Introduction
During the past decades, the increased knowledge of biological mechanisms involving tumor proliferation and progression has led to the introduction of novel approaches for the treatment of cancer. The epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases (TKIs) is one such therapeutic target, which is overexpressed or mutated in multiple cancers[1, 2]. Unlike other members of EGFR family, HER2/ErbB2 is a non-ligand-binding member of this family and exerts its activity through heterodimerization with other EGFR family members(EGFR, HER3,HER4)[3, 4]. And HER2 overexpression could also lead to HER2 dimerization and constitutive activation in the absence of ligand. Initially, HER2 overexpression is found in approximately 15-20% of breast cancer[5], then its overexpression was also detected in a subsets of many other cancer types, such as gastric[6], lung[7] or colorectal cancer[8]. In the last two decades, the introduction of monoclonal antibodies (MoAbs), TKIs or antibody-drug conjugates, which directly targets HER2 gene, has impressively improved the outcomes of HER-2 positive breast cancer patient in all disease stages[9-11]. Subsequently, the addition of anti-HER2 MoAbs to chemotherapy in HER-2 positive locally advanced gastric or gastro-oesophageal junction (GEJ) cancer also significantly improve overall survival. Currently, routine assessment of HER2 status in these tumors is mandatory, and the use of anti-HER2 agents have become a standard treatment for in HER-2 positive breast or gastric or GEJ cancer.
However, nearly all patients with metastatic HER2-positive breast cancer or gastric or GEJ cancer would eventually progress on anti-HER2 therapy due to de novo or acquired resistance, potentially due to incomplete blockade of HER2 pathway. Therefore, inhibiting the HER2 signaling pathway more effectively with dual blockade approaches by using improved anti-HER2 therapies has been extensively investigated in both breast cancer and gastric or GEJ cancer, and dual HER2 blockade shows promising results in HER-2 positive breast cancer. Nevertheless, with the increasing use of dual HER2 blockade, particularly in the curative adjuvant setting, concerns regarding cardiac toxicities associated with dual anti-HER2 treatment in breast cancer patients has been increased. Therefore, there is an urgent need to clearly determine the overall incidence and risk of cardiac toxicities associated with dual HER2 blockade. Prior to the present study, Valachis A[12]. performed a meta-analysis to investigate the risk of cardiac toxicities related to dual HER2 blockade in breast cancer, and found that cardiac toxicities in anti-HER2 combination therapy was comparable to that of anti-HER2 monotherapy[12]. But the sample size in that study are relative small, and most of the included studies have updated cardiac toxicities data. In addition, more randomized controlled trials assessing efficacy and toxicities of dual HER2 blockade in breast cancer have been conducted since then. As a result, we perform the present study to comprehensively investigate the incidence and risk of cardiac toxicities associated with dual HER-2 blockade in breast cancer when compared to anti-HER2 monotherapy by using a meta-analysis.