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Study Summary

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This multicenter, randomized, placebo-controlled trial evaluated whether the administration of either the angiotensin-converting enzyme (ACE) inhibitor lisinopril or the cardiospecific β-blocker carvedilol prevented cardiotoxicity in 468 patients with HER2+ breast cancer and normal left ventricular (LV) function at baseline who were treated with adjuvant trastuzumab, with or without anthracyclines. Rates of cardiotoxicity — defined as an absolute decrease in LV ejection fraction (LVEF) of ≥10% or a decrease of ≥5% to an LVEF of <50% — were similar in trastuzumab-alone treated HER2+ breast cancer patients across the three arms with 32% observed in the placebo group, 29% in the carvedilol group and 30% in the lisinopril group. There was no difference in the number of treatment interruptions. In patients treated with both trastuzumab and an anthracycline, however, lisinopril and carvedilol were each associated with reduced rates of cardiotoxicity compared to placebo (lisinopril: HR 0.53, 95% CI 0.30, 0.94, p = 0.015; carvedilol: HR 0.49, 95% CI 0.27, 0.89, p = 0.009) (see accompanying Hurst’s Central Illustration).

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Reduction of Cardiotoxicity Associated with Trastuzumab and Anthracycline

Commentary

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Study Strengths: This study attempts to fill an important knowledge gap in cardio-oncology in a randomized, double blinded trial conducted across multiple centers. In trastuzumab-alone treated HER2+ breast cancer patients, the incidence of cardiotoxicity is approximately 30%, uninfluenced by prophylactic treatment with a beta blocker or ACE inhibitor over one year. The increased incidence to 47% in those who are concomitantly treated with an anthracycline is mitigated by treatment with either an ACE inhibitor or carvedilol.

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Study Limitations: It is well known that patients at highest risk for trastuzumab-related cardiac dysfunction are those treated with concomitantly with anthracyclines. It was in this subgroup of trial patients that both lisinopril and carvedilol individually were effective in preventing the cardiotoxic side effect of worsening LV function. The follow up period of only 1 year is relatively limited, not allowing for conclusions over a longer follow up about the potential for reversibility of cardiotoxicity.

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Next Steps/Clinical Perspective: It is possible that pre-treatment with both ACE inhibitor and beta blocker, as is standard of care for the treatment of both asymptomatic and symptomatic LV dysfunction, may lead to the most benefit in patients with trastuzamab-related cardiac dysfunction treated concomitantly with anthracyclines. Such an approach with dual treatment warrants further study. Additionally, it would be worthwhile to investigate further whether cardiotoxicity associated with other chemotherapeutic agents, such as 5-fluoruracil, could be avoided by targeted cardioprotective medications.

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