Publications

Targeting cardioprotective strategies to patients at the highest risk for cardiac events can help maximize therapeutic benefits. Dexrazoxane, liposomal formulations, continuous infusions, and neurohormonal antagonists may be useful for cardioprotection for anthracycline-treated patients at the highest risk for heart failure. Prevalent cardiovascular disease is a risk factor for cardiac events with many cancer therapies, including anthracyclines, anti-human-epidermal growth factor receptor-2 therapy, radiation, and BCR-Abl tyrosine kinase inhibitors, and may be a risk factor for cardiac events with other therapies. Although evidence for cardioprotective strategies is sparse for nonanthracycline therapies, optimizing cardiac risk factors and prevalent cardiovascular disease may improve outcomes.

OBJECTIVES: Breast cancer and heart failure (HF) are frequently interconnected due to shared risk factors and the cardiotoxicity of breast cancer treatment. However, the association between HF and hospital outcomes among breast cancer patients has not been studied. This study examined the association between HF and hospital outcomes among hospitalized patients with breast cancer.

METHODS: This cross-sectional study using the 2015-2018 Healthcare Cost and Utilization Project-National Inpatient Sample data included hospitalized women who were aged 18 years or older and had a primary diagnosis code for breast cancer. Logistic regression, negative binomial regression, and generalized linear models with log-link and gamma distribution were used to assess the associations of HF with in-hospital mortality, length of stay (LOS) and hospital costs.

RESULTS: Among 17,335 hospitalized patients with breast cancer, 4.2% (n = 1021) had HF. Compared to breast cancer patients without HF, those with HF were more likely to die during hospitalization (odds ratio = 1.65, 95% CI = 1.27-2.16, p < .001), stay in the hospital longer (incidence rate ratio = 1.22, 95% CI = 1.15-1.30, p < .001) and have higher hospital costs (cost ratio = 1.09, 95% CI = 1.03-1.14, p = .003) during hospitalization, controlling for covariates.

CONCLUSION: HF has a substantial negative impact on health outcomes among hospitalized breast cancer patients. Breast cancer and HF are often considered separate medical conditions, but promoting effective management of comorbid HF in breast cancer patients may help to improve hospital outcomes in this population.

OBJECTIVES: This study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction.

BACKGROUND: Doxorubicin and trastuzumab can result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined.

METHODS: In a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy-related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to <50%.

RESULTS: Over a median of 2.1 years (interquartile range [IQR]: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e' velocities, and increases in E/e' (p < 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (-2.1%; 95% confidence intervals [CI]: -3.1 to -1.2; p < 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e' ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022).

CONCLUSIONS: A modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy [CCT]; NCT01173341).

A man with a presumed diagnosis of hypertrophic cardiomyopathy presented after a ventricular fibrillation arrest. Review of prior cardiac magnetic resonance imaging revealed a pattern of late gadolinium enhancement that was atypical for hypertrophic cardiomyopathy and most consistent with cardiac sarcoidosis, with diagnosis confirmed by endomyocardial biopsy. (Level of Difficulty: Beginner.).

BACKGROUND: Observational studies suggest that regular physical activity may reduce cardiovascular morbidity and cancer recurrence in survivors of breast cancer. The association between physical activity and cardiac function with breast cancer therapy is unknown.

METHODS: Self-reported physical activity was assessed using the Godin Leisure-Time Exercise Questionnaire at repeated intervals in a longitudinal cohort study of 603 breast cancer participants treated with doxorubicin and/or trastuzumab. Multivariable regression models estimated associations between clinical variables and physical activity. Generalized estimating equations adjusted for prespecified variables estimated associations between baseline physical activity and longitudinal echocardiographic measures of systolic and diastolic function.

RESULTS: Physical activity was low at baseline, prior to cancer therapy initiation. More than half of participants reported no moderate-strenuous physical activity, and only 12.1% met guideline recommended levels of physical activity. Physical activity increased after chemotherapy completion; however, only 26.0% of individuals were sufficiently active 3 years after cancer diagnosis. Body mass index, hyperlipidemia and higher cancer stage were significantly associated with lower total physical activity at baseline. Higher baseline physical activity was very modestly associated with an attenuation in the absolute decline in left ventricular ejection fraction over time (β 0.4%, 95% CI 0.1, 0.7, P = .02 for each 10-unit increase in total activity). There tended to be a cardioprotective association with cardiotoxicity risk, although this was not statistically significant (HR 0.83, 95% CI 0.66, 1.04, P = .097).

