European Journal of Gynaecological Oncology. 2025; 46(1): 10-22. doi: 10.22514/ejgo.2025.002
Systematic Review

Efficacy and safety of anti-HER2 therapy in solid tumors except breast cancer: a systematic-review and meta-analysis

Xuan Chen1,*,, Yuqing Li2, Yufu Lu1, Mingfei Lin1

1Department of Thoracic Surgery, The People’s Hospital of Wenchang, 571300 Wenchang, Hainan, China

2Department of Orthopaedic Surgery, Graduate School of Medicine, Tohoku University, 980-8577 Sendai, Japan

*Corresponding Author(s):owenlee@alumni.nudt.edu.cn (Xuan Chen)

History Submitted: 26 February 2023 | Accepted: 23 April 2023 | Published: 15 January 2025
Copyright:  ©2025 The Author(s). Published by MRE Press.
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

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Abstract

Background: A meta-analysis was conducted to systematically evaluate the efficacy and safety of anti-Human epidermal growth factor receptor 2 (anti-HER2) therapy in solid tumors except breast cancer. Methods: The Cochrane Library, PubMed, EMbase, Clinical Trials and Web of Science databases were searched for studies published up to August 2022, which reported clinical randomized controlled trials (RCTs) of groups with anti-HER2 therapy (the experimental groups) and without anti-HER2 therapy (the control groups) for solid tumors except breast cancer. A structured meta analysis was conducted on fifteen studies using R 4.2.1, based on the extraction of the data and the risk of bias assessment under the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. Results: Ten studies reported progression-free survival (PFS) with significantly lower risk of tumor progression in experimental groups than in control groups (hazard ratio (HR) = 0.82, 95% confidence interval (CI) (0.75, 0.90), p < 0.01). Seven studies reported overall survival (OS) with significantly longer overall survival in experimental groups than in control groups (HR = 0.89, 95% CI (0.79, 0.99), p = 0.03). The incidences of serious adverse events (SAEs) and any adverse events (AEs) in experimental groups were significantly higher than those in control groups (risk ratio (RR) = 1.35, 95% CI (1.04, 1.75), p = 0.03), (RR = 1.03, 95% CI (1.01, 1.06), p < 0.01). There was no significant difference between the incidences of anemia and fatigue in grade ≥3 AEs between the two groups (p > 0.05). The incidences of diarrhea, neutropenia, nausea, and vomiting were significantly higher in experimental groups than those in control groups (p < 0.05). Conclusions: The results reveal that anti-HER2 therapy is effective in the treatment of solid tumors except breast cancer, however some side effects should be carefully managed in clinical practice. The PROSPERO Registration: CRD42024625436.

Keywords:Anti-HER2 therapy;Solid tumors;Breast cancer;Efficacy;Safety;Systematic-review;Meta-analysis
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Cite this article

Xuan Chen, Yuqing Li, Yufu Lu, Mingfei Lin. Efficacy and safety of anti-HER2 therapy in solid tumors except breast cancer: a systematic-review and meta-analysis. European Journal of Gynaecological Oncology. 2025; 46(1): 10-22. doi: 10.22514/ejgo.2025.002

