Myocardial damage in anthracyclines and breast cancer: take a look at the bull’s eye

This editorial refers to ‘Anthracyclines therapy and regional myocardial damage in breast cancer patients: how, when and where? A multicenter study from the working group on drug cardiotoxicity and cardioprotection, Italian Society of Cardiology (SIC)’ by C. Zito et al., pp. 406–15. Anthracyclines are a major cornerstone of oncology therapy in a variety of cancer entities. However, cardiotoxicity presents an important acute and long-term side effect, especially as survival in cancer has impressively improved in the last decades.1 Baseline cardiovascular risk assessment has recently been advocated to identify patients at increased hazard and mitigate cardiac complications during cancer therapy.2 Cardiac imaging, especially echocardiography, plays a pivotal role in monitoring potentially cardiotoxic oncology therapies.3–5 In the current Italian multicentre registry, eight participating centres enrolled breast cancer patients undergoing adjuvant anthracycline standard therapy and performed sequential echocardiography every 3 months focusing on left ventricular ejection fraction (LVEF) along with speckle tracking 2D global longitudinal strain (GLS).6 Patients with previous cardiotoxic treatments due to other malignancies or history of cardiac disease were excluded from the study. Overall, 144 women and 2 men with mean age 56 ± 11 years were prospectively included and divided into three groups according to their anthracycline regimen with additionally either cyclophosphamide, fluorouracil, and/or taxanes [AC/EC group: doxorubicin or epirubicin plus cyclophosphamide; AC/EC/Tax group: plus taxanes (docetaxel or paclitaxel); FEC/Tax group: epirubicin and fluorouracil plus taxanes]. Trastuzumab was also administered in 38% of the cohort who were HER-2 positive (56 patients). Additional endocrine therapy was established in 80% of patients, and ∼70% of patients also underwent radiotherapy. A few patients with advanced disease received pertuzumab (3%), and other chemotherapeutic agents in combination in 3% (carboplatin, cisplatin, bevacizumab, vinerelbine, gemcitabine, and capecitabine).6 Coronary disease or other history of overt cardiac disease was an exclusion criteria in this study. In this real-life setting nevertheless, cardiac baseline risk factors were commonly present as arterial hypertension in >1/3 of the patients, dyslipidaemia in 1/5, diabetes mellitus in 1/4, and smoking in 1/6 of the cohort. Cancer therapeutics-related cardiac dysfunction (CTRCD) was defined by ≥10% points decrease in LVEF to <50%, and a relative reduction of LV GLS of ≥15% was considered as significant as currently recommended.3,7 During the regular follow-up by the cardio-oncology teams, no patient developed overt heart failure symptoms, although a significant increase of the biomarker BNP still within the normal range was observed at 3 months, accompanied by a slight rise in troponin (Tn-I). In about one-quarter of patients, a ≥10% drop in LVEF was observed at 3 and 6 months, with the absolute LVEF values, however, remaining >50%. In contrast, a major part of the cohort (61%, 3/5 of patients) expressed signs of subclinical myocardial damage by drop of GLS by ≥15% after initiation of chemotherapy. Strikingly, there was a significant—albeit numerically small—decline in GLS in practically all patients of the treated cohort, especially in the fluorouracil (FEC/Tax) group at 3 and 6 months. The impairment of LVEF was more pronounced in additional taxanes (AC/EC/Tax group) after 6 months and in the fluorouracil (FEC/Tax) group already early after 3 months. The addition of the monoclonal antibody trastuzumab to the other chemotherapy protocols was associated with a lower LVEF at 12 months, as well as progressive worsening of GLS as compared to patients without trastuzumab. In patients meeting the criteria of subclinical cardiotoxicity with GLS drop of >15%, the baseline and corresponding treatment speckle tracking bull’s eye plot at the follow-up peak of GLS reduction were compared for segmental analysis. Notably, greater regional longitudinal strain (LS) impairment was visualized in the anterior septum and LV apex, whereas the inferior and lateral wall appeared relatively spared by myocardial injury. In the present cohort, patients with previous coronary disease were not included. It remains unclear, why the apical and anterior septal wall as part of the left anterior descending coronary artery (LAD) territory might be more affected by anthracyclines. Similarly, regional manifestations with significantly blunted 3D-LS of the apical anterior and septal walls have also been observed in lymphoma patients undergoing anthracycline containing R-CHOP chemotherapy and other previous smaller studies in various malignancies.8 Future studies need to explore whether regional segmental deformation differences are associated with long-term systolic or diastolic heart failure events and the underlying mechanisms. Recently, decreased coronary vasoreactivity and vasodilation in doxorubicin-induced cardiotoxicity was demonstrated in an experimental computed tomography (CT) model study.9 Endothelial cell apoptosis with pursuant endothelial dysfunction has been observed in doxorubicin application.10 In experimental cardiac magnetic resonance (CMR) studies, changes in myocardial tissue composition were evident with patchy oedema and/or focal fibrosis development, which might partly be in agreement with regional differences in the clinical strain measurements in this study.11,12 It has been well recognized that impaired GLS predicts development of heart failure, hospitalization, and major adverse cardiac events (MACE) in patients treated with anthracyclines, e.g. in breast cancer or lymphomas who have a preserved pre-chemotherapy LVEF of >50%.13,14 Looking at the bull’s eye, importantly even in preserved GLS within normal limits, in patients undergoing chemotherapy regional deformation might deteriorate as sign of early, beginning cardiotoxicity. This becomes even more crucial, as timely initiation of cardiac co-medication during anthracycline therapy by strain-oriented surveillance has been recently shown cardinal for successful continuation and completion of the life-saving chemotherapy.15–17 Speckle tracking echocardiography has currently evolved into a practical tool which, if quality is feasible, can point to on-going myocardial injury.18,19 This study confirms the impact of GLS and early deterioration in many patients already after 3 months of chemotherapy. Breast cancer patients with fluorouracil and/or taxanes in combination with anthracyclines may present with even more considerable cardiotoxicity than anthracyclines alone and should be closely monitored. Different application methods, e.g. liposomal formulation next to the cumulative dose of anthracyclines may influence the overall cardiotoxicity.20 Not only in patients with pre-existing cardiac risk factors, committed cardio-oncology programmes can optimize cardiovascular concomitant treatment, while enabling the patient to undergo the most advantageous oncology therapy.21 The multidisciplinary approach will further enhance the survival of cancer and heart patients.22 A look at the bull’s eye strain colour plot can lead the view to diagnosis of early and prevention of late cardiotoxicity. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association or the European Society of Cardiology.