New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review.

Cardiotoxicity induced by breast cancer therapies is a potentially serious complication associated with the use of various breast cancer therapies. Prediction and better management of cardiotoxicity in patients receiving chemotherapy is of critical importance. However, the management of cancer therapy-related cardiac dysfunction (CTRCD) lacks clinical evidence and is based on limited clinical studies. AIM: To provide an overview of existing and potentially novel biomarkers that possess a promising predictive value for the early and late onset of CTRCD in the clinical setting. METHODS: A systematic review of published studies searching for promising biomarkers for the prediction of CTRCD in patients with breast cancer was undertaken according to PRISMA guidelines. A search strategy was performed using PubMed, Google Scholar, and Scopus for the period 2013-2023. All subjects were >18 years old, diagnosed with breast cancer, and received breast cancer therapies. RESULTS: The most promising biomarkers that can be used for the development of an alternative risk cardiac stratification plan for the prediction and/or early detection of CTRCD in patients with breast cancer were identified. CONCLUSIONS: We highlighted the new insights associated with the use of currently available biomarkers as a standard of care for the management of CTRCD and identified potentially novel clinical biomarkers that could be further investigated as promising predictors of CTRCD.

How to identify anthracycline-induced cardiotoxicity early and reduce its clinical impact in everyday practice.

Discovered in the 1960s, anthracyclines are still among the most widely used chemotherapy drugs, but are associated with cardiotoxicity. To date, the main strategies that seem to be effective in reducing its incidence and severity include screening and treating preexisting cardiovascular risk factors, limiting the cumulative anthracycline dose with a preference for less toxic analogues, and administering cardioprotective drugs as early as possible after its diagnosis. A better understanding of the underlying mechanisms and greater refinement of the diagnostic tools at our disposal has led to considerable progresses in the detection of this serious side effect at a preclinical stage, allowing for prompt intervention. However, despite increasing efforts to identify early predictors of cardiotoxicity and growing evidence of the importance of cardiac biomarkers for this purpose, large randomized multicenter clinical trials are still lacking and so there is still no scientific agreement on the best approach for early diagnosis. Nonetheless, dosing troponin at each chemotherapy cycle and initiating, when it increases above the threshold, a therapy with renin-angiotensin-aldosterone system inhibitors and/ or ß-blockers has proved to be an effective strategy in reducing the progression of microscopic myocardial damage into left ventricular remodelling and clinically evident cardiotoxicity.

Characteristics, Management, and Outcomes of Acute Coronary Syndrome Patients with Cancer.

Patients with cancer are at increased risk of cardiovascular disease, with a reported prevalence of acute coronary syndrome (ACS) ranging from 3% to 17%. The increased risk of ACS in these patients seems to be due to the complex interaction of shared cardiovascular risk factors, cancer type and stage, and chemotherapeutic and radiotherapy regimens. The management of ACS in patients with cancer is a clinical challenge, particularly due to cancer's unique pathophysiology, which makes it difficult to balance thrombotic and bleeding risks in this specific patient population. In addition, patients with cancer have largely been excluded from ACS trials. Hence, an evidence-based treatment for ACS in this group of patients is unknown and only a limited proportion of them is treated with antiplatelets or invasive revascularization, despite initial reports suggesting their beneficial prognostic effects in cancer patients. Finally, cancer patients experiencing ACS are also at higher risk of in-hospital and long-term mortality as compared to non-cancer patients. In this review, we will provide an overview on the available evidence of the relationship between ACS and cancer, in terms of clinical manifestations, possible underlying mechanisms, and therapeutic and prognostic implications.

Circulating biomarkers and cardiac function over 3 years after chemotherapy with anthracyclines: the ICOS-ONE trial.

