Advances in Cardioprotection Strategies: Focusing on Breast Cancer and Beyond Through Novel Biomarkers and Pharmacological Approaches

Advances in cancer therapies have significantly increased long-term survival, highlighting the need to manage cardiovascular complications. Cardio-oncology focuses on preventing and treating heart disease related to cancer and its treatments.¹ Shared risk factors, such as diabetes, smoking and older age, create a strong link between cardiovascular and oncological conditions. As survival rates improve, addressing the cardiovascular side effects of cancer treatments becomes increasingly important due to their high morbidity and mortality.²

The 2022 European Society of Cardiology (ESC) guidelines emphasise the importance of evaluating cardiotoxicity risk both before and during cancer therapy to inform treatment decisions and enable effective monitoring. As oncological therapies evolve, the demand for cardioprotective strategies increases, highlighting the need for continuous risk reassessment with each change in treatment regimen.³ Current guidelines suggest tools such as the Heart Failure Association-International Cardio-oncology Society (HFA-ICOS) risk score for accurate cardiovascular risk stratification in cancer patients.⁴

Cardiac imaging and biomarkers play a key role in identifying patients at high risk of cardiovascular complications before and during cancer therapy. Echocardiography remains the first-line imaging modality for screening, diagnosis and surveillance in oncology patients. Its 2D and Doppler techniques allow for the detection of structural and functional cardiac alterations, while 2D and 3D myocardial deformation imaging (also known as strain imaging) enhances sensitivity for identifying subclinical cancer therapy-related cardiac dysfunction (CTRCD).

Among advanced imaging techniques, cardiac magnetic resonance (CMR) using cine steady-state free precession sequences provides detailed assessment of cardiac structure and function, including left and right ventricular ejection fraction. CMR is also capable of detecting subclinical CTRCD and alternative causes of abnormal global longitudinal strain (GLS) through strain imaging protocols.

Coronary CT angiography (CCTA) and stress echocardiography or single photon emission computed tomography/positron emission tomography are valuable tools for identifying or ruling out exercise- or drug-induced ischaemia, which contributes to cardiovascular risk stratification before initiating chemotherapy.

However, the current evidence in many areas is still limited to small studies and several centres are unable to follow guideline recommendations due to restricted access to advanced imaging techniques.^5–9

In this context, the appropriate use of biomarkers may serve as a particularly valuable tool for centres with limited access to imaging resources. This article focuses on biomarkers that are in use in clinical practice and offers guidance on their interpretation to support risk stratification and preventive strategies, especially regarding therapeutic approaches in cardio-oncology.

Methods

This narrative review included studies investigating the efficacy of biomarkers and pharmacological strategies for cardioprotection during cancer treatment. Focus was placed on studies evaluating early detection of cardiotoxicity and the monitoring of cardiac function in patients receiving potentially cardiotoxic therapies. We searched PubMed, Google Scholar and the Cochrane Library using the keywords cardioprotection, cardio-oncology, chemotherapy-induced cardiotoxicity, cardiac biomarkers and heart failure in cancer patients. Studies were primarily included if they were published within the last 5 years (a minority of studies may date back to earlier years), with preference given to original research and reviews addressing mechanisms of cardiotoxicity, risk stratification, early detection and preventive strategies. Studies not relevant to cardioprotective interventions or the use of biomarkers were excluded.

Biomarkers in Cardio-oncology

In the past two decades, the use of cardiac biomarkers has emerged as a key strategy for the early detection of subclinical cardiac injury.¹⁰ Biomarkers are proteins or other biochemical entities in the blood that reflect pathophysiological cardiovascular dynamics. They are particularly useful in clinical practice because they provide objective results that are reproducible, inexpensive and easy to access.¹¹

There is growing interest in the use of these biomarkers to detect cardiac injury at a preclinical stage, to confirm damage or ventricular dysfunction when imaging is inconclusive, and to guide treatment decisions and cardioprotective strategies.¹²

It is essential to emphasise that biomarkers should not be used in isolation, but rather as part of a comprehensive assessment that includes cardiac imaging, risk factors, clinical symptoms and the oncological context.

