Candesartan Does Not Prevent Trastuzumab-Related Cardiotoxicity

Trastuzumab-related cardiotoxic effects are not reduced with the concurrent use of the angiotensin II–receptor blocker candesartan versus placebo in patients with early-stage HER2-positive breast cancer

medwireNews: Dutch researchers find no cardioprotective benefits of concomitant treatment with the angiotensin II–receptor blocker candesartan in HER2-positive breast cancer patients receiving adjuvant trastuzumab after anthracycline therapy.

Cardiac events – defined as a greater than 15% decline from baseline in left ventricular ejection fraction (LVEF) or a decrease below 45% – occurred in 20 of 103 patients given oral candesartan alongside trastuzumab and in 16 of 103 participants given placebo, equating to a 3.8% increase in the candesartan group.

And the 2-year cumulative incidence of cardiac events was also higher in the candesartan versus the placebo arm, at 0.28 and 0.16, respectively.

The concomitant use of candesartan and trastuzumab therefore does not prevent or alleviate the development of trastuzumab-related cardiac damage, as measured by serial LVEF measurements, the researchers say in JAMA Oncology.

And they add: “Consequently, our study does not support a role for the use of this drug as scheduled in conjunction with trastuzumab in this population of patients with breast cancer.”

The double-blind trial comprised 206 women with early-stage HER2-positive breast cancer who were scheduled to receive adjuvant treatment with an anthracycline-based regimen followed by trastuzumab for 1 year. Participants were randomly assigned to receive either oral candesartan 32 mg/day, starting on the day trastuzumab treatment began and continuing until 26 weeks after completion, or placebo.

Ana Barac and Sandra Swain, both from MedStar Washington Hospital Center in DC, USA, say in an linked commentary that the late timing of candesartan initiation could be one reason for the negative findings.

“Candesartan and trastuzumab therapies were started concomitantly a median of 84 days after the initiation of anthracycline treatment, raising the possibility that this lag limited candesartan’s ability to counteract an ongoing process of cardiac injury”, they write.

The commentators think that another limitation is the exclusion of high-risk patients, who “represent the population of greatest need (ie, are likely to not otherwise receive trastuzumab treatment) [and] who might reap the greatest benefit.”

Researcher Jan Schellens, from the Netherlands Cancer Institute in Amsterdam, and fellow authors acknowledge these limitations and add that the use of the “rather insensitive” parameter LVEF could also account for the lack of effect.

They continue: “More sensitive parameters that estimate subclinical changes such as tissue velocities, strain, and diastolic function were not assessed in this study, meaning that smaller toxic effects of trastuzumab may not have been detected by changes in LVEF.”

References

Boekhout AH, Gietema JA, Kerklaan BM, et al. Angiotensin II–receptor inhibition with candesartan to prevent trastuzumab-related cardiotoxic effects in patients with early breast cancer. A randomized clinical trial. JAMA Oncol 2016; Advance online publication 23 June. doi: doi:10.1001/jamaoncol.2016.1726

Barac A, Swain SM. Cardiac protection in HER2-targeted treatment. How should we measure new strategies?JAMA Oncol 2016; Advance online publication 23 June. doi: 10.1001/jamaoncol.2016.0283

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