Cardiac Meds Appear to Protect Heart From Herceptin Damage

Kate Johnson

December 15, 2015

SAN ANTONIO ― Breast cancer patients treated with trastuzumab (Herceptin, Genentech, Inc) had significantly lower risk for left ventricular (LV) dysfunction and consequent treatment interruptions when treated prophylactically with heart failure medications, researchers reported at San Antonio Breast Cancer Symposium (SABCS) 2015.

Results of the MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) study, which was terminated early owing to positive results, could have practice-changing implications, noted lead investigator Edith Pituskin, RN, PhD, from the University of Alberta, in Calgary, Canada.

"There's a whole lot of people out there who have cardiac risk factors and higher risk of cardiac dysfunction, and oncologists are very concerned when it comes to proceeding safely [with trastuzumab]," she told Medscape Medical News.

Trastuzumab-related cardiac toxicity "is frequent and potentially lethal" in breast cancer patients, she added. LV dysfunction occurs in about 20% of patients, and heart failure, though less frequent (1% to 5%), "is extremely devastating, with a 50% 5-year mortality," she said.

"There are no effective prevention strategies to date. This approach may provide additional safety."

Dr Edith Pituskin

The study is the first randomized, double-blind, controlled trial to evaluate antihypertensive pharmacotherapy for the prevention of trastuzumab-related cardiotoxicity in HER2-positive, invasive, early breast cancer patients.

Enrollment was stopped after 99 patients had been randomly assigned to receive either the beta blocker bisoprolol (n = 33), the angiotensin-converting enzyme (ACE) inhibitor perindopril (n = 34), or placebo (n = 32) for 1 year along with trastuzumab therapy.

At baseline, patients across all groups were similar with respect to age (mean, 51 years), cancer stage, left-sided radiotherapy (41%), trastuzumab dose intensity, and cardiovascular risk factors.

Cardiac medications were uptitrated in the first 3 weeks and were continued for the 1-year duration of trastuzumab treatment.

Multiparametric cardiac MRI was performed at baseline and at 3, 12, and 24 months.

At the end of trastuzumab therapy, neither drug had an impact on the primary outcome of change from baseline in left ventricular end-diastolic volume, also known as LV remodeling

"Trastuzumab-associated LV remodeling was not prevented by ACE inhibitors or beta blockers," noted Dr Pituskin.

However, for the secondary outcome of change in left vehicular ejection fraction (LVEF), upon multivariate analysis, each drug was found to be of benefit.

Dr Pituskin first presented the univariate analysis findings for the three treatment arms.

In that analysis, only bisoprolol was associated with preservation of baseline function (from 62% to 61%). In contrast, for both placebo-treated and perindoprol-treated patients, LVEF significantly declined (from 61% and 62%, respectively, to 56% and 59%).

However, in multivariate analysis, use of both cardiac drugs significantly predicted preserved LV function (for perindopril, P = .013; for bisoprolol, P < .001).

For eight placebo-treated patients, trastuzumab treatment was interrupted because of drops in LVEF. Treatment was interrupted for one patient in the perindopril and for one patient in the bisoprolol arm (P = .002), she noted.

The sum of the findings is paradoxical, said another study author.

"This was surprising to us," said principal investigator Ian Paterson, MD, a cardiologist from the University of Alberta. "Usually, remodeling goes along with left ventricular dysfunction...so we were a little surprised in this study that we had remodeling yet preserved cardiac function with these medications," he told Medscape Medical News.

"What it means to me as a cardiologist is I'd be very interested to follow these patients who developed remodeling. Does it mean they are going to develop heart failure or LV dysfunction down the road? They didn't for the 1 year they were on the medications, so we've built into the study to image them again at 2 years."

Both cardiac medications were "very well tolerated," with no patients having to stop treatment because of adverse events, reported Dr Pituskin.

However, there were some dose alterations due to hyperkalemia, bradycardia dizziness, hypotension, and patient preference.

Table.

  Placebo (n = 30) Perindopril (n = 33) Bisoprolol (n = 31)
Premature study drug termination 0 0 0
Dose reductions for:      
Hyperkalemia/renal 3% 18% 19%
Bradycardia 3% 0 3%
Dizziness 0 0 6%
Hypotension 3% 0 3%
Patient preference 0 6% 0

 

Serena Wong, MD, a medical oncologist at Rutgers Cancer Institute of New Jersey, in New Brunswick, was enthusiastic but cautious about the new findings.

"Results of this study are encouraging and add to the growing cardio-oncology literature,” she said when asked by Medscape Medical News for comment.

"I think this may be something to consider in patients who appear to be at high risk for cardiovascular toxicities from our therapies, but at this point in time, I don't think I will be offering it across the board to all of my patients," she noted.

"Clinicians have for years been treating cardiac dysfunction from antineoplastic therapy according to general cardiology guidelines for heart failure, although this practice has been based more on extrapolation rather than on evidence specifically addressing the problem in the cancer population. I would like to see the study replicated on a larger scale and with longer follow-up. We also need to figure out a way to stratify patients according to cardiovascular risk. If we can identify those who are most likely to develop cardiac dysfunction from our therapies, we can then focus our efforts on treating those patients rather than exposing everyone to additional cardiac drugs with their own potential side effects. But overall, I think these results are exciting and help move this field forward," Dr Wong said.

Dr Pituskin has received material support from Servier Canada Inc and peer review funding from the Canadian Institutes for Health Research, the Alberta Cancer Foundatoin, and the Mazankowski Alberta Heart Institute/University Hospital Foundation. Dr Paterson has disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2015: Abstract S1-05. Presented December 9, 2015.

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