Biomarkers in Use: Troponins and Natriuretic Peptides

Traditional biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponins (cTn) are fundamental in assessing myocardial function and injury and are already included in guidelines for risk stratification and monitoring of patients receiving cardiotoxic cancer therapies.⁴

Cardiac troponins, including I (cTnl) and T (cTnT) isoforms, are considered the gold-standard biomarkers for detecting myocardial damage and cardiomyocyte necrosis.^13,14 Thanks to their high specificity, even minimal myocardial injury can be identified, allowing timely interventions to prevent irreversible left ventricular dysfunction. Persistent elevation of cTnI is associated with worse cardiac outcomes and a higher incidence of cardiac events compared to transient elevations.¹⁵

Natriuretic peptides, including B-type natriuretic peptide (BNP) and NT-proBNP, are key biomarkers for monitoring myocardial stress and CTRCD. They are released by cardiomyocytes in response to wall stress and neurohormonal activation, including stimulation by norepinephrine and angiotensin II. NT-proBNP is effective for monitoring haemodynamic stress and is useful for identifying CTRCD and managing long-term heart failure.^16–21

Measuring cardiac biomarkers – troponins, BNP and NT-proBNP – before initiating cancer treatment is essential to establish a baseline and detect any pre-existing cardiac damage, particularly in patients with underlying cardiovascular disease. These baseline values are critical for interpreting changes during treatment and for effective surveillance of cardiotoxicity. Additionally, the timing and frequency of biomarker testing should be adapted to the specific cancer therapy being administered.¹¹

Importantly, an elevation in cardiac biomarkers must be interpreted within the broader clinical context and does not automatically warrant the discontinuation of oncological therapy. Instead, such findings should prompt collaboration between cardiologists and oncologists to assess the risks and benefits of continuing treatment and to determine whether more intensive monitoring or cardioprotective strategies are needed.¹¹

In the context of anthracycline therapy, troponins and natriuretic peptides (NPs) are valuable biomarkers for detecting both clinical and subclinical cardiotoxicity, demonstrating a strong negative predictive value. Troponins are particularly effective for early identification of myocardial injury, while NPs better reflect late-onset cardiotoxicity and heart failure. Elevated troponin levels during chemotherapy have been consistently associated with increased risk of CTRCD.^{11,13,15,22–28} Specifically, a study of 204 patients receiving high-dose anthracyclines showed that cTnI elevations above 400 ng/l predicted a more pronounced and persistent decline in left ventricular ejection fraction (LVEF).¹³ Similarly, in a cohort of 703 patients, those with persistent cTnI elevation experienced significantly higher rates of CTRCD and adverse outcomes compared to patients with consistently normal levels.¹⁵

Elevated NT-proBNP before cancer treatment has also been linked to higher mortality risk (HR 1.54), with increases at 1-year follow-up after anthracycline or trastuzumab therapy correlating with a significant decline in LVEF.^21,29 One study further reported that all cardiac events occurred in patients with BNP levels exceeding 100 ng/l prior to the event.³⁰

Regarding trastuzumab therapy, cTnI predicted CTRCD in patients treated with both doxorubicin and trastuzumab.²⁴ Data from the HERA trial involving 533 human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients demonstrated that elevated high-sensitivity cTnI or cTnT after anthracycline but before trastuzumab initiation was associated with a higher risk of CTRCD during trastuzumab treatment.^16,31 However, routine troponin monitoring during trastuzumab therapy was not consistently predictive, whereas NT-proBNP showed greater sensitivity in detecting new-onset cardiac dysfunction.^16,31,32

In patients treated with trastuzumab, troponin assays have shown a 99% negative predictive value across multiple studies. For instance, Cardinale et al. found that 62% (total patients enrolled = 251) of troponin-positive patients developed cardiotoxicity compared to 5% of those with normal troponin, and troponin-positive patients had poorer responses to heart failure therapy and lower rates of LVEF recovery.¹⁴

Troponin also plays a critical role in identifying myocarditis related to immune checkpoint inhibitors (ICIs). Most patients with ICI-induced myocarditis (94%) show elevated troponin levels, making it the main diagnostic biomarker in this setting.^33,34

