Protecting Hearts From Herceptin: MANTICORE Data 'Unclear'

Kristin Jenkins

December 13, 2016

Antihypertensive pharmacotherapy can prevent chemotherapy-related cardiac dysfunction and life-threatening treatment interruptions in patients with invasive early breast cancer given adjuvant trastuzumab (Herceptin, Genentech/Roche), show the now-published results from 5-year Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE) trial.

However, neither of the pharmacotherapies prevented trastuzumab-mediated concurrent left ventricular (LV) end-diastolic volume — also known as LV remodeling — which was the study's primary endpoint.

So, while the investigators say these results could be "practice-changing," others are not so sure.

The MANTICORE results were published November 28 in the Journal of Clinical Oncology, having previously been reported at a conference.

Trastuzumab adjuvant therapy for human epidermal growth factor receptor 2 (HER2)–positive early breast cancer significantly improves cancer outcomes, the authors note. However, significant rates of LV dysfunction and heart failure are consistently reported. The risk for heart failure has been reported as 2% to 4% and for LV dysfunction as 11% in clinical trials, with higher rates in cohort studies. "By comparison, the rate of CTRCD [chemotherapy-related cardiac dysfunction] in our placebo group using current definitions was 20% at 12 weeks," the authors note.

In the MANTICORE study, the angiotensin-converting enzyme (ACE) inhibitor perindopril and the β-blocker bisoprolol were both "well tolerated in patients with HER2-positive early breast cancer who received trastuzumab," say the authors, led by D. Ian Paterson, MD, from the Department of Medicine, Division of Cardiology, University of Alberta Mazankowski Alberta Heart Institute in Edmonton, Alberta, Canada.

Both cardiovascular drugs "protected against cancer therapy–related declines in LVEF [ventricular ejection fraction]," and they were also associated with fewer interruptions in trastuzumab adjuvant therapy, the authors note.

Secondary analyses of 33 patients who received perindopril, 31 patients who received bisoprolol, and 30 who received placebo for 1 year along with trastuzumab showed that chemotherapy-mediated decline in LVEF was reduced in bisoprolol-treated patients (–1% ± 5%) relative to the perindopril (–3% ± 4%) and placebo (–5% ± 5%) groups (P = .001).

After 17 cycles of trastuzumab, however, cardiac MRI showed that indexed LV end diastolic volume increased in patients treated with perindopril (+7 ± 14 mL/m2), bisoprolol (+8 mL ± 9 mL/m2), and placebo (+4 ± 11 mL/m2; P = .36).

"The long-term significance of LV remodeling in our study is unclear," Dr Paterson and colleagues acknowledge.

It also isn't clear whether protecting against chemotherapy-related declines in LVEF improves clinical outcomes, "either cancer or cardiac," Dr Paterson said in an email.

Most of the existing data on prevention of LV remodeling come from studies of ACE inhibitors after myocardial infarction, he explained.

"We hypothesized that we would find a similar protective effect of ACE inhibitors and β-blockers for patients on trastuzumab," he explained. "Obviously this was not the case, and this implies a different mechanism of cardiac injury for trastuzumab."

Despite these unknowns, the findings suggest antihypertensive pharmacotherapies are "an effective option for patients and clinicians concerned about trastuzumab-mediated cardiac dysfunction," Dr Paterson told Medscape Medical News. "Therefore, the threshold for discontinuing these treatments while on trastuzumab should be high."

"We think this is practice-changing," said coinvestigator Edith Pituskin, RN, PhD, in a statement. "This will improve the safety of the cancer treatment that we provide," said Dr Pituskin, who is assistant professor in the faculty of medicine and dentistry at the University of Alberta.

Enthusiasm for Findings, But Also Questions

When asked to comment, several cardiologists expressed enthusiasm for the study but also had some questions and concerns.

MANTICORE's findings are "both important and encouraging," said Douglas L. Mann, MD, cardiologist-in-chief at Barnes Jewish Hospital in St. Louis, Missouri. "With proper primary prevention for chemotherapy-induced LV dysfunction, physicians may be able to prevent the development of heart failure."

Dr Mann also noted the study's small numbers, its failure to meet the primary endpoint, and the lack of a clearly defined mechanism for the increase in LVEF.

"I think one needs to be cautious about overinterpreting the findings of MANTICORE," he told Medscape Medical News.

When asked whether these findings would have any effect on clinical practice, Dr Mann said, "No. It would be unusual to have a change in practice guidelines based on very small changes in a secondary endpoint in a single trial that was stopped prematurely because it did not meet its primary endpoint. To my knowledge this would be unheard of."

