Trastuzumab’s product labeling carries a black box warning about the potential for the development of drug-induced cardiomyopathy in patients receiving the biological for breast cancer (BC). The prescribing information for trastuzumab recommends assessing left ventricular ejection fraction (LVEF) at baseline, every 3 months during and upon completion of treatment, repeating LVEF measurements at 4-week intervals if the medication is withheld because of the appearance of the adverse cardiac event, and checking LVEF every 6 months for at least 2 years following the completion of trastuzumab adjunctive therapy. However, guidelines are less clear on how to manage patients on continuous trastuzumab for metastatic BC (MBC).
To help answer this question, researchers from the Netherlands Cancer Registry analyzed data from eight Dutch hospitals from between January 2000 to December 2014 of patients with HER2-positive MBC who received >1 cycle of trastuzumab-based treatment. Exclusion criteria for this observational cohort study included lack of a baseline LVEF measurement within 30 days of the initiation of trastuzumab, baseline LVEF <50%, no follow-up LVEF measurement, or incomplete clinical data.
Nonsevere + severe cardiotoxicity and severe cardiotoxicity was defined based on guidelines of the European Society of Cardiology and the European Society of Medical Oncology, respectively. Nonsevere + severe cardiotoxicity referred to a LVEF decline of >10% points from baseline and LVEF <50% measured with a multigated acquisition (MUGA) scan or decline from good/normal cardiac function to at least mild cardiac dysfunction and at least mild cardiac dysfunction measured by an echocardiogram if a MUGA scan was not available.
Declines on a MUGA scan could be followed by an echocardiography to assess for the presence of false-negative low LVEF measurements if there was uncertainty about the results. Severe cardiotoxicity was defined as a LVEF <40% as measured by a MUGA scan or moderate or severe cardiac dysfunction as determined by echocardiography if a MUGA scan was not available.
Nonsevere caridiotoxicity was deemed to occur if the LVEF was <50% but >40% or mild cardiac dysfunction was present as determined by echocardiography. Cardiotoxicity from prior treatment was defined as a LVEF decline >10% points to a LVEF <50% during neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline. Patient-specific variables included age, body mass index, hypertension, diabetes status, smoking history, history of cardiovascular disease, baseline LVEF <60%, occurrence of cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline, prior cumulative anthracycline exposure, and radiation exposure to the breast.
Reversibility of cardiotoxicity was broken down into reversible, partially reversible, or irreversible based on whether the there was any LVEF increase to a value <5% below baseline, any absolute LVEF increase >10% from the nadir and to a value >5% below baseline, and if there was any absolute LVEF increase <10% from nadir and a value >5% below baseline, respectively.
The yearly incidence of cardiotoxicity was assessed. After the occurrence of an event, the patient was no longer at risk for that type of cardiotoxicity.
A total of 429 patients were eligible for analysis (mean age: 54 years). Almost three quarters (72%) had metachronous distant metastases and a little over a one-quarter (28%) had synchronous distant metastases. Patients were followed for cardiotoxicity for a median of 15 months with a median frequency of LVEF measurements of four per year. The median overall survival for all patients was 42 months.
The total follow-up incidence of nonsevere + severe cardiotoxicity was 22% with 11.7% of cases occurring in the first year of trastuzumab therapy. This decreased to 9.1% in the second year and 3.6% by Year 6. Cardiotoxicity, if present, occurred within 11 months of initiating therapy with the biological agent.
Only 6% of patients developed severe cardiotoxicity. The incidence following the first year of treatment was 2.8% and hovered around 2% thereafter (1.9% in Year 2 to 2.4% in Year 6). The median time for this cardiac event to occur was 10 months.
An examination of risk factors revealed that BMI >30 kg/m2 (adjusted hazard ratio (aHR) 2.16), smoking (aHR 1.73), and cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracyclines (aHR 4.48) were independent risk factors for nonsevere + severe cardiotoxicity. Independent risk factors for severe cardiotoxicity included smoking (aHR 6.15), baseline LVEF <60% (aHR 7.64), and cardiotoxicity during prior neoadjuvant/adjuvant treatment with trastuzumab and/or anthracycline therapy (aHR 5.60).
Examining data from all patients according to risk status, 56.2% had no risk factors for cardiotoxicity, 35.4% had one to two risk factors, and 8.4% had three or more risk factors. The cumulative incidence for both nonsevere + severe cardiotoxicity and severe cardiotoxicity increased with the increase in the number of risk factors. Patients with no risk factor for severe cardiotoxicity had a cumulative incidence of 3.1% after a total follow-up of 4 years. A total of 69 patients had developed nonsevere + severe cardiotoxicity to nonsevere cardiotoxicity and 25 patients had developed severe cardiotoxicity. Data were available for analyses in only 58 and 16 patients, respectively.
In the total group, the LVEF decline was reversible in 59% (58 patients) with nonsevere cardiotoxicity but in only 35% (6 patients) of those with severe cardiotoxicity. Fifteen patients in the nonsevere cardiotoxicity group discontinued treatment with trastuzumab for at least one cycle. LVEF was restored in 57%, partially reversed in 14%, and remained irreversible in 29% in this group. Among the 43 patients with nonsevere cardiotoxicity who continued treatment, 56% had normalization of their LVEF, 15% had a partial improvement in LVEF, and for 29% the drop in LVEF remained irreversible. Almost one-quarter (23%) of those developing nonsevere cardiotoxicity had cardiac symptoms, which included shortness of breath or angina pectoris.
For those with severe cardiotoxicity, among the 19 patients who discontinued therapy, LVEF decline reversed in 40% but only partially reversed or remained irreversible in 30% of patients. Among the six patients with severe cardiomyopathy who continued trastuzumab, LVEF decline was reversible in 33%, partially reversible in 50%, and irreversible in 17%. Unlike in patients with nonsevere cardiotoxicity, 72% of those with severe-toxicity manifested cardiac symptoms.
The authors concluded that the cumulative incidence of severe cardiotoxicity was low in nonsmoking patients with a baseline LVEF >60% who had no cardiotoxicity during prior neoadjuvant/adjuvant therapy with trastuzumab and/or anthracycline after 4 years of trastuzumab. It advises against the use of serial cardiac monitoring in this low-risk population.
This study provides a monitoring plan for pharmacists who monitor patients with MBC who are receiving long-term trastuzumab therapy.
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