AIMS: A multicentre trial, ICOS-ONE, showed increases above the upper limit of normality of cardiac troponin (cTn) in 27% of patients within 12 months after the end of cancer chemotherapy (CT) with anthracyclines, whether cardiac protection with enalapril was started at study entry in all (prevention arm) or only upon first occurrence on supra-normal cTn (troponin-triggered arm). The aims of the present post hoc analysis were (i) to assess whether anthracycline-based treatment could induce cardiotoxicity over 36 month follow-up and (ii) to describe the time course of three cardiovascular biomarkers (i.e. troponin I cTnI-Ultra, B-type natriuretic peptide BNP, and pentraxin 3 PTX3) and of left ventricular (LV) function up to 36 months. METHODS AND RESULTS: Eligible patients were those prescribed first-in-life CT, without evidence of cardiovascular disease, normal cTn, LV ejection fraction (EF) >50%, not on renin-angiotensin aldosterone system antagonists. Patients underwent echocardiography and blood sampling at 24 and 36 months. No differences were observed in biomarker concentration between the two study arms, 'prevention' vs. 'troponin-triggered'. During additional follow-up 13 more deaths occurred, leading to a total of 23 (9.5%), all due to a non-cardiovascular cause. No new occurrences of LV-dysfunction were reported. Two additional patients were admitted to the hospital for cardiovascular causes, both for acute pulmonary embolism. No first onset of raised cTnI-Ultra was reported in the extended follow-up. BNP remained within normal range: at 36 months was 23.4 ng/L, higher (N.S.) than at baseline, 17.6 ng/L. PTX3 peaked at 5.2 ng/mL 1 month after CT and returned to baseline values thereafter. cTnI-Ultra peaked at 26 ng/L 1 month after CT and returned to 3 ng/L until the last measurement at 36 months. All echocardiographic variables remained stable during follow-up with a median LVEF of 63% and left atrial volume index about 24 mL/m2 . CONCLUSIONS: First-in-life CT with median cumulative dose of anthracyclines of 180 mg/m2 does not seem to cause clinically significant cardiac injury, as assessed by circulating biomarkers and echocardiography, in patients aged 51 years (median), without pre-existing cardiac disease. This may suggest either a 100% efficacy of enalapril (given as preventive or troponin-triggered) or a reassuringly low absolute cardiovascular risk in this cohort of patients, which may not require intensive cardiologic follow-up.

Oncologic therapies associated with cardiac toxicities: how to minimize the risks.

INTRODUCTION: Recent breakthroughs in cancer treatment has improved the prospects and life expectancy of cancer patients. Therefore, risk of cardiotoxicity induced by oncologic therapies has become an important determinant of patient's survival and quality of life, independently of the oncologic prognosis. Areas covered: This paper provides an overview of the proposed strategies to mitigate the risk of cardiotoxicity. Limitation of current approaches, the need for early detection and the treatment of cardiotoxicity are also discussed. Possible future research directions are also described. Expert opinion: The most effective approach to minimize cardiotoxicity is early identification and early onset of a prophylactic treatment. However, the current standard of cardiac monitor identifies cardiotoxicity only when a functional impairment has already occurred, precluding any chance of effective prevention. The use of troponins to identify subclinical cardiotoxicity, and early treatment with ACE-inhibitors to prevent cardiac dysfunction and cardiac events have recently emerged, and appear to be an effective tool against this complication.

Acute kidney injury after lung cancer surgery: Incidence and clinical relevance, predictors, and role of N-terminal pro B-type natriuretic peptide.

BACKGROUND: Acute kidney injury (AKI) frequently occurs in several medical and surgical settings, and it is associated with increased morbidity and mortality. In patients undergoing lung cancer surgery, AKI has not been fully investigated. We prospectively evaluated the incidence, clinical relevance, and risk factors of AKI in patients undergoing lung cancer surgery. Moreover, we estimated the accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the prediction of AKI. METHODS: Patients undergoing lung cancer surgery were included in the study. Plasma NT-proBNP was measured before and soon after surgery. Postoperative AKI was defined according to the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 2179 patients were enrolled. Of them, 222 (10%) developed AKI and had a more complicated in-hospital clinical course (overall complication rate: 35% vs. 16%; P < 0.0001), and a longer hospital stay (10 ± 7 vs. 7 ± 4 days; P < 0.0001). The incidence of AKI increased in parallel with the extent of lung resection. Among the independent predictors of AKI, serum creatinine (area under the curve [AUC] 0.70 [95% CI 0.67-0.74]) and NT-proBNP (AUC 0.71 [95% CI 0.67-0.74]) provided the highest predictive accuracy, and their combination further significantly improved AKI prediction (AUC 0.74 [95% CI 0.71-0.77]). No difference in AKI prediction was observed between preoperative and postoperative NT-proBNP (P = 0.84). CONCLUSIONS: Acute kidney injury occurs in 10% of patients undergoing lung cancer surgery, and it is associated with a high incidence of postoperative complications. The risk of AKI can be accurately predicted by the combined evaluation of preoperative serum creatinine and NT-proBNP.

Anthracycline-induced cardiotoxicity: A multicenter randomised trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial.

