Cardiotoxicity of trastuzumab given for 12 months compared to shorter treatment periods: a systematic review and meta-analysis of six clinical trials

Background: Treatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and toxicities. One of the strategies pursued is decreasing trastuzumab treatment duration, with mixed results thus far. Trastuzumab-associated cardiotoxicity, however, may be more frequent with 12 months of trastuzumab compared with shorter treatment lengths. Therefore, we have conducted a meta-analysis to address this question.

Materials and methods: A meta-analysis of trials testing 12 months of adjuvant trastuzumab versus shorter regimens, reporting cardiac outcomes in patients with HER2-positive BC was performed with the random effects model with inverse variance weighting.

Results: Clinical cardiac dysfunction associated with 12 months of trastuzumab versus shorter trastuzumab regimens, including 11 250 patients, showed a pooled OR (pOR) of 1.90 (95% CI 1.37 to 2.64; p value <0.001; I²=65.7%); in the subgroup comparison of 12 versus 6 months, the pOR was 1.57 (95% CI 1.30 to 1.90; p<0.001; I²=5.7%). pOR for low left ventricular ejection fraction was 1.45 (95% CI 1.19 to 1.75; p<0.001; I²=11.9%), 1.55 (95% CI 1.00 to 2.42; p=0.052; I²=0.0%) for congestive heart failure and 3.70 (95% CI 0.27 to 51.60; p=0.33; I²=78.8%) for premature trastuzumab discontinuation due to cardiotoxicity for 12 months versus shorter trastuzumab regimens. Funnel plot analyses indicated a low risk of publication bias.

Conclusions: Compared to shorter treatment durations, there is sufficient evidence that 12 months of trastuzumab yields higher odds for the occurrence of relevant cardiac events. An individual patient-level data meta-analysis is needed in order to provide adequate data on risk factors for cardiotoxicity.