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.