In ICI-treated patients, NPs are mainly useful for detecting new-onset left ventricular dysfunction, which may result from ICI-induced myocarditis. However, NPs are elevated in only about two-thirds of myocarditis cases. More importantly, they are essential for diagnosing non-inflammatory left ventricular dysfunction, a recently recognised condition that presents with elevated NPs and normal troponin levels. This diagnosis requires clinical and imaging evidence of new left ventricular dysfunction in the absence of myocardial inflammation confirmed by cardiac imaging and/or biopsy.³⁴

Last, in patients receiving proteasome inhibitors such as carfilzomib, elevated baseline NP levels have been associated with a higher risk of cardiovascular complications. Monitoring NP levels in these patients may help identify those at greater risk and support improved surveillance and preventive strategies.³⁵

Emerging Circulating and Molecular Biomarkers

In this context, microRNAs (miRs) – non-coding RNA sequences involved in the regulation of gene expression – have shown promise as novel biomarkers. Studies have demonstrated that miRNAs are associated with the early detection of chemotherapy-induced cardiac injury and correlate with different stages of the pathological process, including oxidative stress and cardiac fibrosis. Notably, they are considered potential risk markers for myocardial dysfunction in patients undergoing cancer treatment. However, it is important to emphasise their experimental status and acknowledge the need for further validation in larger studies and among several cohorts before they can be integrated into clinical practice. For example, miR-34a has been found to correlate with troponin levels (cTnT and cTnI) and may reflect early myocardial injury, although it does not correlate with LVEF. Other miRs, such as miR-1, miR-29 and miR-126, increase after anthracycline treatment, with some remaining elevated for months after therapy. MiR-130a, which correlates with TnI levels, suggests CTRCD independently of LVEF or NT-proBNP and represents a predictor of this condition. MiRs are implicated in various mechanisms, including oxidative stress, apoptosis, autophagy and fibrosis, all of which contribute to cardiac dysfunction. Altered expression of miR-130a in murine models has been shown to affect cardiac development, indicating its role in cardiomyopathies. Additionally, miR-130a has improved the predictive performance of risk models for CTRCD, helping to better identify patients at risk.^36,37

Newer biomarkers provide insight into myocardial stress and injury and act as potential predictors of cardiac dysfunction in patients undergoing cancer therapy. Soluble ST2 (sST2), a member of the interleukin-1 receptor family, reflects inflammation and mechanical stress and has been recognised for its prognostic value in conditions such as heart failure and coronary artery disease. However, despite it being suspected of being an early indicator of these conditions, recent studies have failed to show that baseline ST2 levels can predict cardiotoxic events.^38,39

Other novel biomarkers from the fields of genetics, proteomics and immunology have also been explored to predict cardiotoxicity based on their biological mechanisms. Research has identified genetic variants associated with increased susceptibility to cardiotoxicity, including those linked to dilated cardiomyopathy and polymorphisms related to cancer therapy-induced cardiac risk, such as HER2 polymorphisms. It has been suggested that an integrated risk prediction model combining clinical and genetic factors may be more effective in predicting anthracycline-induced CTRCD than models based on either component alone.⁴⁰

Cardioprotective Drugs in Cardio-oncology

CTRCD is a relatively common and potentially serious side effect of conventional and targeted cancer therapies. Agents such as anthracyclines and trastuzumab, as well as various targeted therapies, can lead to cardiotoxic effects such as cardiac dysfunction, arterial hypertension, myocarditis or other manifestations, potentially requiring treatment modification or discontinuation. Randomised controlled trials have evaluated multiple strategies to prevent or mitigate these effects, including cardioprotective pharmacological interventions and surveillance techniques using imaging and biomarkers to identify high-risk patients.^41–43

This section reviews the current evidence on the effectiveness of cardioprotective strategies in reducing the cardiotoxic effects of conventional and targeted cancer therapies in adults.

Neurohormonal Blockade

The use of β-blockers, angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) and mineralocorticoid receptor antagonists is well-established for managing CTRCD. Although promising, current evidence does not yet support the routine use of ACEi or β-blockers in the field of cardio-protection; moreover, there are gaps in the evidence regarding their use to prevent CTRCD, and there are several ongoing randomised controlled trials (RCTs) that are assessing their efficacy in this setting.