CONCLUSIONS: A small proportion of breast cancer patients and survivors are engaged in regular moderate-strenuous physical activity. While only modest associations between self-reported physical activity and left ventricular systolic function were observed, our findings do not exclude a cardioprotective benefit of exercise.

PURPOSE OF REVIEW: Patients with cancer have an elevated risk of cardiovascular disease. This review describes the cardiovascular risks of different cancer therapies and the evidence for cardioprotective strategies.

RECENT FINDINGS: Recent studies have provided additional support for the safety and efficacy of dexrazoxane and liposomal anthracycline formulations in certain high-risk patients receiving anthracyclines and for neurohormonal antagonist therapy in patients with breast cancer receiving sequential anthracyclines and trastuzumab. Ongoing studies are exploring the benefit of: (1) statins for anthracycline cardioprotection; (2) strict blood pressure control during vascular endothelial growth factor inhibitor treatment and; (3) dexrazoxane on long-term cardiac outcomes in pediatric populations. To date, there are no evidence-based cardioprotective strategies specifically for radiation-related heart and vascular disease, immunotherapy myocarditis, fluoropyrimidine cardiotoxicity, vascular endothelial growth factor inhibitor-related hypertension, BCR-Abl multikinase inhibitor vascular disease, and other established and emerging cancer therapeutics with cardiovascular effects. Current evidence supports specific cardioprotective strategies for high risk patients receiving anthracyclines or sequential anthracycline-trastuzumab therapy; however, major evidence gaps exist.

Moderate-level evidence suggests that cardiac troponin and natriuretic peptides are useful for risk stratification and early identification of anthracycline cardiotoxicity; however, many of these studies used older chemotherapy regimens, and thus, the applicability to current anthracycline treatment regimens is uncertain. Further research is needed to determine optimal timing and thresholds for troponin and natriuretic peptides in anthracycline-treated patients and evaluate these and other promising biomarkers for anti-HER2 therapies, thoracic radiation, anti-VEGF therapy, and fluoropyrimidine therapy-related cardiotoxicity. Risk tools that combine cardiac risk factors, cancer treatment variables, biomarkers, and imaging parameters are most likely to accurately identify individuals at highest risk for cancer therapy cardiotoxicity. Clinical trials focusing cardioprotective strategies on high-risk individuals are more likely to result in clinically significant results compared with primary prevention cardioprotective approaches.

BACKGROUND: Anthracycline agents can cause cardiotoxicity. We used multivariable risk prediction models to identify a subset of patients with breast cancer at high risk of cardiotoxicity, for whom the harms of anthracycline chemotherapy may balance or exceed the benefits.

PATIENTS AND METHODS: A clinical prediction model for anthracycline cardiotoxicity was created in 967 patients with human epidermal growth factor receptor-negative breast cancer treated with doxorubicin in the ECOG-ACRIN study E5103. Cardiotoxicity was defined as left ventricular ejection fraction (LVEF) decline of ≥ 10% to < 50% and/or a centrally adjudicated clinical heart failure diagnosis. Patient-specific incremental absolute benefit of anthracyclines (compared with non-anthracycline taxane chemotherapy) was estimated using the PREDICT model to assess breast cancer mortality risk.

RESULTS: Of the 967 women who initiated therapy, 51 (5.3%) developed cardiotoxicity (12 with clinical heart failure). In a multivariate model, increasing age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08), higher body mass index (OR, 1.06; 95% CI, 1.02-1.10), and lower baseline LVEF (OR, 0.93; 95% CI, 0.89-0.98) at baseline were significantly associated with cardiotoxicity. The concordance statistic of the risk model was 0.70 (95% CI, 0.63-0.77). In patients with low anticipated treatment benefit (n = 176) from the addition of anthracycline (< 2% absolute risk difference of breast cancer mortality at 10 years), 16 (9%) of 176 had a > 10% risk of cardiotoxicity and 61 (35%) of 176 had a 5% to 10% risk of cardiotoxicity at 1 year.

CONCLUSION: Older age, higher body mass index, and lower baseline LVEF were associated with increased risk of cardiotoxicity. We identified a subgroup with low predicted absolute benefit of anthracyclines but with high predicted risk of cardiotoxicity. Additional studies are needed incorporating long-term cardiac outcomes and cardiotoxicity model external validation prior to implementation in routine clinical practice.