Aug 2026· European Heart Journal, Supplement· Vol 28· 0 citations
TL;DR
Biomarker elevations were common but rarely translated into functional cardiac impairment, supporting the short-term cardiac safety of pembrolizumab when managed within a structured cardio-oncology surveillance program.
Abstract
Pembrolizumab combined with anthracycline-based chemotherapy has become standard neoadjuvant treatment for early triple-negative breast cancer (TNBC). However, concerns persist regarding potential additive cardiotoxicity. Prospective real-world data on early cardiac safety of this combination remain limited.
To prospectively evaluate early cancer therapy–related cardiac dysfunction (CTRCD) in patients with early TNBC treated according to the KEYNOTE-522 protocol, using the 2022 ESC cardio-oncology definitions.
Consecutive patients with early TNBC receiving neoadjuvant pembrolizumab combined with taxane–carboplatin followed by anthracycline-based chemotherapy were prospectively enrolled. Cardiac monitoring included serial transthoracic echocardiography with left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), electrocardiogram (ECG), and serial measurements of high-sensitivity cardiac troponin I (hs-cTnI) and NT-proBNP prior to the start of anthracyclines administration, at the completion of NACT and at 3 months and 12 months after the end of anthracycline therapy. CTRCD was defined according to ESC criteria.
Fifty-eight patients were included (mean age 54 years). One patient died from cancer progression and was censored from follow-up. Overall, 32 of 57 patients (56.1%) fulfilled the primary endpoint, predominantly driven by biomarker-defined cardiotoxicity. Two patients (3.5%) experienced symptomatic heart failure during the initial phase of treatment with paclitaxel, carboplatin, and pembrolizumab and therefore did not receive anthracyclines. Moderate asymptomatic CTRCD occurred in 2 patients (3.5%) with concomitant LVEF and GLS decline, while 4 patients (7.0%) developed mild CTRCD with isolated GLS reduction. No patient developed symptomatic heart failure during or after anthracycline therapy. Significant hs-cTnI elevation was observed in 17.5% of patients, with 80% occurring during anthracycline administration. NT-proBNP elevations were frequent, resulting in a 49.1% incidence of mild cardiotoxicity according to HFA-ICOS criteria. No cases of myocarditis, acute coronary syndrome, arrhythmia, or atrioventricular block were identified.
In this prospective real-world cohort, with near-complete echocardiographic follow-up (97.8% of planned echocardiographic assessments in patients treated with anthracyclines), the addition of pembrolizumab to anthracycline-based neoadjuvant chemotherapy was not associated with increased early cardiotoxicity. Biomarker elevations were common but rarely translated into functional cardiac impairment, supporting the short-term cardiac safety of pembrolizumab when managed within a structured cardio-oncology surveillance program.
The KEYNOTE-522 study established a new standard of care for patients with high-risk early triple-negative breast cancer by introducing pembrolizumab in combination with neoadjuvant chemotherapy. Myocarditis is a known, although rare, immune-related adverse event associated with anti–PD-1 therapy, with a reported incidence of approximately 0.3–0.4% in clinical trials.
To evaluate cardiac events and treatment safety in patients treated at our University Hospital Centre.
A retrospective analysis was conducted including 45 patients with early triple-negative breast cancer who underwent surgery after completion of neoadjuvant therapy at our University Hospital Centre, between February 2024 and July 2025. Descriptive statistics were used to present demographic and clinical characteristics.
The median age at diagnosis was 52 years (range 30–76). All patients were treated according to the trial protocol with pembrolizumab administered every 3 weeks in combination with chemotherapy (paclitaxel/carboplatin followed by anthracycline/cyclophosphamide), surgery, and one year of adjuvant pembrolizumab. The median number of administered anthracycline cycles was 4 (range 0–4), while the median number of pembrolizumab cycles was 17 (range 3–17). In all patients who completed the planned treatment, transthoracic echocardiography was performed either before treatment initiation or during neoadjuvant therapy prior to anthracycline administration. The median left ventricular ejection fraction (LVEF) was 64% (range 50–70%). Baseline NT-proBNP values were obtained in 76.3% of patients, while troponin I levels were measured in 64.8%.In two patients, NT-proBNP values were <8.3 ng/L; in the remaining patients, values ranged from 20 to 242 ng/L, with a median of 58.5 ng/L. Troponin I levels were <3.7 ng/L in 95.8% of patients, while one patient had a value of 11 ng/L. A total of four patients (6.6%) developed cardiac events, including atrial fibrillation with rapid ventricular response, immune-mediated myositis with severe hypothyroidism and mild pericardial effusion without LVEF impairment, and pulmonary embolism. Neoadjuvant therapy was discontinued in all cases, and patients proceeded to surgery. One additional patient developed suspected immune checkpoint inhibitor–related myocarditis after completion of neoadjuvant therapy and did not continue immunotherapy in the adjuvant setting. The median time to onset of cardiac symptoms was 4.5 months (range 2–8).
