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BackgroundAnthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy.MethodsIn a multicenter prospective randomized open label blinded endpoint trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk non-randomized patients with cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (±2%).ResultsBetween October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy respectively. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between cardioprotection and standard care groups was -0.37% (95% confidence interval, -3.59 to 2.85%; P=0.82). In low-risk non-randomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3% respectively: estimated mean difference, 2.87% (95% confidence interval, 1.63 to 4.10%; P=0.92, not equivalent)ConclusionsCombination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk non-randomized patients had similar declines in left ventricular ejection fraction questioning the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy needs to be better defined in patients receiving high-dose anthracycline regimes.REGISTRATIONEudraCT 2017-000896-99, ISRCTN24439460Clinical PerspectiveWhat is new?In this randomized controlled trial of patients at high risk of anthracycline cardiotoxicity, combined candesartan and carvedilol therapy did not protect against decline in 6-month left ventricular ejection fraction after completion of chemotherapy.Overall decline in 6-month left ventricular ejection fraction occurred irrespective of changes in cardiac troponin concentration during chemotherapy.What are the clinical implications?The Cardiac CARE trial findings do not support recent guideline recommendations advocating the use of cardiac troponin monitoring and early preventive neurohormonal blockade in patients at risk of anthracycline cardiotoxicity.Future studies should focus on factors determining transition to subsequent development of heart failure from initial mild and asymptomatic changes in cardiac function following anthracycline chemotherapy.

Background: Anthracyclines are effective cytotoxic drugs used in the treatment of breast cancer and lymphoma but are associated with myocardial injury, left ventricular dysfunction, and heart failure. Anthracycline-induced cardiotoxicity is highly variable in severity and without a proven therapeutic intervention. β-Adrenergic receptor blockers and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients. Methods: The Cardiac CARE trial is a multicentre prospective randomized open-label blinded end point trial of combination β-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapy in patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy that is associated with myocardial injury. Patients at higher risk of cardiotoxicity with plasma high-sensitivity cTnI (cardiac troponin I) concentrations in the upper tertile at the end of chemotherapy are randomized to standard of care plus combination candesartan and carvedilol therapy or standard of care alone. All patients undergo cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. The primary end point is the change in left ventricular ejection fraction at 6 months after chemotherapy. In low-risk nonrandomized patients, left ventricular ejection fraction before and 6 months after anthracycline will be compared with define the specificity of the high-sensitivity cTnI assay for identifying low-risk participants who do not develop left ventricular systolic dysfunction. Discussion: Cardiac CARE will examine whether cardiac biomarker monitoring identifies patients at risk of left ventricular dysfunction following anthracycline chemotherapy and whether troponin-guided treatment with combination candesartan and carvedilol therapy prevents the development of left ventricular dysfunction in these high-risk patients.

Metformin is an orally available, biguanide derivative that is widely used in the treatment of Type 2 diabetes. Recent preclinical data have demonstrated that it can also act as an anticancer agent by activation of AMPK and subsequent inhibition of mTOR. Metformin is currently being investigated in several Phase II/III clinical trials. This article will review the current evidence for its mechanism of action, efficacy in preclinical and clinical models, and toxicity. Ongoing and planned studies evaluating the impact of metformin on breast cancer outcomes are also discussed.