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Long-Term Risk of Heart Failure After Chemotherapy With Trastuzumab
Study Questions:
What is the long-term risk of developing heart failure (HF) after trastuzumab therapy?
Methods:
The study authors conducted a retrospective cohort study on 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer, identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2 positive, age: 51.7 ± 8.5 years) received chemotherapy including anthracycline, and if they were HER2 positive, trastuzumab was added. Patients were excluded if they did not receive chemotherapy or trastuzumab, were aged ≥70 years, or had a diagnosis of HF prior to the diagnosis of breast cancer. Of the 8,812 patients, 2,117 had HER2-positive disease and received both chemotherapy and trastuzumab treatment, whereas 6,695 patients were HER2 negative and received solely chemotherapy as part of the adjuvant medical treatment. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risk. Risk of HF was examined multivariate in a cause-specific Cox proportional hazards model adjusted for age and baseline comorbidity (ischemic heart disease, acute myocardial infarction, atrial fibrillation, hypertension, type 2 diabetes mellitus, and chronic obstructive pulmonary disease) with the Wald Chi-Squared test applied.
Results:
Median follow-up was 5.4 years (interquartile range, 4.1-6.8 years). There was no difference between the groups regarding cancer and cardiovascular mortality before and after 18 months. In the trastuzumab group, 60 patients (2.8%) had HF by 9 years versus 51 (0.8%) in the group treated with chemotherapy alone corresponding to incidence rates per 1,000 patient-years of 5.3 (95% confidence interval [CI], 4.1-6.8) versus 1.4 (95% CI, 1.1-1.8). The cumulative incidence of HF was higher in the trastuzumab group on both short- and long-term analysis (p < 0.01), yielding adjusted hazard ratios of 8.69 (95% CI, 4.59-16.47; p < 0.0001) for early HF and of 1.9 (95% CI, 1.15-3.25; p = 0.01) for late HF associated with trastuzumab treatment. Including all cases of HF in the Cox proportional hazards model, an age and comorbidity adjusted hazard ratio (HR) of 3.61 (95% CI, 2.47-5.26; p < 0.0001) was found for HF associated with chemotherapy plus trastuzumab treatment relative to chemotherapy alone.
In the multivariate analysis, ischemic heart disease, acute myocardial infarction, and chronic obstructive pulmonary disease were associated with development of early HF, whereas ischemic heart disease, atrial fibrillation, and type 2 diabetes were associated with development of late HF. The isolated association with age in this study was erased when comorbidity was added to the multivariate model. In a sensitivity analysis, a propensity score based on all baseline variables was added to the model without any major change in the HRs associated with trastuzumab, which in this analysis were of 3.87 (95% CI, 2.61-5.74; p < 0.0001) for all cases, 10.19 (95% CI, 5.27-19.70; p < 0.0001) for early cases, and 1.90 (95% CI, 1.10-3.26; p = 0.02) for late cases.
Conclusions:
The authors concluded that trastuzumab therapy is associated with a twofold increased risk of late HF compared with anthracycline-based chemotherapy alone.
Perspective:
The findings of this ‘real-world’ study are important because they suggest that there is a significant long-term risk of HF in recipients of trastuzumab therapy and this risk of HF is weakly associated with baseline comorbidity. These findings raise the question of whether all patients who receive trastuzumab therapy when seen in survivorship clinics, may benefit from annual surveillance for HF risk including assessment of New York Heart Association class, N-terminal pro–B-type natriuretic peptide, and echocardiograms.
Keywords: Anthracyclines, Atrial Fibrillation, Breast Neoplasms, Cardiotoxicity, Chemotherapy, Adjuvant, Coronary Artery Disease, Diabetes Mellitus, Type 2, Heart Failure, Hypertension, Myocardial Infarction, Pulmonary Disease, Chronic Obstructive, Secondary Prevention
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