Neurohormonal activation, which occurs in response to myocardial injury, is associated with CTRCD. This provides a rationale for using neurohormonal antagonists to prevent or manage cancer therapy-induced heart failure.⁴¹

In 2006, a landmark study by Cardinale et al. demonstrated the efficacy of the ACEi enalapril in preventing acute myocardial injury after high-dose chemotherapy. Enalapril was initiated 1 month after chemotherapy was completed in patients with acute myocardial damage indicated by elevated troponin levels. Results showed that the incidence of a >10% decrease in LVEF to below the normal threshold of <50% was significantly higher in untreated patients than in those treated with enalapril (43% versus 0%; p<0.001), highlighting the effectiveness of this intervention in preventing CTRCD.⁴⁴

However, subsequent trials testing ACEi, ARBs and β-blockers have yielded mixed results, with limited or no benefits on primary outcomes. Among ongoing studies, the PRADA trial is one of the most relevant (Table 1). It evaluated the efficacy of candesartan and metoprolol in preventing a decline in LVEF during anthracycline-based therapy, with or without trastuzumab. Candesartan produced a modest but statistically significant reduction in LVEF decline compared to placebo, whereas metoprolol did not show significant effects. This suggests that candesartan may provide cardioprotection during chemotherapy, although its impact on LVEF decline – as measured by CMR – was numerically modest.⁴⁵ Extended follow-up revealed no significant differences in LVEF changes or in troponin I levels between patients treated with candesartan or metoprolol and controls, indicating that these treatments did not significantly improve cardiac function outcomes.⁴⁶

The CECCY trial investigated the role of carvedilol in preventing anthracycline-induced cardiotoxicity in patients with HER2-negative breast cancer. No significant differences in cardiotoxicity (defined as a ≥10% reduction in LVEF after 6 months) were observed between carvedilol and placebo groups. However, carvedilol was associated with a reduction in cTnI elevation during treatment, suggesting a protective effect against acute myocardial injury. At 2-year follow-up, no significant differences were seen in cardiotoxicity rates or cardiac function.⁴⁷

Preliminary results from the four-arm SAFE trial assessed the effects of bisoprolol, ramipril and their combination on anthracycline-induced subclinical cardiac injury (Table 1). At 12 months, the placebo group showed a 4.4% LVEF decline, compared with 3.0%, 1.9% and 1.3% in the ramipril, bisoprolol and combination groups, respectively. Deterioration in global longitudinal strain (GLS) was also significantly lower in treated groups (ramipril –0.1%, bisoprolol 0.6%, combination 1.5%) versus placebo (6.0%). While these interim findings are promising, final 24-month data are needed for definitive conclusions.⁴⁸

The ICOS-ONE study examined two cardioprotective approaches with enalapril in anthracycline-treated patients: administration before chemotherapy or only after troponin elevation (Table 1). Among the 273 patients enrolled, no significant differences were observed between groups in troponin elevation or CTRCD incidence, with very low rates of LVEF decline in both arms. At 3-year follow-up, no new cases of CTRCD were reported. These findings suggest that in low cardiovascular risk patients, the risk of severe myocardial damage or CTRCD is limited – even in the absence of prophylactic enalapril.^49,50

The SUCCOUR study compared two echocardiographic surveillance strategies – serial LVEF versus GLS measurements – in patients undergoing anthracycline therapy (Table 1). Patients who developed cardiac dysfunction received ACEi or ARBs followed by β-blockers. After 1 year, no significant differences in LVEF or GLS changes were observed between groups, but the GLS-guided group had a lower incidence of CTRCD (5.8% versus 13.7%). Despite greater neurohormonal therapy use in the GLS group, findings suggest that neurohormonal inhibition may be less effective for patients having moderate anthracycline doses, possibly due to the limited severity of myocardial damage.⁵¹

Unlike anthracyclines, trastuzumab-induced cardiotoxicity is not associated with cardiomyocyte necrosis and tends to be at least partially reversible after treatment is discontinued.⁴¹

The MANTICORE 101-Breast trial enrolled 99 patients with early-stage HER2-positive breast cancer, randomised to bisoprolol, perindopril or placebo during trastuzumab therapy (Table 2). The trial was terminated early for futility, as no significant differences in left ventricular remodelling were found. However, secondary analyses showed that both perindopril and bisoprolol attenuated LVEF decline associated with trastuzumab. Although the primary endpoint was not met, the study demonstrated beneficial secondary effects on LVEF and good tolerability of the interventions and fewer interruptions to therapy.⁵²