BACKGROUND: Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit. METHODS: The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; 'prevention' arm), and enalapril started only in patients with an increase in troponin during or after CT ('troponin-triggered' arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold. FINDINGS: Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270-360] and 240 [240-240] mg/m2, respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%. INTERPRETATION: Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.

The breast cancer patient in the cardioncology unit.

The breakthroughs of breast cancer management have led to a significant improvement in patient survival. However, to obtain this outcome a considerable price has been paid regarding cardiovascular side effects. Indeed, cardiovascular disease is the main cause of mortality in patients with breast cancer over fifty years of age, contributing more than cancer mortality in older cancer survivors. Thus, the identification and the management of patients with breast cancer at risk for cardiovascular events has become critical in order to reduce morbidity and mortality from cardiovascular toxicity due to cancer therapy, which may blunt its effectiveness. Today, cardioncology is a novel and recognized medical discipline, which aims to encourage a close interaction between cardiology and oncology, explore new strategies, collect evidence-based indications, and develop interdisciplinary expertise with the ultimate goal of minimize the risk of developing cardiovascular disease during and after anticancer therapy, prevent the breast cancer patient cured today from becoming the heart patient of tomorrow, and avoiding the possibility that pre-existent cardiac disease be a barrier leading to a reduction of a patient's therapeutic opportunities. In this review we discussed the advantages of a cardioncology approach in terms of risk stratification, monitoring for early diagnosis, prevention, and early treatment of cardiotoxicity.

Cardio-oncology: Gaps in Knowledge, Goals, Advances, and Educational Efforts.

Over the past 20 years, cancer treatments have become more effective, leading to significant improvements in survival rates. However, anticancer drugs can have several possible cardiovascular side effects; in particular, the development of left ventricular dysfunction with chemoradiation therapy can negatively affect patients' cardiac outcome, and can limit anticancer treatments. This is an ongoing issue that will continue to persist, due to the ongoing development of new antitumor agents with potential cardiotoxic effects, and the prolonged life expectancy of long-term cancer survivors. Thus, the need for cooperation between oncologists and cardiologists in the management of cancer patients has led to the development of a new medical discipline-cardio-oncology-where the issue of cardiotoxicity is a topic of intense interest and research. However, several issues remain-the proper definition and diagnosis of cardiotoxicity, as well as monitoring and treatment strategies. In this review, the current advances in cardio-oncology, limitations of current approaches, and future research fields will be discussed.

Diagnostic and Prognostic Utility of Circulating Cytochrome c in Acute Myocardial Infarction.

RATIONALE: In contrast to cardiomyocyte necrosis, which can be quantified by cardiac troponin, functional cardiomyocyte impairment, including mitochondrial dysfunction, has escaped clinical recognition in acute myocardial infarction (AMI) patients. OBJECTIVE: To investigate the diagnostic accuracy for AMI and prognostic prediction of in-hospital mortality of cytochrome c. METHODS AND RESULTS: We prospectively assessed cytochrome c serum levels at hospital presentation in 2 cohorts: a diagnostic cohort of patients presenting with suspected AMI and a prognostic cohort of definite AMI patients. Diagnostic accuracy for AMI was the primary diagnostic end point, and prognostic prediction of in-hospital mortality was the primary prognostic end point. Serum cytochrome c had no diagnostic utility for AMI (area under the receiver-operating characteristics curve 0.51; 95% confidence intervals 0.44-0.58; P=0.76). Among 753 AMI patients in the prognostic cohort, cytochrome c was detectable in 280 (37%) patients. These patients had higher in-hospital mortality than patients with nondetectable cytochrome c (6% versus 1%; P<0.001). This result was mainly driven by the high mortality rate observed in ST-segment-elevation AMI patients with detectable cytochrome c, as compared with those with nondetectable cytochrome c (11% versus 1%; P<0.001). At multivariable analysis, cytochrome c remained a significant independent predictor of in-hospital mortality (odds ratio 3.0; 95% confidence interval 1.9-5.7; P<0.001), even after adjustment for major clinical confounders (odds ratio 4.01; 95% confidence interval 1.20-13.38; P=0.02). CONCLUSIONS: Cytochrome c serum concentrations do not have diagnostic but substantial prognostic utility in AMI.

Prevention of Atrial Fibrillation in High-risk Patients Undergoing Lung Cancer Surgery: The PRESAGE Trial.

