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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02273973.

Keywords: HER2-positive breast cancer; cardiotoxicity; meta-analysis; trastuzumab.

Conflict of interest statement

Competing interests: DE: funding for his fellowship: Novartis. Research grant for his institute: Roche/GNE, Radius, AstraZeneca, Lilly, MSD, Novartis, Synthon, Servier and Pfizer. MAF: research grant for her institute: Roche/GNE, Radius, AstraZeneca, Lilly, MSD, Novartis, Synthon, Servier and Pfizer. NFP: honoraria: MundiPharma, AstraZeneca; travel grants: Novartis, Astrazeneca, MundiPharma, Roche. MB: research grant for her institute: Roche/GNE, Radius, AstraZeneca, Lilly, MSD, Novartis, Synthon, Servier and Pfizer. EdA: honoraria and advisory board: Roche/GNE, Novartis, Seatle Genetics; travel grants: Roche/GNE, GSK/Novartis; co-principal investigator of the LORELEI trial (NCT02273973). Research grant for his institute: Roche/GNE, AstraZeneca, Novartis and Servier.

© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.

Figures

Figure 1

Flowchart diagram of study selection, showing that from an initially retrieved 814 studies from PubMed/Medline, six were selected for this meta-analysis.

Figure 2

RoB assessment of the five domains (bias arising from the randomisation process; due to deviations from intended interventions; due to missing outcome data; bias in measurement of the outcome; and bias in selection of the reported result) per trial, indicating that some concerns always arose from the measurement of the cardiac outcome. RoB, risk of Bias.

Figure 3

Forest plots in log scale for each cardiac outcome. The size of the squares represents the weight of the studies. Error bars represents 95% CIs. The vertical black line sets the 1, and the vertical red line sets the overall pOR. The blue diamonds indicates the overall pOR, whereas the yellow ones indicate the subgroup pORs, all with their respective 95% CIs. A pORs higher than 1 indicate that treatment with trastuzumab for 12 months increases the rate of a given cardiac outcome compared with a shorter trastuzumab regimen, with statistical significance seen whenever the CI does not cross the 1. (A) Random effects model with inverse variance weighting meta-analysis of clinical cardiac dysfunction associated with 12 months of trastuzumab versus short trastuzumab regimens, including 5 studies/11 250 patients, showing a pOR=1.90 (95% CI 1.37 to 2.64; Z-value=3.84; p value 2=65.7%). Subgroup analysis shows for the 12 months versus 6 months comparison a pOR=1.57 (95% CI 1.30 to 1.90; Z-value=4.67; p<0.001; I2=5.7%) and for the 12 months versus 9 weeks comparison a pOR=2.59 (95% CI 1.52 to 4.40; Z-value=3.50; p<0.001; I2=58.1%). (B) Meta-analysis of low LVEF associated with 12 months of trastuzumab versus short trastuzumab regimens including two studies (7342 patients) showing a pOR=1.45 (95% CI 1.19 to 1.75; Z-value=3.74; p<0.001; I2=11.9%). (C) Meta-analysis of congestive heart failure associated with 12 months of trastuzumab versus short trastuzumab regimens including three studies (5788 patients) showing a pOR=1.55 (95% CI 1.00 to 2.42; Z-value=1.95; p=0.052; I2=0.0%). Subgroup analysis shows for the 12 months versus 9–12 weeks comparison a pOR=1.68 (95% CI 1.01 to 2.81; Z-value=1.99; p=0.047; I2=0.0%). LVEF, left ventricular ejection fraction; pOR, pooled OR.