Two studies link breast cancer treatments to a higher rate of cardiac toxicity

Both trastuzumab and radiation to left side of chest associated with increased cardiotoxicity; damage may be reversed.

Issue: October 1, 2006

Women with advanced breast cancer receiving trastuzumab had a 28% higher incidence of cardiac toxicity than reported to date in other clinical trials, according to a recent study. The researchers also concluded that the majority of this heart damage could be reversed by discontinuing trastuzumab or taking beta-blockers.

The study, which appeared in the Journal of Clinical Oncology, concluded that use of trastuzumab (Herceptin, Genentech) in patients with metastatic breast cancer was “an acceptable risk,” according to senior researcher, Francisco J. Esteva, MD, PhD, an associate professor in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

Other clinical trials that tested trastuzumab in combination with chemotherapy have found that between 10% and 26% of patients experienced cardiac toxicity, depending on the treatment protocol. That finding led to an FDA warning in 2003 that trastuzumab use could result in congestive heart failure or ventricular dysfunction.

Reversible toxicity

Prior to this study, there had been no research into patients who were treated in a clinic, outside of an organized trial, after they used trastuzumab for at least a year. “We often give it for several years if patients are responding to the treatment, so we set out to quantify the risks,” Esteva said in a prepared statement.

Esteva and colleagues followed 173 patients with metastatic breast cancer treated at MD Anderson. Patients were enrolled in the study after one year of trastuzumab use and underwent a baseline cardiac assessment along with regular cardiac check-ups throughout the trial period. After a median follow-up of more than 32 months, the researchers found that 28% (n=49) of the patients experienced a cardiac event. Of these patients, 46 experienced cardiac toxicity potentially associated with heart failure and three patients experienced an asymptomatic, yet significant, decrease in ventricular function. Thirty six patients had a cardiac event on their first round of trastuzumab at a median treatment duration of 7.8 months. Another eight patients had a cardiac event during their second round of trastuzumab at a median treatment duration of 16 months. Thirty one of these patients experienced cardiac toxicity while receiving trastuzumab alone and 13 had a cardiac event after trastuzumab and chemotherapy (paclitaxel or docetaxel). Five patients had a cardiac event while receiving neither trastuzumab nor a taxane, researchers wrote.

All but three patients improved cardiac function with the discontinuation of trastuzumab and adding such cardiac treatments as beta-blockers and ACE inhibitors to their treatment protocols. After repairing the damage, patients could resume trastuzumab treatment, Esteva said.

“The drug substantially prolongs survival, and while we found substantial cardiac toxicity, we also discovered that this side effect can be successfully treated, which was not clearly known before this study,” Esteva said. “If the cardiac side effects of Herceptin treatment can be managed, the drug is safe to use.”

Monitoring patients

The researchers did not determine why treatment with trastuzumab and/or chemotherapy caused cardiac toxicity; however, Esteva said that some animal studies have shown that HER2 proteins play an important role in the development of cardiac cells, so the treatment might affect their normal functioning. They could not conclude that all observed toxicity was caused by trastuzumab. Many of the patients had prior treatment with chemotherapy drugs known to affect the heart, were diabetic or had other illnesses.

Esteva said that patients with advanced breast cancer should receive a baseline cardiac assessment before the drug is used, and then follow-up care with a cardiologist. These results do not apply to use of the drug in patients with early-stage disease. Cardiac toxicity may be a concern for such patients, but they were not included in this study, he said.

“This is an accurate representation of clinical practice in that patients have other important comorbidities placing them at risk for cardiotoxicity,” Esteva said. “It shows the need for good cardiac care for advanced breast cancer patients.”

In an accompanying editorial, Daniel Hayes, MD, from the University of Michigan Comprehensive Cancer Center, and Michael H. Picard, MD, from Massachusetts General Hospital, wrote, “careful and frequent monitoring of patients treated with trastuzumab should include a history and physical examination in addition to noninvasive imaging of ventricular function.”

Radiation risk

In another study, which also appeared in the Journal of Clinical Oncology, researchers at the University of Pennsylvania, Philadelphia, found that women with early-stage breast cancer who received radiation therapy to the left side of the chest were more likely to develop heart disease during the subsequent two decades than those who received right-sided radiation. However, left-sided radiation therapy did not increase the risk of death from heart-related problems.

“Our findings showed that radiation therapy in patients with cancer in the left breast has a small but finite risk of coronary artery disease that may not show up for more than 10 years after treatment,” said lead researcher Eleanor Harris, MD, associate professor and clinical director of radiation oncology at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla. “Women receiving radiation to the left side of their chest need to be aware of this risk, and take the appropriate steps to monitor their cardiovascular health,” she said in prepared statement.

Harris and colleagues compared heart disease incidence and mortality between 477 women with right-sided early-stage breast cancer and 484 women with left-sided breast cancer who were treated with contemporary radiation oncology techniques between 1977 and 1994, and were followed for up to 20 years. The rate of death from a cardiac cause was similar between the two groups: 6% for the left-sided group vs. 4% for the right-sided group.

However, more women who received radiation to the left side of the chest developed coronary artery disease (25% vs. 10%) or had a heart attack (15% vs. 5%). In addition, having high blood pressure before therapy increased the risk of heart disease associated with radiation therapy in the left-sided group. Harris said that recent advances in radiation techniques allow more accurate monitoring of heart volumes, and that further dose reductions to heart tissue are achievable.

In an accompanying editorial, Abram Recht, MD, from Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, said that studies evaluating the effects of left-sided radiation on heart disease risk have reported different findings, and that the effects of anti-cancer drugs that may damage the heart (such as anthracyclines) should also be considered. However, he encouraged women who receive radiation therapy to the left side of the chest to be sure to have regular screenings for cardiac risk factors. “I strongly encourage patients to vigorously treat high blood pressure and high cholesterol, and to avoid smoking,” he said.

For more information:

Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center Experience. J Clin Oncol. 2006;24:4107-4115.

Harris, ER, Correa C, Hwang WT, et al. Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol. 2006;24:4100-4106.

Hayes DF, Picard MH. Heart of darkness: the downside of trastuzumab. J Clin Oncol. 2006;24:4056-4058.

Recht A. Which breast cancer patients should really worry about radiation-induced heart disease — and how much? J Clin Oncol. 2006;24:4059-4061.