A Dutch study by Boekhout et al. (Table 2) included 210 HER2-positive breast cancer patients who received anthracycline-based chemotherapy, randomised to candesartan or placebo. No significant differences in cardiotoxicity (defined by LVEF reduction, cTnT or NT-proBNP levels) were observed 40 weeks after trastuzumab was discontinued.⁵³

The SAFE-HEaRt and Scholar trials investigated cardioprotective strategies in HER2-positive breast cancer patients with mild left ventricular dysfunction undergoing trastuzumab therapy (Table 3). In SAFE-HEaRt, 30 patients receiving β-blockers and ACEi completed treatment without major cardiac events. In Scholar, 20 patients with mild cardiotoxicity continued trastuzumab with observed improvement in LVEF. These findings suggest that with appropriate monitoring and treatment, continuing trastuzumab despite mild CTRCD may be safe, although further studies are needed to confirm these benefits.^54,55

The efficacy of sacubitril/valsartan as a preventive strategy for anthracycline-related cardiotoxicity is currently under investigation. The PRADA II trial is a multicentre, placebo-controlled RCT evaluating its cardioprotective effect in patients with early-stage breast cancer (Table 4). Another trial, MAINSTREAM, is exploring the safety and efficacy of sacubitril/valsartan for cardiotoxicity prevention in early-stage breast cancer patients initiating anthracycline and/or anti-HER2 therapy, excluding those with baseline LV dysfunction or previous treatment with anthracycline or chest radiotherapy (Table 4).^42,56

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)

SGLT2i are emerging as a promising option for cardiovascular protection, especially in oncology patients. A systematic review and meta-analysis involving nearly 100,000 participants showed that these drugs significantly reduce hospitalisations for heart failure and all-cause mortality.⁵⁷ This is particularly relevant for patients receiving cardiotoxic chemotherapy, including anthracyclines, trastuzumab and tyrosine kinase inhibitors, as well as those with comorbidities, such as diabetes, which increases cardiovascular risk. SGLT2i protects the heart by improving myocardial metabolism, reducing cardiac preload and afterload, and attenuating systemic inflammation. These mechanisms may allow for the safer administration of higher doses of antineoplastic agents without compromising treatment efficacy.

Available data suggest that SGLT2i may provide significant benefits to oncology patients with a lower number needed to treat compared to patients with diabetes alone. These data are derived from a meta-analysis of observational and retrospective studies rather than prospective ones and are therefore subject to potential confounding factors, such as sex-specific effects of SGLT2 inhibition, variations in its use based on socioeconomic status, concomitant heart failure therapies and cancer staging, which may influence a patient’s prognosis.⁵⁷ Although current evidence is largely derived from populations with non-oncological heart failure, SGLT2is are emerging as a promising option for cardiovascular protection, highlighting the need for prospective studies of its use for oncology patients.

Ongoing trials, such as PROTECT (NCT06341842) and SCARA-B (NCT06443645), are currently evaluating the efficacy of these drugs in breast cancer patients undergoing anthracycline-based chemotherapy, but results have not yet been published. These trials will provide key insights into the cardioprotective effects of SGLT2i, including changes in LVEF and cardiac biomarkers.⁵⁷

Mineralocorticoid Receptor Antagonists and Statins

Aldosterone, stimulated by angiotensin II, is a key factor in the fibrotic response to myocardial injury, providing a rationale for the cardioprotective use of mineralocorticoid receptor antagonists. However, evidence regarding the effectiveness of these drugs is mixed. In a Turkish study, spironolactone reduced the decline in LVEF and the rise in cTnI, but had no significant impact on diastolic function.⁵⁸

Observational studies suggest that statins may reduce cardiovascular risk, while other drugs such as colchicine and aspirin may help mitigate myocardial inflammation and fibrosis, though clinical evidence remains lacking.⁵⁹

Onco-specific Treatments

From an oncological perspective, certain targeted treatments may help reduce the cardiotoxicity associated with cancer therapy.

