Beta blockers and ACE inhibitors may prevent trastuzumab-induced cardiotoxicity in breast cancer patients

Although neither lisinopril nor carvedilol prevented cardiotoxicity caused by trastuzumab in patients with HER2-positive breast cancer, both may effectively preserve left ventricular ejection fraction (LVEF) in patients previously exposed to doxorubicin, according to results from a late-breaking clinical trial presented at the American College of Cardiology’s 67th Annual Scientific Sessions.

"Th[ese] data [are] the crucial first step towards establishing a new standard of care to reduce the risk of cardiotoxicity for patients undergoing treatment for HER2-positive breast cancer," said study chair Maya E. Guglin, MD, director, Mechanical Assisted Circulation Program, and medical director, VAD Program, Gill Heart & Vascular Institute, University of Kentucky's Gill Heart & Vascular Institute, Lexington, KY.

Trastuzumab is a monoclonal antibody used in the treatment of HER2-receptor positive metastatic breast cancer that can be used alone or in combination with other chemotherapeutic agents. Despite trastuzumab’s superior efficacy in reducing cancer recurrence and improving survival, its use has been associated with asymptomatic decreases in LVEF or heart failure.

One in four women treated with trastuzumab develops potentially dangerous cardiac problems. Clinicians often choose to either suspend or reduce the frequency of trastuzumab treatment in patients with an LVEF of less than 50%.

In response, the American Heart Association issued a warning to clinicians and patients to consider the risks of treatment when developing a treatment plan.

"[Trastuzumab] is arguably the most effective treatment for HER2-positive breast cancer," said Dr. Guglin. "These patients are already anxious about their future. We don't want to avoid this exceptionally effective treatment just because it might cause damage to the heart."

Dr. Guglin and colleagues conducted this prospective, multicenter clinical trial to determine whether concurrent treatment with an ACE inhibitor or a beta-blocker would prevent decreased LVEF.

They randomized 468 patients receiving adjuvant or neoadjuvant trastuzumab to treatment with lisinopril, carvedilol phosphate (extended release), or placebo. Researchers also sought to determine whether subjects treated with lisinopril or carvedilol had fewer interruptions of trastuzumab therapy, and if the effects of treatment were consistent in both the anthracycline and nonanthracycline cohorts.

Patients were followed for 2 years, which were comprised of 1 year of trastuzumab treatment and 1 year of follow-up.

The number of patients with interrupted trastuzumab treatment did not differ in the three arms. In patients previously treated with doxorubicin, both lisinopril and carvedilol effected statistically significant results compared with placebo (two-tailed P-values < 0.05). Significantly fewer cardiac events occurred in patients treated with carvedilol or lisinopril, compared with placebo (31% and 37% vs 47%, respectively).

In patients previously treated with doxorubicin, the hazard ratios were 0.49 for carvedilol and 0.53 for lisinopril, showing a large drug benefit. Finally, patients treated with carvedilol had fewer adverse events than those treated with lisinopril.

"The data clearly demonstrated that, for patients with HER2-positive breast cancer taking both doxorubicin and [trastuzumab], adding either an ACE inhibitor or a beta blocker to the treatment regimen can significantly offset the chance of heart problems," said Dr. Guglin.

"In the past few decades, we've made huge strides in successfully treating cancers that used to be very deadly for patients," said B. Mark Evers, MD, FACS, director, UK Markey Cancer Center, Lexington, KY. "But it's important to also think about the patient's future and to help them maintain the best possible quality of life. This study provides valuable information for oncologists who are treating patients with HER2-positive breast cancer and may help shape the new standard of treatment for this cancer in years to come."

And while these results are promising, many more studies are needed before a standard of care for these patients is determined.

"For example, should we always treat with both doxorubicin and [trastuzumab]? Should we re-evaluate our minimum standards for heart function? What if the patient's EF is less than 50% but is asymptomatic? And should the patient's wishes carry more weight in the equation?" asked Dr. Guglin. "All of these questions require careful consideration, but this part is clear: giving an ACE inhibitor or beta blocker to patients taking doxorubicin and [trastuzumab] for HER2-positive breast cancer will significantly reduce the risk of cardiotoxic side effects."

This study was cosponsored by the University of South Florida and the National Cancer Institute.