Cardiovascular toxicity surveillance in metastatic breast cancer patients receiving long-term HER2-targeted therapy: A retrospective multicentre study

Abstract

Background: Long-term HER2-targeted therapies improve survival in metastatic HER2-positive breast cancer (BC) (1) but are associated with cancer therapy related cardiac dysfunction (CTRCD) (2); indefinite cardiac surveillance is therefore mandated (3). EMA guidance recommends 3 monthly imaging, although recent guidelines suggest clinicians consider increased surveillance intervals (3). Rationalising cardiac surveillance could improve patients' quality of life and reduce costs, but doing so requires better understanding of CTRCD in this population. Purpose(s): To investigate the incidence, severity and timing of CTRCD in metastatic HER2-positive BC patients receiving long-term HER2 targeted therapy. Method(s): A retrospective multicentre cohort study of metastatic HER2-positive BC patients receiving HER2 targeted therapy between 2012-2024. Patients were identified from cancer therapy prescriptions at two large oncology centres. CTRCD was defined as per the European Society of Cardiology (ESC) Cardio-Oncology guidelines (3). Patients were stratified by Heart Failure Association and International Cardio-Oncology Society (HFA-ICOS) cardiotoxicity risk (4). Result(s): 191 patients (median age 53 [interquartile range [IQR] 45-62], 99% female, 45% non-Caucasian) were identified. Median HER2 treatment duration was 38 months [IQR 19-57]), each with a median of 12 [IQR 8-18] echocardiograms (total n=2091) for CTRCD surveillance (Table 1). CTRCD occurred in 43% (n=82) at a median of 62 weeks (IQR 25 - 122) from treatment initiation; most commonly mild asymptomatic (50%, n=41) followed by moderate asymptomatic (41%, n=34), symptomatic (5%, n=4) and severe asymptomatic (4%, n=3). Symptomatic and moderate or severe asymptomatic CTRCD occurred significantly earlier than mild asymptomatic (median 41, 18 and 6 vs 87 weeks respectively, p<0.05). HER2 targeted therapy was interrupted in 33% of patients with CTRCD (n=27) for a median of 12 [4-16] weeks; 96% were re-challenged successfully with cardio-protective therapies. Moderate, high or very high-risk patients, by baseline HFA-ICOS risk, were significantly more likely to develop CTRCD than low risk (hazard ratio 3.1, 95% confidence interval 1.7-5.9; p = 0.028). Conclusion(s): In the largest-to-date multicentre analysis of cardiotoxicity surveillance in metastatic HER2-positive BC patients receiving long-term HER2-targeted therapies, CTRCD was common but generally mild, asymptomatic. With cardio-oncology support, most patients were able to continue HER2 targeted therapies. The HFA-ICOS cardiotoxicity risk score can identify those most at risk of CTRCD. Only half of all cases of CTRCD were symptomatic or moderate or greater asymptomatic, and 63% presented within 12 months. For patients receiving long-term HER2 targeted therapies in the metastatic setting, reducing the frequency of cardiac surveillance after the first 12 months is unlikely to significantly impact the sensitivity of detection of clinically significant CTRCD.