look forward to the future investigations that will follow the path and be guided by this AHA Statement.