A meta-analysis of cardiac toxicity of concurrent epirubicin and trastuzumab in early breast cancer.

person Minghan Yang National Taiwan University Hospital Hsinchu branch, Hsinchu City, Taiwan info_outline Minghan Yang, Chiun-Sheng Huang, Dwan-Ying Chang, I-Chun Chen, Ching-Hung Lin, Yen-Shen Lu

Authors person Minghan Yang National Taiwan University Hospital Hsinchu branch, Hsinchu City, Taiwan info_outline Minghan Yang, Chiun-Sheng Huang, Dwan-Ying Chang, I-Chun Chen, Ching-Hung Lin, Yen-Shen Lu Organizations National Taiwan University Hospital Hsinchu branch, Hsinchu City, Taiwan, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taipei, Taiwan, National Taiwan University Hospital, Taipei, Taiwan, National Taiwan University Cancer Center, Taipei, Taiwan Abstract Disclosures Research Funding No funding received None. Background: The concurrent use of doxorubicin and trastuzumab has been limited due to the increased risk of cardiac toxicity. Epirubicin is a less cardiotoxic alternative to doxorubicin, and the change in ejection fraction occurs until its cumulative dose doubles that with doxorubicin. This study aims to evaluate the cardiotoxicity and pathological complete response (pCR) rate associated with concurrent usage of epirubicin and trastuzumab in patients with HER2 positive early breast cancers (EBC). Methods: A literature search was conducted on NCBI/PubMed, and Cochrane database for phase II or III randomized controlled trials of concurrent use of epirubicin and trastuzumab in HER2 positive EBC between January 1, 2000 and February 28, 2021.The definition of adverse cardiac events varied among these trials, including changes in left ventricular systolic function and clinical heart failure. To compare the risk of cardiotoxicity and the odds of pCR rate between concurrent and non-concurrent regimens, a meta-regression analysis utilizing fixed-effects and mixed-effects linear models was conducted to investigate the relationship between various covariates. Results: Seven trials containing concurrent use of epirubicin and trastuzumab involving 1797 patients were analyzed. All of them are neoadjuvant studies. The median cumulative dose of epirubicin used was 300mg/m 2 and there were a total of 96 reported cardiac adverse events. The concurrent use of epirubicin and trastuzumab did not result in a statistically significant increase in cardiotoxicity compared to non-concurrent regimens (risk ratio = 1.18, 95% CI: 0.68-2.05). Meanwhile, there was a significant increase in pCR rate with the concurrent regimens (odds ratio = 1.48, 95% CI: 1.04-2.12). Mixed-effects meta-regression analysis showed that in trials with higher proportion of hormone receptor-positive EBC patients, the risk ratio of cardiotoxicity significantly increased with concurrent regimens and pathological complete response rate became less significant. Conclusions: The concurrent use of a limited dose of epirubicin and trastuzumab demonstrated a positive impact on pCR rate without a significant increase in cardiotoxicity. Further research is necessary to fully comprehend the long-term safety profile in individuals with metastatic breast cancer. Characteristics of selected trials. Study Name Epirubicin cumulative dose (mg/m 2 ) Median Follow up (months) Definition of ACE Buzdar MDACC 2005 300 20 LVEF decrease >10% CHER-LOB combo 300 6 LVSD >gr 1 GeparQuinto GBG 44 360 55 Gr1-4 congestive heart failure TRYPHAENA seq 300 61 All grade LVSD TRYPHAENA non-anthra 300 61 All grade LVSD ACOSOG Z1041 300 5.52 LVSD EORTC 10054 300 4.14 Absolute drop ≥ 15% in LVEF from baseline TRAIN-2 270 19 LVEF decline ≥10% AND LVEF < 50% Abbreviations: ACE adverse cardiac event; LVEF left ventricular ejection fraction; LVSD left ventricular systolic dysfunction.