1. Introduction

Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene, located on the 17th chromosome q21, encoding the transmembrane tyrosine kinase receptor. HER2 is capable of activating key signaling pathways of cells, including phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) (PI3K-AKT) and mitogen-activated protein kinase (MAPK) signaling pathways, involved in the regulation of cell proliferation, apoptosis, differentiation, and migration. Therefore, the activation of tyrosine kinase receptor caused by HER2 over-expression or amplification contributes to the occurrence and development of various malignant tumors [1, 2, 3, 4]. In addition to replicating number variation, it has been established through the expanding clinical use of second-generation sequencing technology that HER2 mutations occur in a variety of malignancies, including bladder, breast, lung, colorectal, pancreatic and gallbladder cancers [5, 6, 7, 8, 9, 10, 11]. In the clinical use, targeting the rescue treatment of neoadjuvant or advanced breast cancer, anti-HER2 therapy has achieved significant levels of efficacy in the treatment of breast cancer [12]. However, for the treatment of gastric cancer, trastuzumab is only recommended by guidelines in first-line medication in patients with advanced HER2 positive gastric cancer. Thus, for the application of anti-HER2 therapy in other tumors except breast cancer, there is still a controversy among the findings in literature [13, 14, 15]. In recent years, anti-HER2 drugs were increasingly used in the treatment of solid tumors except breast cancer [16]. Currently, anti-HER2 drugs mainly include monoclonal antibodies, small molecule tyrosine kinase inhibitors, antibody-conjugated drugs, and other therapeutic drugs being explored for HER2 targets [17]. Specific therapies involving monoclonal antibodies can directly inhibit the proliferation, differentiation, and migration of cancer cells. Such treatments include drugs such as trastuzumab and pertuzumab, etc. [18]. Small molecule tyrosine kinase inhibitors such as Lapatinib are a tyrosine kinase inhibitor that blocks the signaling cascade produced by HER2 to achieve the purpose of anti-HER2 [19]. The antibody-conjugated drugs (antibody-drug conjugates, ADC) are regarded as a combination of conventional chemotherapy and monoclonal antibody advantages such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (DS-8201/T-DXd), and gosatzumab, etc. [20]. The present meta-analysis aimed at assessing the efficacy and safety of the group with anti-HER2 (experimental group) and the group without anti-HER2 (control group) in solid tumors except breast cancer, to provide a scientific basis for clinical applications.

2. Materials and methods

2.1 Inclusion criteria

2.1.1 Study design

Randomized controlled trials (RCT) of treatment with anti-HER2 for solid tumors except breast cancer, whether blind or not.

2.1.2 Study subjects

① The pathological diagnosis was solid tumors except breast cancer; ② Patients were ≥18 years old; ③ According to Eastern Cooperative Oncology Group (ECOG), the physical performance status should be 0 or 1 (0 represents fully active and capable of all activities freely; 1 represents limited physical activity but suffers from ambulatory and mild or sedentary work) [21]; ④ Left ventricular ejection fraction (LVEF) was ≥50%.

2.1.3 Interventions

The experimental groups were the treatments with anti-HER2 therapy, while the control groups were the treatments without anti-HER2 therapy. The treatments of both groups are not limited by the dosage and course of treatment.

2.1.4 Outcome indicators

Efficacy outcomes: progression-free survival (PFS), and overall survival (OS). Safety outcomes: incidences of serious adverse reactions (SAEs), any AEs, and Grade ≥3 AEs. The adverse reactions include Diarrhea, Neutropenia, Nausea, Anemia, Vomiting, Fatigue. Grade refers to the severity of the AEs. The National Cancer Institute Common Toxicity Criteria (NCICTC) (Version 2) or the Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) displays Grades 1~5 with unique clinical descriptions of severity for each AE based on the general guideline.

2.2 Exclusion criteria

① The clinical trial was not completed; ② The purpose of the trials were inconsistent with our study’s; ③ The studies reported non-randomized control trials, such as observational studies, retrospective studies, etc.; ④ Abstracts only without full text, duplicate publications or incomplete data; ⑤ The review, reviews, expert views, experience summaries, individual cases, animal experiments and other non-clinical trial studies.

2.3 Search strategy

Studies were identified by searching PubMed (January 1966 to August 2022), EMbase (January 1974 to August 2022), ClinicalTrials.gov, Cochrane Library, and web of science, using medical subject headings (MeSH) and the keywords: “Cancer”, “Neoplasm(s)”, “Tumor(s)”, “Neoplasm(s)”, “Cancer(s)”, “HER2-targeted”, “anti-HER2”, “Trastuzumab”, “Pertuzumab”, “T-DM1”, “Lapatinib”, “pyrotinib”, “Neratinib”, “Tucatinib”, “T-DXd” and so on. In terms of the characteristics of the different databases, corresponding search strategies were used.