OBJECTIVE: We performed a prospective, randomized clinical study to assess whether prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, reduces the incidence of postoperative atrial fibrillation. BACKGROUND: Postoperative atrial fibrillation is a well recognized complication after lung cancer surgery, with an incidence as high as 30%. Perioperative increase of NT-proBNP has been demonstrated to be a strong independent predictor of postoperative atrial fibrillation in this setting. METHODS: NT-proBNP concentration was measured 24 hours before surgery and soon after surgery in 1116 patients. Three hundred twenty (29%) patients showed a high NT-proBNP value and were enrolled: 108 were assigned to the metoprolol group, 102 to the losartan group, and 110 to the control group. RESULTS: Overall, the incidence of postoperative atrial fibrillation was 20% (n = 64); it was significantly lower in the metoprolol and losartan groups compared with the control group [6%, 12%, and 40%, respectively; relative risk 0.19, 95% confidence intervals (CIs), 0.09-0.37; P < 0.001 in the metoprolol group; and 0.29, 95% CI, 0.16-0.52; P < 0.001 in the losartan group). No significant difference was found when the metoprolol and losartan groups were directly compared (P = 0.21). CONCLUSIONS: A prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with high NT-proBNP levels, significantly reduced the occurrence of postoperative atrial fibrillation.

Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.

BACKGROUND: Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking. We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. METHODS AND RESULTS: We assessed left ventricular ejection fraction (LVEF), at baseline, every 3 months during chemotherapy and for the following year, every 6 months over the following 4 years, and yearly afterward in a heterogeneous cohort of 2625 patients receiving anthracycline-containing therapy. In case of cardiotoxicity (LVEF decrease >10 absolute points, and <50%), heart failure therapy was initiated. Recovery from cardiotoxicity was defined as partial (LVEF increase >5 absolute points and >50%) or full (LVEF increase to the baseline value). The median follow-up was 5.2 (quartile 1 to quartile 3, 2.6-8.0) years. The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3-6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year. Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery. At multivariable analysis, end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33-1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04-1.15 for each 50 mg/m(2) increment) were independent correlates of cardiotoxicity. CONCLUSIONS: Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.

Cardiac complications of chemotherapy: role of biomarkers.

OPINION STATEMENT: Both conventional and novel antineoplastic drugs may cause damage to the heart, ultimately affecting patients' survival and quality of life. In fact, the most frequent and typical clinical manifestation of cardiotoxicity, asymptomatic or symptomatic left ventricular dysfunction, may be induced not only by conventional cancer therapy, like anthracyclines, but also by new antitumoral targeted therapy such as trastuzumab. At present, left ventricular ejection fraction assessment represents the main standard practice for cardiac monitoring during cancer therapy, but it detects myocardial damage only when a functional impairment has already occurred, not allowing for early preventive strategies. In the last decade, a newer approach based on the measurement of cardiospecific biomarkers has been proposed, proving to have higher prognostic value than imaging modalities. In particular, cardiac troponin elevation during chemotherapy allows us to identify patients who are more prone to develop myocardial dysfunction and cardiac events during follow up. In these patients, the use of an angiotensin-converting enzyme inhibitor, such as enalapril, has shown to be effective in improving clinical outcome, giving the chance for a cardioprotective strategy in a selected population.

TnI-Ultra assay measurements in cancer patients: comparison with the conventional assay and clinical implication.

The serial monitoring of cardiac troponin represents an effective approach for the early identification, assessment, and monitoring of chemotherapy-induced cardiac injury. Over the last few years new generations of troponin assays, referred to as sensitive and high sensitivity assays, able to detect very low concentrations of troponin, have been progressively released on different platforms. Some studies have assessed the comparability of the cTnI measurements with the new assays versus the conventional ones, but none of these in the oncological population. We compared the cTnI results determined on Stratus CS and ADVIA Centaur CP System in 70 breast cancer patients, for a total of 327 samples collected during different cycles of treatment. Correlation (Spearman = 0.732) and agreement (91.4%) between the assays were good (244 concordant negatives and 55 concordant positives), with a frequency of 8.6% discordant results among the cTnI measurements. Despite the well-known lack in the harmonization and standardization of the currently commercially available cTnI methods, we found a good clinical concordance of cTnI determination on both systems.

Managing cardiotoxicity of chemotherapy.