Our findings are consistent with limited real-world data, showing a 10–12% incidence of cardiovascular symptoms during chemo-immunotherapy and myocarditis rates comparable to clinical trials (~0.3–1.1%). The retrospective design limits the ability to attribute cardiac events solely to immunotherapy, underscoring the importance of baseline cardiovascular risk assessment and early detection of cardiotoxicity.
P. Sertić, M. Trajbar, L. Ledinsky et al.· European Heart Journal, Supp...· 0 citations
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype that predominantly affects younger women. Pembrolizumab combined with chemotherapy improves outcomes in TNBC. However, anthracyclines, pembrolizumab and radiotherapy are potentially cardiotoxic but cardiovascular safety data in routine practice are limited.
To describe cardiotoxicity and investigate predictive factors in patients treated with pembrolizumab, with or without anthracyclines, for early-stage TNBC. We hypothesised that baseline cardiovascular risk factors would predict cardiotoxicity.
We conducted a single-centre, retrospective observational study including 61 patients with triple-negative breast cancer treated between January 2022 and November 2024. The primary endpoint was a composite cardiotoxicity outcome defined according to ESC guidelines as cardiovascular death, cardiac dysfunction, myocarditis, pericarditis, arrhythmia or conduction disorder, acute coronary syndrome (ACS), or ischaemic stroke. Predictors were assessed using univariable Cox models; overall survival by Kaplan–Meier and log-rank, and cardiotoxicity incidence by cumulative incidence with competing risk of non-cardiovascular death.
Among the 61 patients (mean age 55 ± 13 years), 33% were obese, 23% had hypertension, and 23% had dyslipidaemia. After a median follow-up of 14 months (IQR 10–21), cardiotoxicity occurred in 13% of patients with a median onset time of 6 (IQR 3–8) months. No cases of cardiovascular death were observed. 7% of patients presented with cardiac dysfunction, 2% with myocarditis, 2% with atrial fibrillation, 2% with ACS, and 2% with ischaemic stroke. Patients with cardiotoxicity had a higher rate of all-cause death than patients without cardiotoxicity (29% vs 4%; p<0.001). In univariable analysis, predictors of cardiotoxicity were age (HR 1.07; 95% CI 1.00–1.13; p=0.036), family history of coronary artery disease (HR 9.17; 95% CI 1.10–76.2; p=0.040), hypertension (HR 6.01; 95% CI 1.43–25.4; p=0.015), and reduced estimated glomerular filtration rate (HR 1.5; 95% CI 1.11–2.07; p=0.008).
In patients with early-stage TNBC treated with pembrolizumab, cardiotoxicity was frequent and associated with a significant reduction in overall survival. Larger prospective studies are required to better characterise predictors of cardiotoxicity in this setting.Annualised all-cause death events Cardiotoxicity by hypertension
L. Dib, B. Sibila, C. Regragui et al.· European Heart Journal, Supp...· 0 citations
Anthracyclines remain a cornerstone of breast cancer therapy but carry a significant risk of cancer therapy-related cardiac dysfunction (CTRCD). This study evaluates the incidence of CTRCD in an Indonesian setting using the latest 2022 ESC Cardio-Oncology guidelines, focusing on subclinical markers such as high-sensitivity Troponin I (hs-cTnI), Global Longitudinal Strain (GLS) and Mechanical Dispersion (MD).
This retrospective analytical cohort study involved 98 breast cancer patients treated with anthracyclines at a national referral hospital in Indonesia from July 2018 to February 2020. Clinical assessments, hs-cTnI, and echocardiography (LVEF, GLS, and MD) were performed at baseline, 1, 3, and 6 months. CTRCD was defined per the 2022 ESC criteria.
CTRCD occurred in 74.5% of patients, predominantly as asymptomatic mild cases (63.26%). While symptomatic CTRCD was relatively low (7.14%), asymptomatic dysfunction was detected as early as one-month post-chemotherapy. A significant progressive decline was observed in LVEF (68.2 ± 6.2% to 61.3 ± 8.8%,
p
< 0.001) and GLS (-19.7 ± 2.9% to -17.1 ± 3.5%,
p
< 0.001). Notably, mechanical dispersion significantly increased over time (
p
= 0.029), and median hs-cTnI surged from 1.6 ng/L to 82.2 ng/L (
p
< 0.001) by month 6.