2.4 Data extraction and quality evaluation

Literature screening and data extraction were independently conducted by two authors. The articles that lacked original data or did not meet the inclusion criteria were excluded. If more than one publication reported results from the same trial or included the same or overlapping patient cohorts, only the outcomes from the largest and most recent publications were included [22]. The following information was recorded from eligible studies:

① basic information of the studies including title, first author’s name, year of publication, publishing journal, etc.;

② the basic characteristics of the studies, including the number of cases and age;

③ interventions;

④ primary outcome indicators;

⑤ the risk assessment of bias.

The risk of bias in the studies included in the analysis was evaluated using the RCT bias assessment tool, that is using the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [23, 24]: ① random sequence generation (selection bias); ② allocation concealment (selection bias); ③ blinding of participants and personnel (performance bias); ④ blinding of outcome assessment (detection bias); ⑤ incomplete outcome data (attrition bias); ⑥ selective reporting (reporting bias); ⑦ other biases. The risk of bias was rated as high, low or unclear [25]. The Egger’s test and Begg’s test was used to evaluate the occurrence of publication bias.

2.5 Statistical methods

The preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines were followed to perform this meta-analysis using the R software (version 4.2.1, GNU project, Cambridge, MA, USA) [26, 27]. The hazard ratio (HR) and 95% confidence interval (CI) were pooled for PFS and OS, the number of events extracted directly from clinical trials was used to calculate the risk ratio (RR) and 95% CI for adverse events (AEs). Heterogeneity in the results of the included studies was evaluated both visually through forest plots and p-values using the I-squared (I2). If statistically significant heterogeneity was observed (I2 ≥ 50%), the pooled effect was calculated using a random-effect model; otherwise, a fixed-effect model was employed (I2 < 50%) [28]. Sensitivity analysis was performed by recalculating the pooled outcome estimates after excluding each study one at a time (leave-one-out procedure) [29].

The HR is usually calculated from a Cox proportional hazards model, which is one of the standard methods for analyzing survival end points in oncology RCTs. The HR provides an estimate of the ratio of the hazard rates between the experimental group and the control group over the entire study duration. If the HR (E (Experimental) versus C (Control)) is <1, then the experimental treatment is better than the control and vice versa if HR (E versus C) >1. If the log HR is taken, it not only determines whether the benefits of the treatments are different (or not) but also indicates how one treatment compares to the other [30]. Furthermore, both PFS and OS can only be compared with studies of the same type, while HR values can be compared across studies and even diseases by adjusting the influence of confounding factors through multivariate Cox proportional hazard regression model.

3. Results

3.1 Studies inclusion

A total of 3717 studies were initially identified. These studies were processed by screening the titles and/or abstracts, removing duplicates, and removing articles with similar data and study designs. Finally, fifteen eligible studies were included. The PRISMA flow diagram detailing the process of inclusion and exclusion of publications is shown in Fig. 1. The PRISMA 2020 Checklist is in the Supplementary material.

Flow diagram of the trial search and selection process. RCT: Randomized controlled trials.

Fig. 1.Flow diagram of the trial search and selection process. RCT: Randomized controlled trials.

3.2 Basic characteristics of the included studies

Of the fifteen RCTs included, there were 3302 patients, including 1681 patients in the experimental groups and 1621 patients in the control groups. The basic characteristics of the included studies are presented in Table 1 (Ref. [31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]).