OPINION STATEMENT: The increase in survivorship of cancer patients makes the understanding of the available options for prevention and treatment of cardiotoxicity induced by antineoplastic agents a crucial topic both for cardiologists and oncologists. The most frequent and typical clinical manifestation of cardiotoxicity is asymptomatic or symptomatic left ventricular dysfunction, which may progress to overt heart failure. It may be induced not only by conventional cancer therapy, like anthracyclines, but also by new antitumoral targeted therapy such as trastuzumab. The current standard for monitoring cardiac damage during antineoplastic treatment, mainly based on the quantification of left ventricular ejection fraction, detects cardiac toxicity only when a functional impairment has already occurred. Evaluation of cardiac biomarkers such as troponin, however, has shown excellent sensitivity in the early detection of cardiotoxicity by the identification of patients with subclinical cardiac injury that precedes the development of cardiac dysfunction. The use of angiotensin-converting enzyme inhibitors in patients with troponin elevation during chemotherapy may be an effective tool to prevent left ventricular ejection fraction reduction and late cardiac events. There are no well established recommendations for treatment of cancer patients who develop cardiac dysfunction. Angiotensin-converting enzyme inhibitors and beta-blockers have proven to be effective in this setting. However, there are concerns in using these medications in cancer patients, and therefore the tendency is to treat patients only if symptomatic. However, the clinical benefit of these medications may be more evident in asymptomatic patients, and the recovery of cardiac function strongly depends on the amount of time elapsed from the end of chemotherapy to the start of heart failure therapy. This observation suggests that the early detection of cardiac damage is crucial and early use of angiotensin-converting enzyme inhibitors and beta-blockers should be considered in patients with left ventricular dysfunction induced by antineoplastic agents.

Strategies to prevent and treat cardiovascular risk in cancer patients.

Cardiotoxicity due to cancer treatment is of rising concern, for both cardiologists and oncologists, because it may have a significant impact on cancer patient management and outcome. The most typical manifestation of cardiotoxicity is a hypokinetic cardiomyopathy leading to heart failure. However, the spectrum of the toxic effects that can impair the cardiovascular system may also include acute coronary syndromes, hypertension, arrhythmias, and thromboembolic events. Patients undergoing cancer treatment are more vulnerable to cardiovascular injuries, and their risk of premature cardiovascular disease and death is higher than that of the general population. Prevention of cardiotoxicity remains the most important strategy, and several measures, including cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogues and cardioprotectants, and early detection of myocardial cell injury by biomarkers, have been proposed. The response to modern heart failure therapy of cancer treatment-induced cardiomyopathy has never been evaluated in clinical trials, and currently there are no definitive guidelines. Although it is likely that medications used for other forms of cardiomyopathy, particularly angiotensin-converting enzyme inhibitors and ß-blockers, may be highly effective, there is still some unjustified concern regarding their use in cancer patients. Specific guidelines that take cardiologic conditions of cancer patients into account are currently lacking and need to be developed.

Circulating cytochrome c as potential biomarker of impaired reperfusion in ST-segment elevation acute myocardial infarction.

In patients with ST-segment elevation acute myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI), abrupt reperfusion can induce myocardial injury and apoptotic cell death. Reperfusion-induced myocardial damage, however, cannot be easily evaluated in clinical practice because of the lack of specific biomarkers. Cytochrome c, a mitochondrial protein, is released on reperfusion into the cytosol, where it triggers the apoptotic process. It can reach the external fluid and circulating blood when cell rupture occurs. We measured the cytochrome c circulating levels in patients with STEMI undergoing pPCI, and correlated them with the clinical signs of myocardial necrosis and reperfusion. The plasma creatine kinase-MB mass and serum cytochrome c (enzyme-linked immunosorbent assay method) were serially measured in 55 patients with STEMI undergoing pPCI. The angiographic and electrocardiographic signs of myocardial reperfusion were also assessed. Cytochrome c transiently increased in all patients with STEMI, with a curve that paralleled that of creatine kinase-MB. A significant relation was found between the peak values of the 2 biomarkers (R = 0.35, p = 0.01) and between the areas under the 2 curves (R = 0.33, p = 0.02). The creatine kinase-MB peak value correlated significantly with the clinical features of infarct extension. In contrast, the cytochrome c peak value correlated inversely with the myocardial blush grade. Patients with clinical signs of myocardial reperfusion injury had a significantly greater cytochrome c peak value than patients without reperfusion injury (median 1.65 ng/ml, interquartile range 1.20 to 2.20, vs 1.1 ng/ml, interquartile range 0.65 to 1.55; p = 0.04). In conclusion, serum cytochrome c is detectable in the early phase of STEMI treated with pPCI and is associated with clinical signs of impaired myocardial reperfusion.