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LVEF Decline After Anthracyclines Predicts Trastuzumab Cardiotoxicity
Study Questions:
Are there clinical, biochemical, or genomic predictors of trastuzumab-related cardiotoxicity (TRC)?
Methods:
CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was a multicenter cohort study that recruited women with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and left ventricular ejection fraction (LVEF) ≥50% scheduled to undergo treatment with conventional anthracycline-based chemotherapy given with trastuzumab, followed by trastuzumab alone for 52 weeks. LVEF, troponin T (TnT), and N-terminal pro–B-type natriuretic peptide (NT-proBNP) were measured at baseline, after anthracycline therapy, and every 3 months during trastuzumab therapy. Germ-line single nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure, cardiac death/arrhythmia/infarction, or either asymptomatic decrease in LVEF of >15% from baseline or decrease in LVEF of >10% to a value <50%.
Results:
Of 222 patients recruited, five were excluded (three due to loss to follow-up, two due to incomplete data), yielding a study cohort of 217 patients. TRC occurred in 18 of 217 subjects (8.3%); based on a >10% decrease in LVEF in 14, clinical heart failure in one, and cardiac arrhythmia/infarction in three patients. On multivariate analysis, lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline both were associated with TRC (odds ratio, 3.9; p = 0.0001; and odds ratio, 7.9; p < 0.0001 for a 5% absolute change in LVEF). Higher post-anthracycline NT-proBNP was associated with TRC on univariate, but not multivariate analysis. There were no associations between TnT or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a “low-risk TRC score” to identify individuals with low TRC incidence.
Conclusions:
Low baseline LVEF and greater LVEF decline after anthracycline therapy both were independent predictors of TRC. Cardiac biomarkers and germ-line single nucleotide polymorphisms did not further improve the ability to predict TRC.
Perspective:
Trastuzumab is a monoclonal antibody directed against HER2, with substantial management implications for HER2-over-expressing breast cancer. It generally is well tolerated, albeit with a major adverse effect of dose-independent, reversible cardiotoxicity. This study found that the relatively low incidence of trastuzumab-related cardiotoxicity (predominantly consisting of an asymptomatic >10% decline in LVEF to a value <50%, with less common cardiac arrhythmia/infarction or clinical heart failure) was statistically associated with lower baseline LVEF and greater LVEF decline after anthracycline therapy, without independent power of cardiac biomarkers TnT and NT-proBNP. If reproduced in larger trials, this suggests that monitoring echocardiographic LVEF may be sufficient during therapy, without also monitoring TnT and NT-proBNP. That a decline in LVEF after anthracycline therapy is associated with TRC suggests that anthracycline-induced cardiotoxicity induces or unmasks subclinical myocardial injury, predisposing to subsequent TRC.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound
Keywords: Anthracyclines, Antibodies, Monoclonal, Arrhythmias, Cardiac, Breast Neoplasms, Cardiotoxicity, Echocardiography, Genomics, Germ Cells, Heart Failure, Myocardial Infarction, Natriuretic Peptide, Brain, Peptide Fragments, Polymorphism, Single Nucleotide, Stroke Volume, Troponin T
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