Table 1.Basic characteristics of included studies.
First Author YearCancerLineTreatment statusTreatment armsPopulationsEiffcacy endpointHER2 statusAge (median (range)/mean (SD)), years
S.B. Kaye 2013 [31]Ovarian≥Second lineRelapsedA: P + Chemotherapy B: ChemotherapyA: 74 B: 75PFSUndefinedA: 58.1 (26–76) B: 55.3 (19–83)
J.Randolph Hecht 2016 [32]Gastric, Esophageal, or Gastroesophageal AdenocarcinomaFirst lineAdvanced/MetastaticA: CapeOx + Lapatinib B: CapeOx + PlaceboA: 249 B: 238PFS OSFISH+ and/or IHC 3+A: 61.0 (19–86)B: 59.0 (27–84)
Tianshu Liu 2019 [33]Gastric or gastroesophageal junction cancerFirst lineMetastaticA: H + P + Chemotherapy B: H + Chemotherapy + PlaceboA: 82B: 81PFSOSORRIHC 3+ or IHC 2+ and FISH+A: 59.0 (25–78) B: 59.0 (23–73)
Amanda N 2018 [34]Uterine SerousCarcinomas≥Second lineAdvanced/recurrentA: C + Paclitaxel + HB: C + PaclitaxelA: 32 B: 29PFSIHC 3+ or IHC 2+ and FISH+A: 67.0 (64–69)B: 73.0 (68–78)
Akitaka Makiyama 2020 [35]Gastric or Gastroesophageal Junction CancerFirst lineAdvancedA: Paclitaxel + HB: PaclitaxelA: 45 B: 46PFSOSIHC 3+ or IHC 2+ and FISH+A: 65.0 (50–89) B: 67.0 (33–81)
JM del Campo 2011 [36]Squamous cell carcinoma of the head and neckFirst lineLocally advancedA: Lapatinib + ChemoradiotherapyB: Placebo + ChemoradiotherapyA: 71B: 36ORRUndefinedA: 58.0 (33–80)B: 55.0 (37–78)
Kevin Harrington 2015 [37]Squamous Cell Carcinoma of the Head and NeckFirst lineAdjuvantA: Lapatinib + ChemoradiotherapyB: Placebo + ChemoradiotherapyA: 346 B: 342DFSOSUndefinedA: 54.0 (27–74)B: 55.0 (24–74)
Thomas Powles 2017 [38]Bladder Cancer≥Second lineMetastaticA: LapatinibB: PlaceboA: 116B: 116PFSOSIHC 3+ or IHC 2+A: 70.7 (63.9–77.2)B: 71.1 (63.8–76.3)
U Gatzemeier 2004 [39]NSCLC≥Second lineAdvancedA: Gemcitabine + Cisplatin + HB: Gemcitabine + CisplatinA: 51B: 50PFS OSIHC 3+ or FISH+A: 57.0 (35.0–76.0)B: 60.0 (35.0–76.0)
Sharmila Makhija 2010 [40]Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer≥Second lineAdvancedA: Gemcitabine + PertuzumabB: Gemcitabine + PlaceboA: 65B: 65PFSORRUndefinedNR
Christian Kurzeder 2016 [41]Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer≥Second lineRefractoryA: P + ChemotherapyB: Chemotherapy + PlaceboA: 78 B: 78PFSUndefinedA: 65.0 (32.0–79.0) B: 64.0 (26.0–80.0)
Yung-Jue Bang 2010 [42]Gastric or gastro-oesophageal junction cancerFirst lineAdvancedA: H + ChemotherapyB: ChemotherapyA: 294 B: 290OSFISH+ and/or IHC 3+NR
Howard P Safran 2022 [43]Esophageal adenocarcinomaFirst lineNeoadjuvantA: H + ChemoradiotherapyB: ChemoradiotherapyA: 102B: 101DFSFISH+ and/or IHC 3+NR
Stéphane Oudard 2015 [44]Urothelial carcinomaFirst lineAdvanced/metastaticA: H + ChemotherapyB: ChemotherapyA: 32B: 29PFS OS ORRIHC 3+ or IHC 2+ and FISH+NR
Taito Esaki 2018 [45]Gastric cancer≥Second lineAdvancedA: H + PaclitaxelB: PaclitaxelA: 44B: 45PFSOSFISH+ and/or IHC 3+NR
A: Experiment group; B: Control group; HER2: human epidermal growth factor receptor 2; HR: hazard ratio; D: Docetaxel; P: Pertuzumab; H: Trastuzumab; T-DM1: Trastuzumab emtansine; cap: Capecitabine; NR: not reported; ORR: objective response rate; PFS: progression-free survival; OS: overall survival; DFS: Disease-free survival; CapeOx: capecitabine and oxaliplatin; C: carboplatin; NSCLC: non-small-cell lung cancer; IHC: Immunohistochemistry; ISH: In situ hybridization; SD: standard deviation.