Dexrazoxane is an intracellular iron chelator whose mechanism is not fully understood but is believed to inhibit iron-mediated oxidative damage and the topoisomerase II-ß isoenzyme is implicated in anthracycline-induced cardiotoxicity. It is recommended that patients with adult breast cancer are treated with 300 mg/m² of doxorubicin 30 minutes before each anthracycline cycle, as it has been shown to delay and reduce treatment-related cardiac dysfunction. It is also recommended in adults receiving high cumulative anthracycline doses (>250–300 mg/m² of doxorubicin equivalent), as it protects against symptomatic and asymptomatic cardiac dysfunction without compromising the efficacy of anthracycline. However, switching to alternative regimens or using liposomal formulations is preferred for patients with advanced cancer who are expected to receive high anthracycline doses. Therefore, dexrazoxane is not routinely used in clinical practice.

Liposomal anthracyclines have demonstrated non-inferior anti-tumour efficacy and a reduced risk of treatment-induced cardiac dysfunction. They represent an alternative option for oncology patients at high risk of cardiotoxicity, such as older people, those who have had previous exposure to anthracycline or patients with cardiovascular risk factors. Liposomal anthracyclines have not shown superiority over conventional anthracyclines, prompting ongoing research into liposomal membrane modification with targeting ligands, such as antibodies, peptides or cell-penetrating enhancers, to improve drug delivery and efficacy. Current findings remain limited to preclinical studies.^3,60–66

Integration of Biomarkers and Drugs in Personalised Therapy

The multi-hit model of heart failure, where multiple risk factors interact to provoke it, suggests that patients with pre-existing or subclinical cardiovascular disease have reduced cardiac reserve and tolerate less damage before developing overt CTRCD. Modifiable cardiovascular risk factors, including smoking, obesity, physical inactivity, hypertension and diabetes, increase the risk of CTRCD. Preventive interventions such as lifestyle modification and pharmacological treatments can improve cardiovascular health and mitigate this risk. A cardiology evaluation is therefore essential for oncological patients with established or high cardiovascular risk before initiating potentially cardiotoxic cancer therapies.⁴¹

Cancer-related factors such as hypercoagulability, tumour invasion into the heart or vessels and high-output states can also contribute to cardiovascular risk. Additionally, cancer therapies, such as radiotherapy (especially targeting the heart or mediastinum), anthracyclines or target therapies can increase the likelihood of cardiac damage. Effective CTRCD management includes addressing modifiable risk factors and adjusting oncological therapy dosage or delivery methods. The use of cardioprotective drugs such as β-blockers, ACEi or ARBs is a useful strategy, although long-term benefits remain unclear. A risk-based cardioprotective approach, rather than universal administration, is considered most appropriate. Angiotensin antagonists and/or β-blockers may be recommended for patients with high cardiovascular risk profiles, such as having elevated troponin levels or high cumulative anthracycline doses.⁶⁷

Current guidelines promote integrating biomarkers and cardiovascular imaging to detect early forms of CTRCD in patients treated with anthracyclines and trastuzumab (Figure 1). This combined approach allows timely detection of cardiac dysfunction and enables corrective interventions. Identifying modifiable cardiovascular risk factors, such as elevated troponins or cumulative anthracycline exposure, is crucial for the identification of vulnerable patients. For such patients, cardioprotective agents, such as β-blockers or ACEi/ARBs, are recommended to reduce cardiac risk.

If cardiac function deteriorates during cancer treatment, initiating cardioprotective therapy should be prioritised and maintained throughout the course of oncological treatment. While the optimal duration of such therapy has not been fully established, it may be necessary to temporarily suspend oncological treatment to concentrate on heart failure management when clinical signs of heart failure emerge. Although sacubitril/valsartan shows promise, further RCTs are needed to confirm its effectiveness in CTRCD prevention.^3,41

Gaps in Research

Risk stratification is essential for predicting and preventing cardiotoxicity and validated guidelines now incorporate biomarkers and cardiovascular imaging for early detection. However, the predictive value of certain biomarkers, such as genetic and molecular markers, is still poorly understood and not currently included in formal risk scores.⁶⁸ To improve personalised risk stratification, genetic, immune and molecular patient profiles should be considered, but further validation of these biomarkers is needed in large, representative clinical cohorts.

