Anthony F. Yu

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

PURPOSE Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer. METHODS We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab. RESULTS Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis. CONCLUSION Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.

Exercise and Risk of Cardiovascular Events in Women With Nonmetastatic Breast Cancer

PURPOSE Cardiovascular disease (CVD) is a leading cause of death among women with nonmetastatic breast cancer. Whether exercise is associated with reductions in CVD risk in patients with breast cancer with an elevated CVD risk phenotype is not known. METHODS Using a prospective design, women (n = 2,973; mean age, 57 years) diagnosed with nonmetastatic breast cancer participating in two registry-based, regional cohort studies, completed a questionnaire that assessed leisure-time recreational physical activity (metabolic equivalent task [MET]-h/wk). The primary end point was the first occurrence of any of the following: new diagnosis of coronary artery disease, heart failure, valve abnormality, arrhythmia, stroke, or CVD death, occurring after study enrollment. RESULTS Median follow-up was 8.6 years (range, 0.2 to 14.8 years). In multivariable analysis, the incidence of cardiovascular events decreased across increasing total MET-h/wk categories (Ptrend < .001). Compared with < 2 MET-h/wk, the adjusted hazard ratio was 0.91 (95% CI, 0.76 to 1.09) for 2 to 10.9 MET-h/wk, 0.79 (95% CI, 0.66 to 0.96) for 11 to 24.5 MET-h/wk, and 0.65 (95% CI, 0.53 to 0.80) for ≥ 24.5 MET-h/wk. Similar trends were observed for the incidence of coronary artery disease and heart failure (P values < .05). Adherence to national exercise guidelines for adult patients with cancer (ie, ≥ 9 MET-h/wk) was associated with an adjusted 23% reduction in the risk of cardiovascular events in comparison with not meeting the guidelines (< 9 MET-h/wk; P < .001). The association with exercise did not differ according to age, CVD risk factors, menopausal status, or anticancer treatment. CONCLUSION Exercise is associated with substantial, graded reductions in the incidence of cardiovascular events in women with nonmetastatic breast cancer.

Cardiac Surveillance Guidelines for Trastuzumab-Containing Therapy in Early-Stage Breast Cancer: Getting to the Heart of the Matter

Trastuzumab-containing regimens for breast cancer have significantly improved survival both in the early-stage and metastatic settings.1-8 Nevertheless, given the early signals of cardiotoxicity, a prevailing concern exists regarding the risk of cardiotoxicity, defined as a decline in left ventricular ejection fraction (LVEF) both asymptomatic and symptomatic. This concern that LVEF decline would be an early and actionable surrogate for subsequent development of congestive heart failure (CHF) led to the design and implementation of specific eligibility criteria and LVEF surveillance guidelines for the pivotal randomized adjuvant trials. These guidelines were subsequently adopted as the standard of care. However, it is increasingly unclear whether these specific recommendations are justified for all patients. Resolution of this matter is critical for our community because adherence to these guidelines was recently proposed as a quality metric.9 This issue raises the general question of the level of evidence needed to accept a toxicity screening schedule as a quality indicator. If following these guidelines is not associated with improved outcomes, then adherence to them as a quality metric should be challenged. Cardiotoxicity screening can serve to illuminate this issue. Here, we review the historical events that led to the development of the current guidelines and highlight critical knowledge gaps with regard to the benefits of screening and intervention.

Roadmap for biomarkers of cancer therapy cardiotoxicity

Contemporary cancer treatment uses multiple modalities such as chemotherapy, targeted therapy and radiotherapy. These therapies, often used in combination, are associated with an increased risk of cardiotoxicity, specifically cardiomyopathy and heart failure. Cardiologists and oncologists are faced with the challenge of maximising the clinical benefit from cancer therapy while minimising the risk of early and late-onset cardiotoxicity. The current paradigm for cardiotoxicity detection and management relies primarily upon the assessment of left ventricular ejection fraction (LVEF). However, LVEF alone is limited in both diagnostic and prognostic ability. There is growing enthusiasm over the identification of newer biomarkers of cardiotoxicity that can detect cardiac injury at earlier stages of disease and could be used as an adjunctive prognostic measure to routine LVEF assessment. Thus, imaging and circulating biomarkers are currently under active investigation for use throughout the continuum of cancer care—for risk stratification of cardiotoxicity prior to treatment, detection of early cardiotoxicity during treatment and diagnosis of late cardiotoxicity in survivorship. Myocardial strain, cardiac troponin and brain natriuretic peptide are the most prominent biomarkers currently being studied, although data on novel circulating biomarkers are emerging.