3.3 Quality evaluation

The fifteen included studies were all RCTs and six among them were double-blind trials. The baseline of Patient Demographics and Disease Characteristics are reported in all the studies. Based on the risk of bias assessment of the studies, the overall quality assessment was moderate. The risk of bias summary and bias graph of the included studies are shown in Figs. 2,3.

The risk of bias summary.

Fig. 2.The risk of bias summary.

The risk of bias graph.

Fig. 3.The risk of bias graph.

3.4 Progression-free survival

Ten studies reported that progression-free survival (PFS) exhibited low heterogeneity between studies (p = 0.11, I2 = 38%). There were 1079 cases in the experimental groups and 1063 cases in the control groups. The pooled results using a fixed-effects model demonstrated that the risk of tumor progression in the experimental groups was significantly lower than that in the control groups (HR = 0.82, 95% CI (0.75, 0.90), p < 0.01), as shown in Fig. 4. The sensitivity analysis yielded I2 = 25% after sequential exclusion of the data from Amanda N 2018, Thomas Powles 2017, indicating the heterogeneity source, as shown in Fig. 5. Additionally, there was found no evidence of publication bias in any of the analysis, using both Begg’s test (p = 0.4843) and Egger’s test (p = 0.5234).

Forest plot of PFS (progression-free survival). CI: confidence interval; SE: Standard Error of Mean; HR: hazard ratio.

Fig. 4.Forest plot of PFS (progression-free survival). CI: confidence interval; SE: Standard Error of Mean; HR: hazard ratio.

Sensitivity analysis of PFS (progression-free survival). CI: confidence interval; HR: hazard ratio.

Fig. 5.Sensitivity analysis of PFS (progression-free survival). CI: confidence interval; HR: hazard ratio.

3.5 Overall survival

There were seven studies that revealed no heterogeneity in overall survival (OS) (p = 0.29, I2 = 18%), considering 1163 cases in the experimental groups and 1158 cases in the control groups. The pooled results using a fixed-effects model demonstrated that the overall survival of patients in the experimental groups was significantly longer than that in the control groups (HR = 0.89, 95% CI (0.79, 0.99), p = 0.03). This suggest that the treatment with anti-HER2 therapy could reduce the risk of tumor progression, as shown in Fig. 6. There was found no evidence of publication bias in any of the analysis using Begg’s test (p = 0.1361) and Egger’s test (p = 0.1053).

Forest plot of OS (overall survival). CI: confidence interval; SE: Standard Error of Mean; HR: hazard ratio.

Fig. 6.Forest plot of OS (overall survival). CI: confidence interval; SE: Standard Error of Mean; HR: hazard ratio.

3.6 Serious adverse events

Three studies reported the incidence of serious adverse events (SAEs) with no heterogeneity between studies (p = 0.96, I2 = 0%), considering an analysis of 428 and 421 patients in the experimental groups and control groups, respectively. The pooled results using a fixed-effects model demonstrated that the incidence of SAEs in the experimental groups was significantly higher than that in the control groups (RR = 1.35, 95% CI (1.04, 1.75), p = 0.03), as shown in Fig. 7.

Forest plot of SAEs (serious adverse events). CI: confidence interval; RR: Risk Ratio.

Fig. 7.Forest plot of SAEs (serious adverse events). CI: confidence interval; RR: Risk Ratio.

