In HER2-positive advanced breast cancers, trastuzumab plus taxanes are one of the most widely used options in first-line treatment . However, not all patients will initially respond, and for those who respond to treatment, resistance will inevitably develop over time . Besides, trastuzumab has lower permeability across the blood-brain barrier, so its benefits are mainly due to better control of extracranial disease [36–38], which is sufficient for patients with HER2-positive brain metastases reduced  and more severe cardiotoxicity . Based on its resistance and cardiotoxicity, pertuzumab makes up for this limitation. Studies have shown that compared with single-anti-HER2-targeting treatment, dual-anti-HER2-targeting drugs increase the number of patients who achieve complete pathological remission [15, 41] and could significantly reduce previously generated cardiotoxicity. However, a study by Urruticoechea et al.  showed that the addition of pertuzumab to trastuzumab and capecitabine did not significantly improve PFS as assessed by independent review agencies. It is that the use of this drug is also controversial. Therefore, there is currently no evident and effective treatment for HER2-positive metastatic breast cancer. This study attempts to start with the addition of an anti-HER2-targeting drug, to explore the current controversial issues in the clinic, for new clinical ideas.
Combining with subgroup analysis, we found that the efficiency of single-anti-HER2-targeting drug was excellent for therapies without anti-HER2-targeting drugs. Moreover, the efficacy of dual-anti-HER2-targeting drugs was superior to single-anti-HER2-targeting drug. The results of this study have caused us great interest. The conclusion was confirmed by Baselga  et al. in clinical trials. This may be related to the synergistic inhibition of the growth of breast cancer cells by trastuzumab and pertuzumab . Studies have shown that the new monoclonal antibodies pertuzumab and trastuzumab have an extracellular structure on HER2 different epitopes of the domain bind HER2 and prevent HER2 from dimerizing with other members of the HER family  to synergistically inhibit the growth of breast cancer cells, thereby improving the prognosis of HER2-positive metastatic breast cancer; it is also possible that anti-HER2 blockers can avoid the side effects of chemotherapy  and improve patients’ quality of life after healing. In addition, we found a phenomenon is that the efficacy of dual-anti-HER2-targeting drugs is best. In this regard, Xie  et al. wrote a network meta by including 13 RCTs and reached the same conclusion as ours, which the efficacy of dual-anti-HER2-targeting drugs is best.
Then, we conducted a subgroup analysis of specific types of anti-HER2-targeting drugs and found that lapatinib had the best benefit, followed by pertuzumab, and trastuzumab had the least benefit. Yardley  et al. showed the research that lapatinib was an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor with anti-tumor activity against HER2-positive breast cancer cells (including trastuzumab-resistant cells) . However, HER2 belongs to the HER receptor tyrosine kinase family. Lapatinib can completely block all HER receptors and induce apoptosis in HER2-positive breast cancer cells . Trastuzumab, which was a humanized monoclonal antibody, could reidentification the extracellular domain of HER2. When HER2 combined with trastuzumab, its functionality could disrupt in several ways, which could lead to growth inhibition and apoptosis of HER2-positive breast cancer cells , and partially act on the HER receptor . Therefore, we speculate that this conclusion may have a great connection with the molecular mechanism of drugs.
Interestingly, trastuzumab did not show the absolute advantages of the drug itself in this analysis. It is speculated that the number of articles about trastuzumab we included this time is too small. In addition, the combination of trastuzumab and other different drugs shows different levels of cardiotoxicity and the cardiotoxicity produced by the function of trastuzumab itself , which will affect the results. All in all, the cardiotoxicity caused by trastuzumab  may also be a reason for its reduced benefit.
Finally, we performed a subgroup analysis of the treatment regimen. The study found that first-line treatment showed more enormous advantages than non-first-line therapy in terms of efficacy. As tracked by Inoue  et al., the effectiveness and safety of the microtubule kinetics inhibitor Brin were beneficial as a first-line or second-line treatment. Therefore, they suggested that Brin may be a first-line treatment for patients with advanced HER2-negative breast cancer. Slamon  et al. also pointed out that patients with first-line treatment of hormone receptor-positive (HR-positive) and HER2-negative advanced breast cancer had a more prolonged median PFS and more significant benefit in phase III clinical trial. Therefore, we recommend the use of anti-HER2-targeting drugs in the first-line treatment of HER2-positive patients, to achieve complete remission of lesions through first-line treatment, reduce the recurrence rate of HER2-positive breast cancer patients, and improve the OS of this population in clinical medicine.