Other biomarkers, such as miRs, have been studied as promising tools for detecting drug-induced cardiotoxicity, but their clinical role requires further validation. Additional studies are also needed to confirm the benefits of using established biomarkers and to determine optimal blood sampling strategies.

Primary prevention of CTRCD is crucial before treatment. Reducing drug dosage, particularly for dose-dependent therapies such as radiotherapy and anthracyclines, is highly effective in lowering risk. However, the effectiveness of cardioprotective drugs remains uncertain as clinical trials have shown no significant benefits so far. Ongoing trials are expected to provide clearer evidence. The benefits of cardioprotection may be underestimated in current trials due to under-representation of high-risk patients who might benefit the most.

For anthracyclines, research into genetic testing to predict CTRCD is ongoing, and there is a need for novel cardioprotective agents targeting specific pathophysiological mechanisms. At present, genetic testing is not recommended as routine practice before anthracycline treatment, though its use may be supported in the future based on pharmacogenomics and cardiovascular biology. However, research into genetic susceptibility to anthracycline-induced cardiotoxicity is still preliminary and limited by small cohorts, preventing the identification of all relevant polymorphisms.

Additionally, the predictive value of baseline cardiovascular biomarkers is not yet fully established. Recent studies, such as PRADA, have shown that mild, asymptomatic troponin elevations during cancer therapy do not always correlate with overt cardiotoxicity, challenging the systematic use of troponin as a stand-alone indicator.⁶⁹

For trastuzumab, further research is required to assess the predictive value of blood biomarkers in low-risk populations, particularly those treated with novel HER2-targeted agents or antibody-drug conjugates. Current cardiac biomarkers lack sufficient validation for risk stratification before anti-HER2 therapy and existing guidelines are inconsistent. Widespread biomarker screening remains controversial, as many patients resent with elevated troponin levels before treatment initiation. The HERA study found baseline cTnI and cTnT abnormalities in a significant proportion of patients, with elevated levels associated with greater LVEF decline during therapy.

Moreover, polymorphisms in the ERbB2 gene, altering the HER2-neu protein sequence, have been associated with an increased risk of trastuzumab-related CTRCD, suggesting that baseline genetic testing may have predictive value.

In the context of immunotherapy, further evidence is needed to understand the role of troponin measurement in predicting cardiotoxicity and to evaluate the efficacy of cardioprotective strategies, which remain poorly defined.⁵

Sex-specific considerations in cardiotoxicity risk remain an underexplored area in cardio-oncology research. Ensuring adequate representation of women in clinical trials involving cytotoxic therapies is crucial to better understand sex-related differences in susceptibility to cardiotoxic effects. Such data could inform the development of sex-specific dosing strategies, thereby optimising treatment efficacy while minimising adverse cardiovascular events in women with cancer. Enhanced inclusion of women in these studies may ultimately lead to more personalised and safer cardio-oncological care.

Conclusion

Cardio-oncology is an evolving field where advanced biomarkers and cardioprotective drugs are gaining prominence in managing treatment-induced cardiotoxicity. While traditional biomarkers such as cTn and NPs are useful for monitoring cardiac function, novel biomarkers, including genetic markers, miRs and other biochemical entities, offer potential for increasingly personalised risk stratification. However, their predictive validity is not yet fully confirmed, and further studies are required to validate their clinical utility in large patient cohorts.

On the pharmacological front, β-blockers, ACEi and ARBs show potential in mitigating cardiotoxicity during cancer therapy, but their long-term effectiveness requires confirmation from larger trials. Although risk-based strategies for identifying patients who would benefit most from their use appear promising, RCTs have not yet supported biomarker- or imaging-guided interventions. This may be due to the limited effectiveness of neurohormonal antagonists in the absence of significant neurohormonal activation. These drugs are not designed to directly counteract oncological cardiotoxic mechanisms but rather to attenuate downstream effects of myocardial injury.

Integrating pharmacogenomics and cardiovascular biology may enhance the personalised care of cancer patients who have a high risk of cardiac dysfunction, but further validation of biomarkers and therapies is needed to better prevent and manage cardiotoxicity.