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Literature and guidelines often cite cardiotoxicity rates of 15-20% associated with trastuzumab in patients with HER2-positive breast cancer, primarily on the basis of early trials. A closer look at the data, however, suggests the risk depends on anthracycline exposure.

For patients not treated with an anthracycline, the risk is comparable to that of the general population, noted Haoyi Zheng, MD, PhD, of Saint Francis Hospital & Heart Center in Roslyn, New York, and colleagues, writing in a review in .

"This review critically analyzes the incidence of trastuzumab-induced left ventricular systolic dysfunction and congestive heart failure (CHF), distinguishing between cases with and without prior anthracycline exposure," the team said. "It highlights the fact that the elevated risk of trastuzumab-induced cardiotoxicity is closely associated with prior anthracycline exposure. In addition, we reevaluate the appropriateness of the existing recommendations and propose a more tailored cardiac monitoring protocol, with an emphasis on anthracycline recipients."

Zheng discussed his group's findings and recommendations in the following interview.

What prompted you to undertake this study?

Zheng: High incidence rates of cardiotoxicity including heart failure were reported in the early oncology studies and have been extensively cited. Current cardio-oncology guidelines mandate three monthly cardiac monitoring, including echocardiography, BNP [B-type natriuretic peptide], and troponin tests for all patients treated with trastuzumab, regardless of their risk categories or prior anthracycline use. However, in clinical practice, trastuzumab-induced cardiotoxicity is uncommon and HF is rare among patients without prior anthracycline exposure.

What did you discover about anthracycline exposure and cardiotoxicity risk in patients treated with trastuzumab?

Zheng: Our comprehensive review showed that trastuzumab-induced cardiotoxicity is notably linked with prior anthracycline use. High incidences of cardiac dysfunction or HF were reported primarily when anthracycline was used concurrently with trastuzumab or at high cumulative doses.

In contrast, cardiotoxicity in patients treated with trastuzumab without anthracycline is very low and comparable to that observed in the age-matched general population. These findings are consistent with clinical observations in practice.

What is known about the mechanisms of trastuzumab-induced toxicity and the role of anthracycline?

Zheng: Trastuzumab disrupts HER2-mediated signaling pathways -- crucial for both tumor suppression and cardiac protection. By binding HER2 on cardiomyocytes, trastuzumab inhibits protective cardiac responses to stress, potentially exacerbating cardiac injury from anthracyclines. This synergy between trastuzumab and anthracyclines leads to increased cardiotoxicity -- particularly noted when anthracyclines are concurrently used with trastuzumab.

What are your proposed new recommendations for surveillance?

Zheng: We propose a modified, risk-stratified monitoring protocol: biannual or annual evaluations for patients at low to moderate risk, and more frequent assessments for those at high or very high risk.

For low-risk patients without prior anthracycline exposure, a baseline echocardiogram may be sufficient. This approach aims to reduce the patient burden and enhance cost-effectiveness, especially in high-cost healthcare settings like the U.S.

Is there anything else you want to make sure oncologists understand about your study or this topic?

Zheng: The key takeaways for oncologists are as follows:

• The high incidence of trastuzumab-induced cardiotoxicity is primarily associated with anthracycline use. For patients without prior anthracycline exposure, the incidence of left ventricular dysfunction and HF is very low and comparable to that in the general population.

• Most cases of trastuzumab-induced cardiotoxicity are transient or reversible.

• We recommend tailoring cardiac surveillance based on a patient's anthracycline exposure and risk level, advocating for less intensive monitoring for low-risk patients.

• Efforts and resources should be directed to prioritize strategies that prevent and mitigate anthracycline-induced cardiotoxicity when such chemotherapy is chosen prior to the treatment of trastuzumab.

Read the review here.