In terms of AEs, we analyzed that the incidence of AEs did not increase significantly with the addition of an anti-HER2-targeting drug. Among all the AEs, the occurrence of AEs was not noticeable. Specific AEs such as decreased appetite, vomiting, rash, and diarrhea, which were consistent with the studies of Krop  et al. In grade 3 and higher AEs, there was no significant increase in the overall incidence of AEs, and diarrhea was the only significant increase in the specific AEs. This conclusion was consistent with the study results of Schneeweiss  et al. We speculated that diarrhea might be related to gastric epidermal cells expressing HER2 . Studies have shown that for elderly patients who are more prone to dehydration, continuous grade 1–2 diarrhea may be debilitating , which prompts us to pay more attention to the association between AEs. In addition, Wildiers et al.  pointed out in the study that the premature cessation of trastuzumab and pertuzumab combination therapy before the condition worsens may be related to the observation of diarrhea in a large proportion of patients. Prompts us that the number of participants in the trial, age, physical fitness, and other factors will affect the AEs. All in all, there were no serious AEs observed according to our analysis. Therefore, we recommend that the dual-anti-HER2-targeting drugs regimen preferred to the treatment of patients with metastatic HER2-positive breast cancer. However, this conclusion still needed to be verified in a large number of clinical trials.
For anti-HER2-targeting drugs, it is the AEs of the heart that one of the specific side effects of the drugs-related. This phenomenon was mentioned by Antonio  et al., in their experiments, so we also conducted a separate analysis of cardiac AEs. The results showed that the risk did not increase in total cardiac AEs. However, in grade 3 and higher cardiac AEs and the severe cardiac AEs, the risk was raised, and the difference was statistically significant. This result also confirmed by Clifton , et al. In specific cardiac AEs, there was no significant increase in the risk of AEs associated with decreased ejection fraction. In contrast, an increase in heart failure grade increased the risk of AEs, with statistically significant differences.
Studies have shown: trastuzumab, pertuzumab, and lapatinib can affect the ErbB2-ErbB4 signaling pathway by inhibiting MAPK (Erk1, Erk2) and Akt . The complex of ErbB2/ErbB4 can control the survival of cardiomyocytes and the disturbance of myofibrils in cardiomyocytes [64, 65]. Furthermore, ErbB4 signaling can also induce myocardial cell proliferation, thereby promoting myocardial regeneration after myocardial injury . Pooja et al.  indicated that cardiotoxicity is the most adverse effect of trastuzumab. Regarding cardiotoxicity, the most common is an asymptomatic decrease in left ventricular ejection fraction, while congestive heart failure is not common . In addition, Chavez-MacGregor et al.  studies have shown that the incidence of cardiac toxicity is variable, depending on the definition used in various clinical trials. It is reported that trastuzumab monotherapy which the overall prevalence is 2–7%, the total incidence of trastuzumab and paclitaxel is 2–13%, and up to 27% when combined with anthracyclines (usually a cumulative dose greater than 300 mg/m2) . This prompts us to consider many factors when evaluating drug side effects comprehensively. Studies have shown that pertuzumab inhibits HER2 signaling by binding to a different HER2 epitope than trastuzumab. Based on this, it is speculated that pertuzumab appears to be associated with minimal cardiac insufficiency , which has minimal toxicity and higher safety factor. Additionally, it was pointed out that pertuzumab may be more active in HER2-positive tumours than HER2-negative breast cancer, which may also be one aspect of pertuzumab’s association with cardiac toxicity. For lapatinib, partly because it recognizes an ErbB2 epitope different from the other two antibodies , and partly because it is a dual tyrosine kinase inhibitor of the epidermal growth factor receptor and HER2 receptors. The early clinical experiment shows that it produces less cardiotoxicity compared to trastuzumab . However, there is no clear explanation about the specific mechanism between anti-HER2-targeting drugs and cardiotoxicity so far .
In a word, our conclusions indicate that the addition of an anti-HER2-targeting drug is tolerable in terms of cardiotoxicity. However, in patients with impaired cardiac function or older patients, doctors need to perform a comprehensive heart examination on the patient before using dual-anti-HER2-targeting therapy; that is, care must be taken when using a dual-anti-HER2-targeting treatment in patients.
This study comprehensively and systematically analyzed the efficacy and AEs of anti-HER2-targeting drugs for the treatment of HER2-positive metastatic breast cancer. However, there are still many deficiencies in this research. First, the number of clinical trials included in the study was insufficient. Besides, the treatment regimens are diversified, and there is some heterogeneity. Therefore, the conclusions of this study need to be further confirmed at the clinical stage.