Breast cancer treatment-associated cardiovascular toxicity and effects of exercise countermeasures

Advances in breast cancer treatment have improved disease-free survival and overall survival in women with early-stage breast cancer. However, these improvements may be attenuated by the adverse cardiovascular effects associated with breast cancer adjuvant therapy. Exercise may be a potential strategy to counteract these toxicities. The purpose of this paper is to provide an overview on the adverse cardiovascular effects of breast cancer therapy as well as the evidence supporting the potential cardioprotective effects of exercise training in breast cancer patients during and after treatment. We will also discuss research gaps and avenues for future research.

Cardiomyopathy Associated With Cancer Therapy

Chemotherapy-associated cardiomyopathy is a well known cardiotoxicity of contemporary cancer treatment and a cause of increasing concern for both cardiologists and oncologists. As cancer outcomes improve, cardiovascular disease has become a leading cause of morbidity and mortality among cancer survivors. Asymptomatic or symptomatic left ventricular systolic dysfunction in the setting of cardiotoxic chemotherapy is an important entity to recognize. Early diagnosis of cardiac injury through the use of novel blood-based biomarkers or noninvasive imaging modalities may allow for the initiation of cardioprotective medications or modification of chemotherapy regimen to minimize or prevent further damage. Several clinical trials are currently underway to determine the efficacy of cardioprotective medications for the prevention of chemotherapy-associated cardiomyopathy. Implementing a strategy that includes both early detection and prevention of cardiotoxicity will likely have a significant impact on the overall prognosis of cancer survivors. Continued coordination of care between cardiologists and oncologists remains critical to maximizing the oncologic benefit of cancer therapy while minimizing any early or late cardiovascular effects.

Cardiac Safety of Paclitaxel Plus Trastuzumab and Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer

The results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer are reported. There were no statistically significant changes in GLS, and TnI and BNP levels. The finding supports the cardiac safety of THP in this group of patients.

Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer

Two-dimensional speckle tracking echocardiography (2DSTE) provides a sensitive measure of left ventricular (LV) systolic function and may aid in the diagnosis of cardiotoxicity. 2DSTE was performed in a cross-sectional study of 134 patients (mean age: 31.4 ± 8.8 years; 55% male; mean time since diagnosis: 15.4 ± 9.4 years) previously treated with anthracyclines (mean cumulative dose: 320 ± 124 mg/m2), with (n = 52) or without (n = 82) mediastinal radiotherapy. The prevalence of LV systolic dysfunction, defined as fractional shortening < 27%, LV ejection fraction (LVEF) < 55%, and global longitudinal strain (GLS) ≤ 16%, was 5.2%, 6.0%, and 23.1%, respectively. Abnormal GLS was observed in 24 (18%) patients despite a normal LVEF. Indices of LV systolic function were similar regardless of anthracycline dose. However, GLS was worse (18.0 versus 19.0, p = 0.003) and prevalence of abnormal GLS was higher (36.5% versus 14.6%, p = 0.004) in patients treated with mediastinal radiotherapy. Mediastinal radiotherapy was associated with reduced GLS (p = 0.040) after adjusting for sex, age, and cumulative anthracycline dose. In adult survivors of childhood, adolescent, and young adult cancer, 2DSTE frequently detects LV systolic dysfunction despite a normal LVEF and may be useful for the long-term cardiac surveillance of adult cancer survivors.

Pathologic Complete Response with Neoadjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel with Trastuzumab and Pertuzumab in Patients with HER2‐Positive Early Stage Breast Cancer: A Single Center Experience

OBJECTIVES Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. METHODS An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). RESULTS Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. CONCLUSION At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry.

Aims The presence of cancer can complicate treatment choices for patients with atrial fibrillation (AF) increasing both the risk of thrombotic and bleeding events. Methods and results Using data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we aimed to characterize AF patients with cancer, to describe their management and to assess the association between cancer and cardiovascular (CV) outcomes. Among 9749 patients, 23.8% had history of cancer (57% solid malignancy, 1.3% leukaemia, 3.3% lymphoma, 40% other type, and 2.2% metastatic cancer). Patients with history of cancer were older, more likely to have CV disease, CV risk factors, and prior gastrointestinal bleeding. No difference in antiarrhythmic and antithrombotic therapy was observed between those with and without cancer. Patients with history of cancer had a significantly higher risk of death (7.8 vs. 4.9 deaths per 100 patient-years follow-up, P = 0.0003) mainly driven by non-CV death (4.2 vs. 2.4 per 100 patient-years follow-up; P = 0.0004) and higher risk of major bleeding (5.1 vs. 3.5 per 100 patient-years follow-up; P = 0.02) compared with non-cancer patients; no differences were observed in risks of strokes/non-central nervous system embolism (1.96 vs. 1.48, P = 0.74) and CV death (2.89 vs. 2.07, P = 0.35) between the two groups. Conclusion A history of cancer is common among AF patients with up to one in four patients having both. Antithrombotic therapy, rates of cerebrovascular accident, other thrombotic events and cardiac death were similar in AF patients with or without a history of cancer. Patients with cancer, however, were at higher risk of major bleeding and non-CV death.