Dynamic cardiac changes in low cardiovascular risk patients with triple negative breast cancer treated with chemo-immunotherapy

BACKGROUND: Neoadjuvant chemotherapy-immunotherapy is the new standard of care for high-risk early-stage triple negative breast cancer (TNBC). As anthracyclines, pembrolizumab, and radiotherapy may each contribute to an increased risk of cardiovascular events, real-world assessment of early cardiovascular changes is of clinical interest. METHODS: Retrospective analysis of 85 women with early-stage TNBC treated with chemotherapy-pembrolizumab between 2018 and 2023 and had ≥ 1 transthoracic echocardiogram (TTE) available. Grade ≥ 2 cardiac common terminology criteria for adverse events (CTCAE) cumulative incidence estimates and Fine-Gray regressions (accounting for non-cardiac death as a competing risk) were calculated. Electrocardiogram (ECG) and TTE parameters during/following systemic therapy (vs. baseline) were compared. RESULTS: The median follow-up from immunotherapy start was 18.7 months [interquartile range (IQR) 13.6-39.1]. The median age was 50 years (IQR 38-61), 19% had hypertension, most (82%) with no detectable coronary artery calcium (CAC = 0), and 0% known cardiovascular disease. 9/85 (11%) experienced a grade ≥2 cardiac event with a median onset of 7.3 months (IQR 4.0-8.0) and a one-year cumulative incidence of 9.6%. Most (7/9) were grade 2 (n = 5 ejection fraction [EF] decline, n = 1 heart failure, n = 1 pericarditis); 2/9 were grade ≥ 3 (myocarditis, urgent percutaneous coronary intervention); all occurred among those receiving carboplatin, paclitaxel, doxorubicin, and cyclophosphamide-based therapy. Adjusting for age and CAC, mean left anterior descending coronary artery radiation dose was associated with an increased risk of cardiac events (sub-distribution hazard ratio 1.16/Gy, 95% confidence interval 1.01-1.35; p = 0.041). QTc prolongation ≥450ms was more common during treatment vs. baseline (39% vs. 15%; p = 0.025). On assessment for recovery, early grade 2 EF decline recovered in 3/5 patients (2/5 with absence of follow-up). In those with baseline and post-treatment TTE, 5/20 (25%) developed new moderate diastolic dysfunction, that persisted in a later TTE in 2/5 patients, downgraded to mild in 1/5, and not reevaluated by TTE in 2/5. CONCLUSION: Early cardiovascular toxicity was observed during multi-modality TNBC treatment, even in young patients with low cardiovascular risk profiles, highlighting the importance of diligent surveillance. Longer follow-up and further studies are warranted, given the degree of recovery and later effects of these treatments may not yet be fully observed.