Reducing Cardiac Toxicity During Cancer Treatment

Chances of left ventricular ejection fraction almost disappeared when patient took the ACE-inhibitor lisinopril during treatment with trastuzumab/anthracycline, according to research presented at ASCO.

Patients treated with anthracycline chemotherapy prior to treatment with trastuzumab (Herceptin, Genentech) for HER2-positive early-stage breast cancer experienced a decline in left ventricular ejection fraction (LVEF) below normal levels, but in patients treated with lisinopril that decline was largely prevented, according to data presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in June 2021.

“The anthracycline-induced decrease in left ventricular ejection fraction women receiving trastuzumab for a year to below 50% was much larger than previously reported,” lead investigator Pamela Munster, MD, professor of medicine at the University of California San Francisco, said at the meeting. “Lisinopril was well tolerated in this group, even in patients without hypertension.

A total of 468 women with HER2-positive early-stage breast cancer from 127 community-based oncology practices were enrolled; 189 (40%) patients were treated once daily with the ACE inhibitor lisinopril (10mg), the beta blocker carvedilol (10mg), or placebo during treatment with trastuzumab, and patients were further stratified by anthracycline use.

In women who received anthracycline prior to treatment with trastuzumab, the drop in LVEF to below 50% in the placebo arm was 30.5%. This drop was prevented in women taking lisinopril. In this group, only 10.8% of women had a drop in left ventricular rejection fraction to below 50%.

Concerns about cardiotoxic effects of cancer treatment, particularly for breast cancer patients, have climbed in recent years, due to both the effects of therapies and comorbidities of the patients; in one study, 62% of the participants had high blood pressure and 50% had elevated cholesterol.

Recently, leading [MC2] professional societies and an FDA advisory committee have discussed the importance of recognizing LVEF between 40% and 49% as a clinically distinctive condition. An article in the Journal of the American College of Cardiology observed that patients in this stratum resembled those with higher levels of LVEF but with more ischemia. There is less consensus on how to treat patients in in the “gray zone” between 40% to 49%, but many treatments are being studied; there is broad consensus to treat those with LVEF below 40%.

Investigators found that the rate of LVEF decline to below normal was much more frequent in patients treated with an anthracycline than those treated with trastuzumab alone (21% vs 4.1%). They also found that the beta-blocker carvedilol had a small effect on LVEF, but it was not significant.

Treatment of HER2-positive breast cancer patients with trastuzumab is highly effective. However, a LVEF and clinical heart failure often lead to discontinuation of treatment.

Cardiovascular events are the most common reason for black box warnings for cancer therapies, according to another abstract presented at ASCO. Investigators looked at the warnings related to cardiovascular events for anticancer drugs approved between 1998 and 2018. There were 125 novel anticancer therapies, including 24 biologics, 10 immunotherapies, and 48 targeted drugs. There were 177 safety communications (41 black box warnings, 7 withdrawals, 4 dose adjustments, and 84 general warnings).

Among all cardiovascular warnings, arrhythmias were the most common (21.6%), followed by heart failure (13.9%), thromboembolic disease (13.9%), uncontrolled hypertension (11.8%), sudden cardiovascular death (9.0%), ischemic disease (6.9%), stroke (4.9%), and other cardiovascular events (12.5%).