Long-term cardiovascular outcomes after anthracycline and trastuzumab therapy in HER2-positive breast cancer: 5-year follow-up from the EMBRACE-MRI study

Background Women with HER2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy are at high risk of cancer therapy-related cardiac dysfunction (CTRCD) during treatment. However, the risk of development of CTRCD after completion of cancer therapy remains poorly characterized. This information will be critical in guiding post-treatment surveillance strategies. Purpose To characterize the timing of onset of CTRCD in women with HER2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy through prospective surveillance during cancer therapy and 5 years post completion of therapy. Methods This sub-study of the prospective EMBRACE-MRI study included women with early-stage HER2-positive breast cancer treated with sequential anthracycline and trastuzumab (2014–2021, University affiliated hospitals). Cardiac function was assessed by echocardiography (using 3D left ventricular ejection fraction [LVEF], or 2D if unavailable), and cardiovascular magnetic resonance (CMR) at pre-anthracyclines, post-anthracyclines, at 3, 6 and 9 months during trastuzumab therapy, and immediately post-completion of trastuzumab. Patients subsequently had annual echocardiographic surveillance at years 1, 2, 3, and 5 and CMR at year 2 and 5. All CMR analyses were performed using CVI42. LV CTRCD was defined using 3 clinically commonly used criteria based on LVEF — CREC,(1) ESC,(2) and ASE (3) — applied to CMR-derived and echocardiographic measurements respectively, to allow cross-definition comparisons. Descriptive statistics were used to summarise baseline characteristics, and Kaplan-Meier analyses were performed to estimate the cumulative incidence of CTRCD over the 5-year follow-up. Results Among the 153 female patients (median age 51.4, IQR: [43.5–57.5] years), 15% had hypertension, and 5% diabetes. During active therapy, CTRCD based on echocardiographic measurements occurred in 43 (28%), 20 (13%), and 34 (22%) patients per CREC, ESC, and ASE criteria, respectively (Figure 1), and in 46 (30%), 16 (10%), and 34 (22%) patients based on CMR-derived measurements (Figure 2). Across all definitions and both imaging modalities, the cumulative incidence of CTRCD plateaued by approximately 12–15 months, coinciding with trastuzumab completion. In longer-term follow-up, the occurrence of CTRCD was infrequent, with 3 (7%) CTRCD cases occurring post cancer therapy according to CREC, and none after cancer therapy with other definitions. Notably, no severe (LVEF <40%) or symptomatic CTRCD as per ESC-definition was observed after trastuzumab completion. Conclusion In this closely monitored prospective cohort using echocardiography and CMR, CTRCD events occurred almost uniformly during cancer therapy and were rare in the next 5 years. This suggests that most of the effort on identifying CTRCD should be focused on during trastuzumab treatment and in the year after anthracycline completion.Figure 1.Cumulative incidences (Echo)Figure 2.Cumulative incidences (CMR)