3.7 Any adverse events

Four studies reported the incidence of any AEs with no heterogeneity between studies (p = 0.25, I2 = 27%). There were 777 and 757 patients in the experimental groups and control groups, respectively. The pooled results using a random-effects model demonstrated that the incidence of any AEs in the experimental groups was significantly higher than that in the control groups (RR = 1.03, 95% CI (1.01, 1.06), p < 0.01), as shown in Fig. 8.

Forest plot of any AEs. CI: confidence interval; RR: Risk Ratio.

Fig. 8.Forest plot of any AEs. CI: confidence interval; RR: Risk Ratio.

3.8 Grade ≥3 adverse events

For the incidence of grade ≥3 adverse events (AEs), including diarrhea, neutropenia, nausea, anemia, vomiting, and fatigue in both groups, no significant study heterogeneity was observed. The pooled estimates using a fixed-effects model showed that there was no significant difference in the incidence of anemia and fatigue between the two groups (RR = 1.34, 95% CI (0.95, 1.89), p = 0.10), (RR = 1.21, 95% CI (0.71, 2.06), p = 0.49), indicating that the incidence of anemia and fatigue was comparable between two groups. The incidence rates of diarrhea, neutropenia, nausea, and vomiting in the experimental groups were both significantly higher than those in the control groups (p < 0.05), as shown in Fig. 9.

Forest plot of grade ≥3 AEs (adverse events). CI: confidence interval; RR: Risk Ratio.

Fig. 9.Forest plot of grade ≥3 AEs (adverse events). CI: confidence interval; RR: Risk Ratio.

3.9 Comparison between studies on PFS and OS

As introduced in 2.5, log (HR) below the horizontal axis (zero line) indicates benefit of groups with anti-HER2 therapy (experimental), while log (HR) above the zero line indicates benefit of groups without anti-HER2 therapy (control), and greater absolute value indicates greater benefit. Accordingly, log (HR) was used to investigate the comparison of studies in PFS and OS on the HER2 positive (HER2+) vs.HER2 not-reported (HER2 undefined) trials and on the therapy naive patients (first line) vs. patients previously received multiple therapies (≥second line).

PFS were reported in 10 studies, of which 7 studies were HER2+ and 3 studies were undefined in HER2 expression. OS was reported in 7 studies, of which 6 studies were HER2+ and 1 study were undefined in HER2 expression. For PFS, the log (HR) values of the two HER2 states were distributed at both sides of the zero line, indicating that the PFS benefit of the HER2+ population was not significantly superior to the PFS benefit of the population with undefined HER2 expression, as shown in Fig. 10A. However, OS cannot be analyzed due to the limited studies included, as shown in Fig. 10B.

PFS were reported in 10 studies, of which 4 studies’ anti-HER2 regiments were first line therapies, and 6 studies’ anti-HER2 regiments were ≥second line therapies. The log (HR) values in the first line trials were all distributed below the zero line, suggesting that the anti-HER2 regiments in the former trials had better PFS benefits. The log (HR) values in ≥second line treatment trials were distributed at both sides of the zero line, indicating that the PFS benefit trend of the first line treatment trials was better than that of the ≥second line treatment trials, as shown in Fig. 11A. The OS in two groups had no obvious advantage benefit trend, as shown in Fig. 11B.

Comparison of HER2+ and HER2 undefined between studies on PFS and OS. (A) PFS. (B) OS. PFS: progression-free surviva; OS: overall survival; HR: hazard ratio; HER: Human epidermal growth factor receptor.

Fig. 10.Comparison of HER2+ and HER2 undefined between studies on PFS and OS. (A) PFS. (B) OS. PFS: progression-free surviva; OS: overall survival; HR: hazard ratio; HER: Human epidermal growth factor receptor.

Comparison of first line and ≥second line between studies on PFS and OS. (A) PFS. (B) OS. PFS: progression-free surviva; HR: hazard ratio; OS: overall survival.

