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Thursday, August 28, 2014

ONLINE FIRST: HERA Trastuzumab Trial Shows Lower Risk of Cardiac Problems in HER2-Positive Breast Cancer Patients



When administered for up to two years, the monoclonal antibody trastuzumab did not increase heart-related problems in otherwise healthy women with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer after chemotherapy or radiotherapy, according to results from the multinational Herceptin Adjuvant (HERA) trial, published in the Journal of Clinical Oncology (2014;32:2159-2165).


During an eight-year median follow-up period, few adverse cardiac events occurred with trastuzumab, which kills HER-2 cells. Moreover, when cardiac problems did arise, discontinuing treatment reversed them.


The drug was approved in 1998, but the Food and Drug Administration issued a black box label warning of potential cardiac risks, especially left ventricular ejection fraction (LVEF). Since then, however, several large trials have found that the risk may be lower unless women received anthracycline-based chemotherapy.


The researchers—first author is Evandro de Azambuja, MD, PhD, Medical Director of the the Breast Adjuvant Study Team (BrEAST) Data Center at Jules Bordet Institute in Brussels--note that they believe this to be the first clinical trial to evaluate cardiac events in patients taking trastuzumab for two years.


Included were 5,102 patients with normal LVEF after receiving neoadjuvant chemotherapy with or without radiotherapy randomized into either one or two years of trastuzumab. LVEF measures how much blood is being pumped from the left ventricle with each contraction. Subjects in the trial had LEVF levels of 55 percent or greater at the start of the study--LVEF of 55 percent or higher is considered normal.


A total of 1,673 patients were treated for two years, while 1,682 received trastuzumab for one year. An additional 1,744 women were in an observational cohort.


Adverse cardiac events that led to having to discontinue trastuzumab occurred in 9.4 percent of patients in the two-year arm, and in 5.2 percent of those taking the drug for one year. Cardiac deaths, incidence of severe congestive heart failure (CHF), and significant decreases in LVEF were low in all three groups of patients.


“This is reassuring for both short- and long-term patients,” de Azambuja said in an interview. “The main message from our study is that when adjuvant trastuzumab was given after the completion of all chemotherapy and radiotherapy, the incidence of trastuzumab-associated adverse events is low and reversible in the vast majority of patients if there are problems.”


Severe CHF occurred in just 0.8 percent in both the one- and two-year treatment groups, while decreased LVEF was observed in 7.2 percent of the two-year patients and 4.1 percent among one-year subjects. Among patients receiving two years of trastuzumab and had a decrease in LVEF, 87.5 percent completely recovered after treatment was halted, as did 81.2 percent of those in the one-year study arm.


He emphasized, however, that despite the low incidence of cardiac toxicity, patients treated with adjuvant trastuzumab do need to have a cardiac assessment before and during administration to ensure early detection and treatment of any cardiological problems that do occur.


“Direct communication between cardiologists and oncologists should take place prior to treatment in these patients,” de Azambuja said. “I believe that it is important for medical oncologists to carefully evaluate the cardiac risk of any of these patients before making a decision on which type of chemotherapy should be used and when adjuvant trastuzumab should be prescribed. A careful cardiac assessment, including LVEF measurement, should take place prior to chemotherapy.”


Problems with Earlier Trials

According to the authors, a problem with prior trials has been that they used LVEF values to define cardiotoxicity: “It lacks sensitivity,” de Azambuja explained. “A decrease in LVEF does not necessarily mean myocardial damage, whereas an unchanged LVEF value does not necessarily exclude myocardial damage.


“The European Society for Medical Oncology released guidelines on the surveillance of cardiac toxicity induced by anti-HER2 drugs, and according to the guides, patients should be followed with cardiac assessment before treatment; at three, six, and nine months during treatment; and then at 12 and 18 months after therapy--and if clinically indicated, patients should have their LVEF assessed at any time.”


Risk Stratification Needed

Asked for his opinion, Jersey Chen, MD, MPH, a research scientist at Kaiser Permanente’s Mid-Atlantic Permanente Research Institute, said he thinks the findings are accurate for the patients included in the study, but for older women--especially those with diabetes and hypertension—the cardiac risks do appear to be significantly greater.


Trastuzumab trials can underestimate these risks because they tend to involve younger subjects with fewer cardiac risk factors, and in this study many subject fell into this category,” he said.


In a paper published in the Journal of the American Heart Association earlier this year, he and his colleagues (first author was Ghideon Ezaz, MD, MPP) found an almost twofold increase in cardiomyopathy and heart failure among women over an average of 73 years of age who had received trastuzumab (doi: 10.1161/JAHA.113.000472). When factors such as adjuvant chemotherapy, coronary artery disease atrial fibrillation or flutter, diabetes, hypertension, and renal failure were stratified, the three-year risk scores ranged from a low of 16.2 percent to a high of 39.5 percent.


 In a 2012 study of Surveillance, Epidemiology, and End Results (SEER) data, published in the Journal of the American College of Cardiology (2012;60:2504-2512), Chen and colleagues at Yale examined the rates of heart failure and cardiomyopathy after trastuzumab therapy and chemotherapy in some 45,000 older women with early-stage breast cancer. The adjusted three-year rates for both heart failure and cardiomyopathy were higher (32.1 per 100 patients) in women receiving trastuzumab and 41.9 for those given anthracycline and trastuzumab, when compared with patients who received no adjuvant therapy (18.1 per 100 patients).


“I think the question remains open,” he said, adding that some kind of risk-benefit system should be created based on all of these factors and each individual person’s risk of cancer mortality. “It could be a trade-off in terms of risk, and where indicated, a shorter course of trastuzumab might be in order.”


He said he and his colleagues are now looking into developing a risk-scoring algorithm similar to the Framingham Risk Score, which is widely used to estimate cardiovascular risk, including comorbidities.


Risks and Benefits

Also asked her opinion, Edith A. Perez, MD, the Serene M. and Frances C. Durling Professor of Medicine and Deputy Director of the Mayo Clinic Cancer Center in Jacksonville, Florida, said she was not surprised by the new findings and that the long-term data are similar to those at Mayo.


“I think what is most important here is that any problems that arise in trastuzumab patients are reversible with discontinuation,” she said. “FDA’s black box was mandated in the 1980s, and treatment has moved beyond that. The real risk is using it with anthracyclines or cytotoxic chemotherapy agents. Since then there is wide awareness of these risks, and today trastuzumab would never be used concurrently with anthracyclines.”


Still, she noted that greater awareness of newer studies is needed by oncologists. There is also a need for longer-term outcomes data with follow-up periods of 10 to 15 years.


“My take is that there is some risk of cardiotoxicity with trastuzumab, but it is reversible in most cases, and the benefit of survival in general outweighs the risk.”