SAN ANTONIO – Prophylactic beta-blockade with bisoprolol during adjuvant trastuzumab therapy for HER2-positive breast cancer prevented trastuzumab-induced decline in left ventricular ejection fraction in MANTICORE, a randomized trial presented at the San Antonio Breast Cancer Symposium.
“MANTICORE provides the first intervention proven in a randomized, double-blind, placebo-controlled, multicenter way to be an effective means of preventing trastuzumab-associated left ventricular dysfunction,” said Edith Pituskin, Ph.D., of the University of Alberta, Edmonton.
MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) randomized 99 patients with HER2-positive early breast cancer and a normal-range left ventricular ejection fraction (LVEF) at baseline to bisoprolol (Zebeta), the ACE inhibitor perindopril (Aceon), or placebo shortly before starting a planned 1-year course of adjuvant trastuzumab (Herceptin). The patients had low background levels of cardiovascular risk factors. Roughly three-quarters of subjects were able to titrate up to the target dose of 10 mg once daily for bisoprolol or 8 mg once daily for perindopril.
Cardiac MRI assessments at baseline, 3, and 12 months – the point when trastuzumab and the cardioprotective medications were stopped – showed that neither bisoprolol nor perindopril prevented trastuzumab-related left ventricular remodeling, which was a disappointment, given that this was the prespecified primary endpoint.
“Our results hint that, potentially, trastuzumab exposure–related left ventricular remodeling is not reversible,” Dr. Pituskin said.
The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant.
On the plus side, both of the once-daily cardiac medications displayed an important side benefit in MANTICORE: an eightfold reduction in the number of interruptions of trastuzumab therapy mandated by a significant drop in LVEF. There were eight such interruptions in the control group versus one each in the bisoprolol and perindopril arms. That’s of practical value in terms of patient convenience, cost of care, and possibly even the efficacy of the adjuvant cancer regimen, she noted.
Audience members raised several questions: what’s the clinical significance of the asymptomatic reduction in LVEF seen in the control group in MANTICORE? Does it place affected patients at risk for overt heart failure as time passes? And since LVEF is just one aspect of cardiac function, isn’t it possible that the cardiac medications were simply propping up LVEF while the underlying cardiotoxic effects of trastuzumab remained unchecked, such that the LVEF will drop once patients are off therapy?
Dr. Pituskin replied that these are good questions, the answers to which may be forthcoming at the planned follow-up cardiac MRI to be conducted at 24 months, a full year after discontinuation of the therapies.
Asked to compare the MANTICORE findings with those of the PRADA trial presented at this year’s annual meeting of the American Heart Association, in which an LVEF drop in breast cancer patients on adjuvant anthracycline and trastuzumab was prevented by prophylactic use of the angiotensin receptor blocker candesartan (Atacand) but not the beta-blocker metoprolol, Dr. Pituskin said she can’t make a definitive comparison until PRADA is published, but that it’s her understanding PRADA was a single-center trial without serial cardiac MRIs, and it included many more participants on an anthracycline-containing regimen, long recognized as a major hazard in terms of cardiotoxicity, and one thought to have a different cardiotoxic mechanism than trastuzumab.
By way of background, she noted that roughly 20% of women with breast cancer have HER2 receptor–overexpressing tumors. In such patients it’s well established that trastuzumab reduces mortality by one-third. However, it’s also well established that one in five patients on trastuzumab experience left ventricular dysfunction, and 1%-5% of patients develop heart failure, an “extremely devastating” complication carrying a 50% 5-year mortality. Beta-blockers and ACE inhibitors or angiotensin receptor blockers are standard, guideline-recommended treatments for patients with established heart failure.