Fig. 11.Comparison of first line and ≥second line between studies on PFS and OS. (A) PFS. (B) OS. PFS: progression-free surviva; HR: hazard ratio; OS: overall survival.

4. Discussion

It has been proved that abnormal HER2 gene activation may lead to tumor formation. Meanwhile, the HER2 protein could promote angiogenesis, increase vascular permeability, and provide rich nutrients for tumors, thus significantly enhancing the invasive ability of tumors [46]. The HER2 gene was found to be associated with the occurrence and development of malignant tumors, and the poor prognosis of patients. The HER2 gene is highly expressed in breast cancer, colorectal cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, and many other tumors, leading to the phosphorylation of intracellular tyrosine kinase residues, which ultimately promotes cell proliferation, differentiation, migration, and survival. Yu-ying Lei reported that HER2 over-expression was associated with poor prognosis in patients with gastric carcinoma (GC), and the HER2 positive rate in GC patients may be related to gender, tumor site, tumor-node-metastasis (TNM) staging system, distant metastasis, lymph node metastasis, Lauren grade, and differentiation grade. HER2 rates may be higher in Asians than in Europeans [47]. Junjie Zhao studied the prognostic role of HER2 in bladder cancer, and assigned it to the presence of HER2 expression with poor prognosis. Therefore, HER2 was known as a useful biomarker for clinical prediction [48]. The Jung-Soo Pyo study revealed the clinicopathological significance and diagnostic accuracy of HER2 immunohistochemistry in colorectal cancer, and indicated that HER2 IHC over-expression was significantly associated with lymph node metastasis and distant metastasis, and the colorectal cancer (CRC) cases with a HER2 IHC score of 0/1+ matched well with the ISH data [49]. Studies have proved that HER2/neu over-expression is associated with reduced overall survival rate and shortened time to recurrence in advanced ovarian cancer, and is one of the prognostic factors for poor treatment outcomes of ovarian cancer.

In recent years, many anti-HER2 therapies were used in the clinical treatment of tumors. According to the targeted sequencing, Jhaver studied ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors except breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas and patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression [50]. The test results indicated that T-DM1 tolerance was high, however, the objective response rate of the tumor did not show a curative effect. Bob et al. [51] noted that trastuzumab (6.4 mg/kg) was used in patients with metastatic her-2-mutant NSCLC patients that did not respond to standard therapy, and concluded that trastuzumab demonstrated durable anticancer activity in previously treated her-2-mutant NSCLC patients. Yelena combined pembrolizumab with trastuzumab in the first-line treatment of positive esophagogastric (EG, or gastric, esophageal, or gastro-esophageal junction) cancer, and concluded that pembrolizumab can be safely combined with trastuzumab and chemotherapy and exhibit strong activity against HER2-positive metastatic oesophageal and gastric cancer [52]. Salvatore applied trastuzumab (DS-8201) in patients with HER2-expressing metastatic colorectal cancer and concluded that trastuzumab showed promising and durable activity against HER2-positive metastatic colorectal cancer, and its safety was consistent with that reported in previous trastuzumab trials [53]. Additionally, interstitial lung disease and pneumonia are important risks that require careful monitoring and timely intervention.

Fifteen clinical trials with a total of 3302 patients were included in this study, all of which were randomized clinical trials. According to the effectiveness evaluation results of meta-analysis, in terms of PFS, the treatment with anti-HER2 therapy reduced the risk of tumor progression compared with the treatment without anti-HER2 therapy. In terms of OS, the treatment with anti-HER2 therapy reduced the risk of death in advanced tumors compared with the treatment without anti-HER2 therapy. In this study, log (HR) values of PFS and OS were used for comparative analysis of benefits in different groups, and the results showed that the treatment regimen containing anti-HER2 had certain advantages and benefits in the application of first line treatment, but due to the small sample size, the conclusions were not accurate to some extent. According to the safety evaluation results of meta-analysis, the incidences of SAEs and any AEs in the treatments with anti-HER2 were higher than those of treatments without anti-HER2 (RR = 1.35, 95% CI (1.04, 1.75), p = 0.03), (RR = 1.03, 95% CI (1.01, 1.06), p < 0.01). In terms of the incidence of grade ≥3 adverse events, there was no significant difference in the incidence of anemia and fatigue between the two groups (p > 0.05). The incidence rates of diarrhea, neutropenia, nausea, and vomiting in the experimental groups were both significantly higher than those in the control groups (p < 0.05).

