NO PROTECTION WITH CANDESARTAN FOR TRASTUZUMAB CARDIOTOXICITY

A tragedy in breast cancer occurs when the treatment works but damages the heart, leaving a cancer survivor with heart failure. But a new attempt at cardioprotection has failed.

The first trial testing the angiotensin II-receptor blocker candesartan (Atacand, AstraZeneca) found that it did not prevent or help neutralize the cardiotoxic effects of trastuzumab (Herceptin, Genentech) in patients with early breast cancer.

"The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer," conclude Annelies H. Boekhout, PhD, from the division of clinical pharmacology at the Netherlands Cancer Institute in Amsterdam, and colleagues.

The research was published online June 23 in JAMA Oncology.

The study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands. A total of 210 women with early breast cancer who tested positive for human epidermal growth factor receptor 2 (HER2) were enrolled. All patients received adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.

Mean age was 49 years and all participants were female. Patients were randomly assigned 1:1 to receive either candesartan 32 mg/day or placebo. This was given along with trastuzumab treatment and continued for 26 weeks after completion of trastuzumab.

Serial measurements of left ventricular ejection fraction (LVEF) — the primary cardiac end point — showed that there were 3.8% more cardiac events in the candesartan group than in the placebo group (P = .58).

The 2-year cumulative incidence of cardiac events was 0.28 in the candesartan group versus 0.16 in the placebo group (P = .56).

Twenty patients (19%) in the candesartan arm and 16 (16%) in the placebo arm met the primary outcome, defined as a 15% decline in LVEF or to less than 45%. This indicated no benefit of candesartan (P = .58), the team reported.

Bad Timing? 

Dr Boekhout and colleagues speculate that if candesartan treatment had been started at the same time as anthracycline and before trastuzumab, the results might have been different.

"Data suggest that starting an intervention sooner after initiation of cardiac damage occurs may result in better outcome," they comment.

In their study, patients with a history of congestive heart failure or baseline LVEF below 50% were excluded.

Instead, the study enrolled a total of 81% of patients who had a baseline LVEF value of 55% or more. "It is therefore possible that angiotensin receptor blockade as a preventive measure could have a more pronounced effect on trastuzumab-related damage in high-risk patient populations," the researchers comment.

Although questions remain, this study "heralds a new era of clinical trials in cardio-oncology," commented Ana Barac, MD, PhD, and Sandra M. Swain, MD, in an accompanying editorial.

Dr Barac is from the MedStar Heart and Vascular Institute at MedStar Washington Hospital Center in Washington, DC, and Dr Swain is from the Washington Cancer Institute at MedStar Washington Hospital Center.

The editorialists agreed that one of several possible explanations for the study's negative result may have been the timing of treatment. The 84-day gap between the initiation of anthracycline treatment and the initiation of concomitant candesartan and trastuzumab therapies may have limited candesartan's ability to counteract an ongoing cardiac injury process, they suggested.

The fact that the trial did not include "the population of greatest need who might reap the greatest benefit" may also have led to a negative result.

In future, studies that include patients with higher cardiovascular risk and use of a risk-based prevention approach might provide "a higher yield," they suggest. A number of trials, including the SAFE-HEaRt pilot trial in patients with mildly reduced LVEF, show promise, they noted.

Biomarker Associated With Reduced Risk?

The Dutch team also suggest that the ERBB2 germline Ala1170Pro single nucleotide polymorphism (formerly HER2 or HER2/neu) may be used to identify patients who are at increased risk for trastuzumab-related cardiotoxic effects. They found that the Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood for the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; P = .003).

These findings "demand prospective validation," the editorialists comment. However, they note that similar findings were made in another study, and the two together support a rationale for investigating this genotype "as a risk stratification tool to identify patients at risk for LV dysfunction during HER2 treatment," they add.