SAN ANTONIO — The frequency of cardiotoxicity declined significantly with prophylactic antihypertensive medication for patients with early HER2-positive breast cancer treated with anthracycline-containing chemotherapy, but not trastuzumab (Herceptin), a randomized trial showed.
Although the trial did not meet the primary endpoint of cardiotoxicity in all treated patients, the incidence decreased by about half in patients who received anthracycline-containing adjuvant or neoadjuvant therapy and cardiovascular prophylaxis with a beta-blocker or angiotensin converting enzyme (ACE) inhibitor. Patients who received trastuzumab (Herceptin) without an anthracycline had a similar rate of cardiotoxicity whether they received one of the antihypertensive drugs or placebo, reported Pamela M. Munster, MD, of the University of California San Francisco, and colleagues.
“Our primary endpoint was similar for all cohorts,” Munster said at the San Antonio Breast Cancer Symposium (SABCS). “However, cardiotoxicity-free survival [CFS versus placebo] is comparable, with a hazard ratio of 0.71 for carvedilol and 0.74 for lisinopril, with a nonsignificant P-value.”
“Cardiotoxicity-free survival was longer with carvedilol or lisinopril than with placebo in patients who received anthracycline-containing regimens, but no differences were seen with the non-anthracycline regimens,” she added. “In patients with HER2-positive breast cancer treated with trastuzumab and anthracyclines, the addition of lisinopril or carvedilol should be considered.”
Two separate studies presented at the 2018 American College of Cardiology meeting in Orlando reported that cardiotoxicity from breast cancer drugs was about half as likely with prophylactic use of heart drugs in higher-risk patients, as well as an early trend for less cardiac damage.
‘Nice,’ but Not Enough?
The results are “very nice” but did not address the key issue for patients with breast cancer treated with anthracyclines and/or trastuzumab, said Steven Vogl, MD, a medical oncologist who practices in the Bronx in New York City.
“You’ve shown that you have fewer decreases in [left ventricular ejection fraction, LVEF], so you can give more trastuzumab, but did these interventions prevent dyspnea, heart failure — something that bothered the patient?” Vogl asked.
Acknowledging that his point was well taken, Munster said investigators struggled over the selection of the primary endpoint and ultimately decided that LVEF was more practical to assess than “subjective symptoms” in a community-based clinical trial involving 127 practices across the U.S.
“We will now analyze, do we in the long term actually have symptomatic changes, or is it just left ventricular ejection fraction?” she added.
Vogl continued, “There is considerable controversy about whether longer trastuzumab is better than shorter, but the bulk of the data suggest, at least for patients with the worse prognosis — positive nodes or bigger tumors — longer is better. In that situation, if that’s correct, then it’s good to give these [cardiovascular drugs] because then you get to give longer trastuzumab, regardless of whether they prevent symptoms or severe congestive heart failure — if you’re going to do the echocardiograms.”
Background and Results
Adjuvant trastuzumab remains standard of care for patients with early-stage HER2-positive breast cancer. The drug’s potential for cardiotoxicity requires monitoring and often leads to dose interruption and/or discontinuation, Munster noted. Results of several small studies suggested that treatment-induced cardiotoxicity might be prevented by prophylaxis with an ACE inhibitor or beta blocker, which are widely used to treat hypertension and heart failure.
Designing a randomized, multicenter, community-based trial of cardiovascular prevention posed several challenges, she continued. Reports about the frequency and severity of cardiotoxicity with HER2-targeted regimens varied widely. Evolving changes in practice pattern preferences for adjuvant neoadjuvant regimens have led to variation by geography and practice setting. Selection of regimens might be influenced by perceived or actual cardiac risk factors of patients with HER2-positive tumors.
Ultimately, investigators designed a randomized, double-blind, placebo controlled community-based trial involving patients with early HER2-positive breast cancer treated with trastuzumab. The design included stratification by use of anthracycline-containing chemotherapy. Patients were randomized to lisinopril (Zestril), carvedilol (Coreg and Coreg CR), or placebo, beginning day 1 of trastuzumab treatment and continuing for 52 weeks.
The trial had a primary endpoint of cardiotoxicity, defined as an absolute 10% decrease in LVEF from baseline or a 5% absolute decrease if LVEF fell below 50%. Eligible patients had early HER2-positive breast cancer and planned treatment with trastuzumab for 1 year, adjuvant or neoadjuvant cytotoxic therapy, LVEF ≥50, systolic blood pressure ≥90 mm Hg, and pulse ≥60 bpm.
Investigators randomized 468 patients 1:1:1 to placebo, lisinopril 10 mg, or carvedilol 10 mg. A total of 193 patients discontinued treatment before 52 weeks, including 86 patients who had a decrease in cardiac function. The patients remained in follow-up and 181 were eligible for efficacy analysis. Munster said 189 of 468 patients received anthracycline-containing chemotherapy in addition to trastuzumab.
The primary analysis showed similar rates of cardiotoxicity for the three treatment arms: 32% for placebo, 29% for carvedilol, and 30% for lisinopril. The carvedilol and lisinopril groups had nonsignificant trends toward better CFS, but neither difference achieved statistical significance:
- Carvedilol: HR 0.71 (95% CI 0.47-1.07, P=0.052)
- Lisinopril: HR 0.74 (95% CI 0.48-1.12, P=0.076)
The prespecified analysis by anthracycline use showed significant advantages for treatment with either cardiovascular agent versus placebo. Patients who received anthracycline-containing chemotherapy in addition to trastuzumab had a 51% reduction in the CFS hazard with carvedilol (95% CI 0.27-0.89, P=0.009) and a 47% reduction with lisinopril (95% CI 0.30-0.94, P=0.015). Cardiovascular prophylaxis did not affect CFS in the patients who received trastuzumab without an anthracycline.
Interruption of trastuzumab therapy occurred significantly more often in the placebo group (26.3% vs 15.4% with carvedilol and 17.3% with lisinopril, P=0.01). Anthracycline use accounted for most of the difference, as trastuzumab interruption occurred in 40.3% of the placebo group versus 19.7% of the carvedilol group and 23.0% of the lisinopril group.
Adverse events associated with carvedilol and lisinopril were consistent with their known safety profiles. Fatigue, dizziness, headache, cough, and hypertension were more common with lisinopril than with carvedilol.
SABCS session moderator Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology in Milan, called the findings “provocative and potentially practice changing.”