This study further analyzed the cause of increase of adverse reactions associated with anti-HER2 therapy. First, of the 15 anti-HER2 therapy studies included in this study, 14 of them were anti-HER2 therapy combined with other chemotherapies, while the common adverse reactions of anti-HER2 drugs include diarrhea, drug-induced liver injury, nausea, vomiting, dermo-toxicity, cardiotoxicity, and oral mucositis, etc. [54]. Common adverse reactions of chemotherapy include myelosuppression, liver and kidney function injury, nausea, vomiting, hair loss, etc. [55]. In this study, the incidences of nausea and vomiting in grade ≥3 AEs were compared. The presence of nausea in anti-HER2 therapy group was significantly higher than that in the group without anti-HER2 therapy, indicating that the combination of the two drugs may increase the severity of adverse reactions. It was found that the incidences of diarrhea in grade ≥3 AEs with anti-HER2 therapy were significantly higher than those of without anti-HER2 therapy, indicating that anti-HER2 drugs also had common adverse reactions to diarrhea.

This study had several limitations. First, not all studies met the inclusion and exclusion criteria and the efficacy determination criteria of publications. Second, limited by the original data, a subgroup analysis of ECOG scores and regional differences was not conducted.

5. Conclusions

In conclusion, the treatments with anti-HER2 therapy could significantly prolong PFS and OS in tumor patients compared with the treatments without anti-HER2 therapy. Nonetheless, this is with significant risk of increased incidence of adverse events. During clinical application, attention should be paid to the relevant adverse events under real-time monitoring. To the best of our knowledge, this study evaluated the solid tumors treated with anti-HER2 therapy based on existing clinical data to provide a novelty reference for the clinical treatment of breast cancer. However, considering that the number of included studies was not substantial, more reasonably designed clinical trials with larger sample size and multi-center clinical trials are needed to draw more reliable evidence to guide clinical medication in the future.

Abbreviations

HER2+, human epidermal growth factor receptor-2-positive; RCT, Randomized controlled trial; PFS, progression-free survival; OS, overall survival; AEs, adverse events; SAEs, serious adverse events; HR, Hazard ratio; RR, Risk ratio; CI, confidence interval; PI3K, phosphatidylinositol 3 kinase; AKT, protein kinase B; MAPK, mitogen-activated protein kinase, T-DM1, trastuzumab emtansine; ADC, antibody-drug conjugates; ECOG, Eastern Cooperative Oncology Group; LVEF, Left ventricular ejection fraction; NCICTC, National Cancer Institute Common Toxicity Criteria; CTCAE, Common Terminology Criteria for Adverse Events; MeSH, medical subject headings; PRISMA, preferred Reporting Items for Systematic reviews and Meta-analysis; I2, I-squared; GC, gastric carcinoma; TNM, tumor-node-metastasis; CRC, colorectal cancer; GEJ, gastroesophageal junction.

Availability of Data and Materials

The data are contained within this article.

Author contributions

XC and YQL—designed the research study, analyzed the data. XC—performed the research. MFL and YFL—provided help and advice on the ELISA experiments. XC and YFL—wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All procedures performed in the included studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. This article does not contain any studies with human participants performed by any of the authors.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

Supplementary material associated with this article can be found, in the online version, at https://oss.ejgo.net/files/article/1879409240660951040/attachment/Supplementary%20material.docx.

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