Trastuzumab-Induced Cardiotoxicity in Early Breast Cancer Patients: A Retrospective Study of Possible Risk and Protective Factors

Study Questions:

What are the risks and cardioprotective factors for cardiotoxicity caused by trastuzumab?

Methods:

This is a single-center institutional retrospective review of consecutive patients treated with adjuvant trastuzumab. Ninety percent of the patients received anthracyclines prior to trastuzumab. Cardiotoxicity was defined as absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or a LVEF <50% or the development of congestive heart failure (CHF) symptoms. Potential cardiac risk factors were assessed with logistic regression including hypertension, hypercholesterolemia, diabetes mellitus, smoking, cardiac ischemia, and history of chest radiation. Protective factors were assessed including beta-blocker (BB), angiotensin-converting enzyme inhibitor (ACEI), and/or angiotensin-receptor blocker (ARB) administration.

Results:

A total of 179 patients were assessed. The majority of patients enrolled were <59 years old with stage I or II nonmetastatic breast cancer. Seventy-eight cases of cardiotoxicity were found (44%; 95% confidence interval [CI], 37%-51%), as well as four cases of heart failure (2%; 95% CI, 0%-4%) classified as class III CHF by the New York Heart Association (NYHA) system. Fourteen patients stopped trastuzumab secondary to cardiotoxicity. None of the cardiovascular risk factors affected the incidence of cardiotoxicity. The only association was found with a cumulative dose of doxorubicin >240 mg/m2 or >500 mg/m2 of epirubicin, with a threefold increased risk of cardiotoxicity (odds ratio, 3.07; 95% CI, 1.29-7.27). Medication records were examined to assess if patients were already taking BBs or ACEI/ARBs for hypertension prior to starting the medication, or whether they were started as cardiac protectors. Forty-four percent of patients had no cardiovascular risk factors at baseline. Forty-two patients were being treated for hypertension prior to receiving trastuzumab: BBs (6), ACEI/ARBs (17), both (10), and other medications (9). Twenty-nine patients started empiric treatment: BBs (21), ACE/ARBs (6), and both (2) at the beginning of treatment. Fourteen patients stopped trastuzumab due to cardiotoxicity. No apparent protective effect was found in patients taking cardioprotective agents in the normotensive patients who started a BB or an ACEI/ARB.

Conclusions:

Cumulative anthracycline dose was associated with cardiotoxicity in breast cancer patients receiving trastuzumab. It is unclear whether cardioprotective agents may alter the incidence of cardiotoxicity.

Perspective:

Trastuzumab is a monoclonal antibody that targets human epidermal growth factor receptor-2 (HER-2) positive breast cancer cells. Approximately 20-30% of breast cancer patients overexpress HER-2/ErbB2 receptors and experience more aggressive tumors with lower survival rates. Treatment with trastuzumab significantly impacts time to progression and clinical survival, and is currently approved as first-line therapy for HER-2 positive metastatic breast cancer. HER receptors are involved in embryonic development and repair mechanisms of the heart, which when altered, may cause cardiac dysfunction. Trastuzumab generally presents with an asymptomatic decline in LV function, with some progressing to overt CHF. It is still unknown whether asymptomatic decline in LVEF in breast cancer patients causes meaningful consequences. Cardioprotective strategies with CHF medications have shown benefit in limited studies with higher dose anthracycline regimens with a “one hit model.” This study had a relatively low dose of anthracyclines with trastuzumab, a “two hit model.” Cardioprotective agents did not prevent events in this two hit model. Different mechanisms of cardiac injury may be responsible. More randomized studies need to be completed to evaluate the mechanisms of these cardiotoxic agents and possible cardioprotective strategies. As molecular understanding of these cardiotoxic agents improves and imaging technology advances, certain high-risk subgroups may benefit from cardioprotective agents.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Homozygous Familial Hypercholesterolemia, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension, Smoking

Keywords: Breast Neoplasms, Risk Factors, Receptor, erbB-2, Anthracyclines, Hypercholesterolemia, New York, Smoking, Heart Diseases, Incidence, Survival Rate, Cardiotoxins, Heart Failure, Hypertension, Diabetes Mellitus, Cardiotonic Agents


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