Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer

Trastuzumab prolongs survival in women with HER2-positive breast cancer, but may increase the risk of heart disease. The occurrence of severe cardiotoxicity, however, is not defined in real-life settings. We performed a meta-analysis of clinical trials and cohort studies to estimate the frequency of cardiotoxicities following trastuzumab treatment. We searched MEDLINE, EMBASE, and the Cochrane Library (1996-January 2014). The primary outcome was the frequency of severe cardiotoxicities up to 3-years after trastuzumab initiation. Among 58 studies (29,598 patients), severe cardiotoxicity occurred in 3.00% (95% CI 2.41-3.64), 2.62% (95% CI 1.97-3.35), and 3.14% (95% CI 2.12-4.37) of overall, early (EBC) and metastatic (MBC) breast cancer patients, respectively. In EBC, the proportion increased from 2.40% at the first year to a plateau of approximately 3% after the second year. In MBC, the proportion increased from 3.00 to 3.68% when trastuzumab was used as first line or further lines of therapy, respectively. In EBC, cardiotoxicity occurred in 2.90% of patients treated with taxanes and anthracyclines compared to 0.92% in patients treated with taxanes without anthracyclines. The occurrence of cardiotoxicity varied according to age, increasing from 2.31% in individuals <50 years, to 3.46% in those 50-59 years, to 4.91% in those >60 years of age. Cardiotoxicity was higher in smokers (5.3%), dyslipidemic patients (3.9%), BMI ≥25 (6.5%), diabetes (6.2%), hypertension (5.5%), or positive history of cardiac disease (19.1%). RCTs consistently report lower cardiac toxicity rates than observational studies (EBC: 1.7 versus 3.2; MBC: 2.8 versus 4.4). Following trastuzumab initiation, approximately three in 100 patients develop severe cardiotoxicity after 2 years. Patients enrolled in cohort studies, who more closely reflect women treated for breast cancer in real-life settings compared to RCTs, are at higher risk of developing cardiac events.