The high incidence of asymptomatic CTRCD underscores the inadequacy of relying on clinical symptoms alone. Integration of hs-cTnI, GLS, and mechanical dispersion monitoring is may be essential for early detection and enables timely cardioprotective intervention.
Neoadjuvant systemic therapy (NST) has become a cornerstone in the management of aggressive early breast cancer (BC) subtypes, including triple-negative (eTNBC) and HER2-positive disease. Immune checkpoint inhibition with pembrolizumab represents an active immunotherapeutic approach, whereas dual HER2 blockade with trastuzumab and pertuzumab constitutes passive immunotherapy in early HER2-positive BC. Although both strategies demonstrate substantial antitumor efficacy, real-world data directly comparing their surgical safety profiles are limited.
This retrospective single-center cohort study included 99 patients with early BC treated with NST between 2014 and 2025. A total of 33 patients with TNBC received pembrolizumab-based therapy according to the KEYNOTE-522 regimen, whereas 66 patients with HER2-positive disease received chemotherapy combined with trastuzumab and pertuzumab. Surgical adverse events within 30 days postoperatively were assessed using the Clavien–Dindo classification and the Comprehensive Complication Index (CCI). Complication rates and severity were compared between groups.
The overall postoperative complication rate was 25.3%, with no significant difference between TNBC and HER2-positive cohorts (27.3% vs. 24.2%,
p =
0.744). Most complications were minor (Clavien–Dindo ≤II), and rates of major complications (≥IIIa) did not differ between groups (
p =
0.706). Mean CCI scores were comparable (22.1 vs. 24.4;
p =
0.630). Seroma formation was the most frequent adverse event in both cohorts. In an exploratory multivariable logistic regression analysis, treatment group was not independently associated with postoperative complications. Pathological complete response rates were 63.6% in TNBC and 45.5% in HER2-positive patients. No clinically relevant delays in adjuvant radiotherapy occurred.
No statistically significant differences in postoperative morbidity were observed between treatment groups. These findings support the feasibility of integrating both neoadjuvant treatment strategies into routine surgical practice; however, confirmation in larger prospective studies is warranted.
K. Wimmer, Katharina Kantner, R. Exner et al.· Frontiers in Medicine· 0 citations
A significant decline in right ventricular function is demonstrated during anthracycline-based cardiotoxic therapy and persisting up to one year after treatment completion, even in patients with low cardiotoxic risk, despite changes being subclinical and largely within normal ranges.
I. G. Dimova, G. Petkovska, I. Ismaili et al.· European Heart Journal, Supp...· 0 citations
Anthracyclines remain a cornerstone of systemic anticancer therapy but are limited by their well-recognized cardiotoxic potential, which may manifest as cancer therapy–related cardiac dysfunction (CTRCD). Despite increasing emphasis on preventive strategies in cardio-oncology, robust evidence supporting pharmacological cardioprotection is scarce. Sacubitril/valsartan has demonstrated clear benefits in heart failure populations; however, its preventive role in patients exposed to anthracyclines has not been systematically evaluated.
We performed a systematic review and meta-analysis of randomized controlled trials assessing sacubitril/valsartan for the prevention of CTRCD in adult patients treated with anthracycline-based chemotherapy (PROSPERO CRD420261278068). PubMed, Embase, Scopus, and the Cochrane Library were searched through December 2025. The primary outcome was CTRCD, defined according to 2022 ESC cardio-oncology guidelines. Secondary outcomes included changes in left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and symptomatic hypotension. Random-effects models were used as the primary analytical approach.
Three randomized trials including 352 patients (mean age 52 ± 9 years; 94% breast cancer) were included. Sacubitril/valsartan was associated with a numerically lower risk of CTRCD that did not reach statistical significance in the random-effects model (RR 0.69, 95% CI 0.38–1.23; p=0.21), while the fixed-effects model showed a significant association favoring sacubitril/valsartan. Directionally favorable but non-significant trends were observed for LVEF and GLS. Sacubitril/valsartan was associated with a higher risk of symptomatic hypotension (RR 4.10, 95% CI 1.46–11.54).
This meta-analysis identifies a consistent, hypothesis-generating signal suggesting that sacubitril/valsartan may reduce CTRCD incidence and favorably influence cardiac imaging parameters in anthracycline-treated patients, at the cost of increased symptomatic hypotension. Larger, adequately powered trials are needed to define its role in cardio-oncology prevention strategies.
M. Camilli, L. Spadafora· European Heart Journal, Supp...· 0 citations
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