ACE Inhibitor, Beta Blocker Lower Trastuzumab Cardiotoxicity Risk in HER2+ Breast Cancer

In patients with early-stage HER2-positive breast cancer who are being treated with adjuvant trastuzumab and anthracyclines, cardiotoxicity-free survival is longer when they receive prophylactic simultaneous lisinopril or carvedilol.

Pamela N. Munster, MD

In patients with early-stage HER2-positive breast cancer who are being treated with adjuvant trastuzumab and anthracyclines, cardiotoxicity-free survival is longer when they receive prophylactic simultaneous lisinopril or carvedilol, according to data from a large, community-based, double-blind, placebo-controlled prospective trial.

Patients who received a nonanthracycline regimen, however, derived no benefit from simultaneous treatment with the ACE inhibitor lisinopril or the beta blocker carvedilol, said Pamela N. Munster, MD, at the 2018 San Antonio Breast Cancer Symposium.

In the study, which randomized 486 patients, cardiotoxicity was defined as an absolute decrease in left ventricular ejection fraction (LVEF) of ≥10%, or a ≥5% decrease for LVEF <50%. Cardiotoxicity developed in 32% of the placebo arm, 29% of the carvedilol arm (P = .270), and 30% of the lisinopril arm (P = .358) in the overall cohort at about 24 months after baseline examination.

In the overall cohort, cardiotoxicity-free survival was also comparable between the arms, with a hazard ratio of 0.71 for carvedilol versus placebo (P = .052) and 0.74 for lisinopril (P = .076). When the study population was stratified by anthracycline use, cardiotoxicity-free survival was significantly lower in the carvedilol (HR, 0.49; P = .009) and lisinopril (HR, 0.30; P = .015) arms in patients taking an anthracycline. No differences were observed in the nonanthracycline cohort.

“In persons with HER2-positive breast cancer treated with trastuzumab, and should you choose an anthracycline, you should consider the addition of lisinopril or carvedilol,” said Munster, professor, department of medicine (hematology/oncology), University of California, San Francisco.

Cardiac side effects associated with trastuzumab require frequent monitoring, resulting in dose interruptions and discontinuation of trastuzumab. “The prevention of trastuzumab-induced toxicity by prophylactic use of an ACE inhibitor or beta blocker has been suggested in smaller studies but not in larger randomized studies,” she said.

When the study was designed, several challenges and potential confounders were barriers. Among those were wide-ranging reports of cardiotoxicity associated with HER2-targeting therapies in the community-based setting. “We were also faced with evolving changes in practice patterns and preferred neoadjuvant and adjuvant regimens by geographic areas and clinical settings,” Munster said. “There may be a strong influence of regimen selection by perceived or actual underlying cardiac risk factors in patients with HER2-positive tumors.”

Ultimately, they settled on a randomized double-blind placebo-controlled multicenter community-based clinical trial to be conducted in patients with early-stage HER2-positive breast cancer with a planned trastuzumab treatment of 1 year.

Patients included had an LVEF ≥50% by either echocardiography or multiple gated acquisition scan, a systolic blood pressure (SBP) ≥90 mm Hg, and a pulse rate ≥60 bpm at baseline. Patients with known past or present cardiac disease or those currently being treated with a beta blocker or ACE inhibitor were excluded.

Patients were randomized to placebo, 10 mg/day of lisinopril, or 10 mg/day of carvedilol started on day 1 of trastuzumab and continued for 52 weeks. The primary endpoint was the rate of cardiotoxicity during the 52 weeks of treatment with trastuzumab and in the year after its completion.

LVEF was measured at baseline and every 12 weeks. Patients who completed 52 weeks of trastuzumab and the study intervention were removed from their study intervention and were assessed for 1 more year. Patients who stopped their study intervention before reaching 52 weeks were discontinued from the study and LVEF was assessed every 6 months until 24 months following the start of the study.

Of the 468 patients enrolled, 250 completed the treatment phase and 193 came off study before the treatment phase was completed. A total of 443 patients entered the follow-up phase. Reasons to discontinue trastuzumab or the study intervention prior to 52 weeks included cardiotoxicity or toxicity from the treatment regimen or the study intervention.

Baseline characteristics were comparable between the 3 arms. At baseline, mean age was 51 years, mean LVEF was 63%, mean body mass index was 28 kg/m2, and mean SBP was 126 mm Hg. Some 86% of patients enrolled were white. Patients on an anthracycline (n = 189) were younger than those not on an anthracycline (n = 279) (mean, 48 vs 53 years) and had a lower mean SBP (120 vs 130 mm Hg), “supporting our worries that there may be a bias towards enrolling patients on an anthracycline versus not,” said Munster.

The interruption of trastuzumab for any reason was nearly twice as high in the placebo arm (26.3%) as that in the carvedilol (15.4%) and lisinopril (17.3%) arms (P = .01 for active intervention vs placebo) in the entire cohort, as well as in the anthracycline-treated cohort (placebo, 40.3%; carvedilol, 19.7%; lisinopril, 23.0%; P = .007 for active intervention vs placebo).

Toxicity by intervention was fairly limited with virtually no grade-3 toxicity. Lisinopril was associated with higher rates of fatigue (26% vs 18%), dizziness (20% vs 10%), cough (11% vs 7%), and hypotension (13% vs. 4%) than carvedilol.

Munster P, Krischer J, Tamura R, et al. A randomized community-based trial of an angiotensin converting enzyme inhibitor, lisinopril or a beta blocker, carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab. Presented at San Antonio Breast Cancer Symposium; December 5-7, 2018; San Antonio, Tx. Abstract GS5-01.