Cardiopulmonary fitness and cancer therapy-related cardiac dysfunction defined by CMR: insights from the EMBRACE-MRI study

Background Cancer therapy-related cardiac dysfunction (CTRCD) is defined by a change in myocardial function that meets prespecified diagnostic thresholds. However, it is unclear if CTRCD detected during treatment is associated with cardiopulmonary fitness at the end of cancer therapy, and whether this relationship varies across CTRCD definitions. Purpose To assess the association between CTRCD detected by CMR during cancer therapy (using multiple established definitions), and cardiopulmonary fitness (a prognostic marker) at the end of therapy. Methods This sub-analysis of the prospective EMBRACE-MRI study included women with early-stage HER2-positive breast cancer treated with sequential anthracycline and trastuzumab. CMR was performed at baseline, post-anthracyclines, and at 3 months, 6 months, and early post-completion of trastuzumab. All CMR analyses were performed using CVI42. Cardiac biomarkers (troponin and BNP/NT-proBNP) were collected at each timepoint. Cardiopulmonary exercise testing was performed on an upright electronically braked cycle ergometer with 12-lead ECG monitoring early after completion of trastuzumab. VO2 peak was defined as the highest rate of oxygen consumption over a 15- to 20-second interval within the last 90 seconds of exercise. CTRCD was assessed by CMR according to ESC, ASE, and CREC criteria.(1–3) Between-group comparisons used Wilcoxon rank-sum tests for binary CTRCD definitions and Jonckheere-Terpstra tests for ordinal severity categories, with p-trend reported. Results Among 136 patients who completed CPET after completion of trastuzumab (median age 51.4, IQR: 43.4–57.6 years), the prevalence of CTRCD was 63.2% by ESC (51.5% mild, and 11.8% moderate CTRCD), 22.8% by ASE, and 30.1% by CREC criteria. Post therapy, those with reduced cardiopulmonary fitness (VO₂ peak <18 ml/kg/min) were older, more frequently had diabetes mellitus and hypertension, and presented with a higher prevalence of CTRCD during cancer therapy as defined by ESC criteria (81.4 vs 49.4%, p<0.001). Patients with CTRCD by ESC and CREC criteria had significantly lower VO₂ peak compared to those without CTRCD (ESC: 18.2 ± 5.1 vs. 21.0 ± 4.8 ml/kg/min, p<0.001 (Figure 1); CREC: 17.6 ± 4.6 vs. 19.9 ± 5.2 ml/kg/min, p=0.015), whereas no statistically significant difference was observed using ASE criteria (Figure 2). Furthermore, higher ESC-CTRCD severity categories were significantly associated with lower VO₂ peak (p-trend <0.001). Conclusion In HER2-positive breast cancer patients treated with anthracycline and trastuzumab, CTRCD identified by CMR during cancer therapies was associated with lower cardiopulmonary fitness at treatment completion. The greatest difference was seen based on the ESC criteria. Overall, our study suggests that CMR-identified CTRCD may have important long term prognostic implications given the lower post therapy cardiopulmonary fitness.