The "modest" differences in LVEF seen between the groups — the study's secondary endpoint — "may or may not be considered clinically significant in patients with chemotherapy-induced heart failure," he said. "We just don't know."

Dr Mann said he hoped MANTICORE's findings will "be the stimulus for a larger trial" evaluating the combination of perindopril and bisoprolol "as a primary prevention with clinically meaningful outcomes such as hospitalization, death, and/or a drop in LVEF greater than 5%."

Using combinations of proven heart failure drugs as primary prevention would be the logical next step, he added. "The lessons learned from these efforts is that combinations of drugs, such as an ACE inhibitor and a β-blocker, work synergistically and are more effective than monotherapy."

Susan Dent, MD, associate professor of medicine at the University of Ottawa, Ontario, Canada, and cochair of the Global Cardio-Oncology Summit, is also in favor of more research. She agreed that larger studies should look at primary prevention strategies for patients with underlying cardiovascular risk factors who are at high risk for cardiotoxicity.

In MANTICORE, protection against decline of LVEF was small in both the perindopril group and the bisoprolol group, she noted, adding that LVEF changes due to trastuzumab tend to be transitory rather than permanent.

"The question is [whether] small asymptomatic decreases in LVEF are clinically important," she told Medscape Medical News. "I don't think we know the answer to this question yet. Further studies are needed."

Baseline cardiovascular risk factors for all patients with cancer starting cancer therapy need to be assessed, and control of cardiovascular risk factors, such as hypertension, need to be optimized as part of the cancer treatment plan, she said.

"The authors should be commended for doing this study since it shows that cooperation among disciplines is feasible and beneficial for patients," commented Daniel J. Lenihan, MD, professor of medicine at Vanderbilt University School of Medicine in Nashville, Tennessee, and president of the International CardiOncology Society, North America.

Many of MANTICORE's findings are "very consistent with what we already know in the heart failure world," he told Medscape Medical News, adding that the study puts into context findings from the European Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA).

PRADA showed that the angiotensin-receptor blocker candesartan cilexetil (Atacand, AstraZeneca) was effective at preserving LVEF among women undergoing anthracycline chemotherapy for breast cancer whereas the β-blocker metoprolol succinate was not.

β-Blockers are more effective for treating existing LV dysfunction than for preventing it, explained Dr Lenihan, "so it's understandable that they [β-blockers] weren't [effective] in this case."

Many of the patients in MANTICORE had not received therapy with anthracyclines before adjuvant trastuzumab, indicating the study population was low risk, he said. Many patients had normal LV function before treatment and no significant cardiac risk factors.

"This study was giving basically well people a not-so-toxic therapy," Dr Lenihan told Medscape Medical News. "It would be different if you took a higher-risk group who were given anthracyclines, which are more toxic. Then I think you would see more of a difference with treatment."

All participants in MANTICORE are undergoing 24-month cardiac MRI — the gold standard for determining cardiac volumes and function — as well as clinical re-evaluation of cardiac geometry, function, and clinical outcomes, Dr Paterson and colleagues said.

Because the patient cohort was younger than most patients with HER-2–positive early invasive breast cancer seen in clinical practice, and had fewer cardiovascular risk factors, "it's possible that the protective effects of drug intervention on LVEF and cancer therapy-related cardiac dysfunction is underestimated compared with a real-world setting," they said.

MANTICORE was financially supported by the Canadian Institutes of Health Research, the Alberta Cancer Foundation, and the University Hospital Foundation. The study drug perindopril was provided in kind by Servier. Dr Paterson and coauthor Dr Pituskin have disclosed no relevant financial relationships. Coauthor John R. Mackey, MD, disclosed that he is employed by Pacylex Pharmaceuticals, and coauthor Kelvin Chow, PhD, disclosed that he is employed by Siemens. Coauthor Justin A. Ezekowitz, MD, disclosed research funding from Novartis, Merck (institutional), Bayer (institutional), Trevena (institutional), Amgen, and Servier. Dr Mann disclosed he is a consultant to Novartis, Bristol-Myers Squibb, and miRagen. Dr Dent disclosed a relationship with Hoffman LaRoche. Dr Lenihan disclosed a consulting role with Roche, Prothena, Amgen, and Bristol-Myers Squibb and research funding from Takeda.

J Clin Oncol. Published online November 28, 2016. Abstract

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