Strain as hallmark to prevent interruption of breast cancer therapy

This editorial refers to ‘Strain-oriented strategy for guiding cardioprotection initiation of breast cancer patients experiencing cardiac dysfunction’ by C. Santoro et al., pp. 1345--1352. As cancer progression-free survival is continuously improving with new and evolving oncology therapies, short- and long-term off-target cardiovascular effects gain crucial importance for overall outcome.1 Chemo-, immuno-, radiation-, and targeted-therapies not only effect the malignant neoplastic cells, but also cardiomyocytes and vascular cells, leading to asymptomatic cardiac impairment up to overt severe heart failure or even fulminant myocarditis.2 The ideal method of early detection of cardiotoxicity in patients undergoing oncology regimens, and when to initiate preventive cardiac medication in cardiotoxicity in order to avoid acute or long-term heart failure development remains controversial. On the other hand, cardiac drugs may aggravate hypotension, hyperkalaemia, or renal function in patients with chemotherapy, e.g. emesis, and therefore, an immediate concomitant cardiac therapy is not established currently and needs further research. Echocardiography plays a pivotal role with monitoring of the left ventricular ejection fraction (LVEF) in 2D- or better 3D technique, when available, as cornerstone of current oncology guidelines.3,4 A drop in LVEF of >10% points to <50% during cancer regimens is defined as cardiotoxicity (overt cancer therapy-related cardiac dysfunction, CTRCD). Repeatedly, the day-to-day and loading condition induced variability of ejection fraction (EF) has been documented, as well as inherent limitations of the EF measurements (e.g. apical foreshortening, border delineation).5 Therefore, before interruption decisions or dosage limitation of chemotherapy EF should be reconfirmed after 2–3 weeks.3 In contrast, speckle tracking derived strain calculates the systolic deformation of the myocardium reflecting its contractile function.6 The prognostic usefulness especially of global longitudinal strain (GLS) in unveiling early subclinical impairment of left ventricular function, importantly preceding reduction in EF, has been corroborated in a variety of myocardial diseases and in cardio-oncology, if image quality is sufficient, despite vendor and software standard differences in acquired values.6,7 In cancer surveillance, strain has emerged as particularly rewarding, with a reduction from baseline GLS of >15% demonstrated to predict early and reliably the development of overt cardiotoxicity even in still preserved EF and is incorporated in the current position recommendations.3,8 Patients receiving potentially cardiotoxic oncology therapies are considered at high risk of heart failure [Stage A, American College of Cardiology/American Heart Association (ACC/AHA) classification], shown to transition to heart failure Stage B in a significant percentage of about 20% of patients with different cancer entities in a recent report.9 In the present study of Santoro et al.10 in 116 women with HER2-positive breast cancer, serial echocardiography with 2D-GLS and LV EF was assessed every 3 months while undergoing a standard adjuvant chemotherapy protocol with the anthracycline epirubicin and cyclophosphamide, followed by paclitaxel and trastuzumab cycles. Patients without previous heart disease were included, and the mean age was 52.5 years. Overt CTRCD was defined as a decrease in EF >10% points to a value <50%, and subclinical CTRCD as a drop in GLS >15% independently of EF values, in accordance with the current European Association of Cardiovascular Imaging/American Society of Echocardiography consensus.8 In overt CTRCD, echocardiography was repeated after 2–3 weeks to confirm the ongoing EF reduction and patients were discussed together with the oncologists for decision whether discontinuation or adaptation of anti-cancer drugs was indicated, especially in the presence of cardiac symptoms.3 Importantly, it was implemented in the protocol design that all women showing either a subclinical CTRCD with GLS drop or overt cardiotoxicity with EF reduction promptly and immediately received cardiac heart failure therapy with the angiotensin converting enzyme-inhibitors ramipril and beta-blocker carvedilol. A relatively high average dose of ramipril could be achieved, titrated to 7.8 ± 2.5 mg, accompanied by carvedilol in a somewhat lower dose of 10.3 ± 3.1 mg, without any significant side effects despite the ongoing cancer treatments. The event of combined CTRCD occurred in almost every fourth woman (23%), in every fifth patient (20%) subclinical CTRCD was observed and appeared across the whole age range of 24–73 years. Due to subsequent overt CTRCD in only 3.4% of patients, chemotherapy needed to be interrupted based on EF reduction <50% and symptoms, e.g. dyspnoea only in few patients. Notably, GLS was reduced by <15% in all patients with CTRCD. Twice as many patients developed CTRCD during the trastuzumab protocol, after the anthracycline period was already absolved. Congruently, trastuzumab has been shown to potentiate cardiomyocyte damage after anthracyclines through a ‘dual-hit’ mechanism, including the inhibition of the neuregulin-1 survival signalling pathway for cardiac repair.11 Most importantly, in the current study, all patients with subclinical GLS reduction were able to complete their chemotherapy regimens with the pinpointed initiation of cardio-protective medication without further progression of cardiotoxicity, and three-fourth of patients with overt CTRCD could continue their oncology protocols due to recovery after start of concomitant cardiac therapy.10 Only one patient showed no recovery despite cardiac treatment. These prospective results enforce the concept that serial GLS measurements can (i) unmask early deterioration of the myocardium during cancer therapy, (ii) serve as easy guidance to start specific heart failure medication, and (iii) most importantly, avert interruption of the life-saving curative cancer treatment.10 Previous heart disease was excluded in the enrolment although more frequently encountered in elder women, as possible limitation of the applicability.10 However, it appears reasonable that an additional drop in strain in patients with pre-existing cardiovascular disease would be even more indicative of further cardiac damage induced through the oncologic therapy and should actuate intensified cardiac treatment. Hypertension when treated appropriately, did not appear to play a significant role in the development of cardiotoxicity in the present study. Remarkably, even in women not developing the cardiotoxicity cut-off definition of CTRCD, a statistically significant, albeit small reduction in systolic EF and/or GLS, as well as trend to diastolic impairment was observed at the end of the anthracycline/trastuzumab protocol treatments. These findings are in accordance with the observation that anthracyclines result in transcriptional activation of collagen synthesis leading to cardiac fibrosis confirmed in a translational animal model.12 An ongoing large multicentre international trial will randomize patients to EF- or strain imaging guidance strategies for the use of cardioprotective therapy during chemotherapy to determine cardiac outcome.13 In conclusion, strain monitoring with GLS guided initiation of targeted cardiac medication permits the continuation of chemotherapy without transition to overt heart failure and can avoid necessitating interruption of the crucial oncology treatments. The strain comparison should be performed with the same echocardiography vendor machines to avoid interaction of software differences, and GLS based on three apical views remains the preferred technique for cardiotoxicity detection.14 Cardio-oncology is a rapidly evolving field to further step up the ladder of survival strategies. Preventing later heart disease while curing the malignant disease is the aim and strain echocardiography is now bringing it closer to reality. 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.