HER3, but Not HER4, Plays an Essential Role in the Clinicopathology and Prognosis of Gastric Cancer: A Meta-Analysis

RESEARCH ARTICLE HER3, but Not HER4, Plays an Essential Role in the Clinicopathology and Prognosis of Gastric Cancer: A Meta-Analysis Guo-dong Cao1☯, Ke Chen1☯, Mao-ming Xiong2*, Bo Chen2* 1 Anhui Medical University, Hefei, Anhui, 230022, China, 2 Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China ☯ These authors contributed equally to this work. * (MMX); (BC) Abstract a11111 Background and Aim OPEN ACCESS Citation: Cao G-d, Chen K, Xiong M-m, Chen B (2016) HER3, but Not HER4, Plays an Essential Role in the Clinicopathology and Prognosis of Gastric Cancer: A Meta-Analysis. PLoS ONE 11(8): e0161219. doi:10.1371/journal.pone.0161219 Editor: Valli De Re, Istituto di Ricovero e Cura a Carattere Scientifico Centro di Riferimento Oncologico della Basilicata, ITALY Received: March 3, 2016 Human epidermal growth factor receptor (HER) family plays an important role in gastric cancer (GC), especially HER2. Too much attention has been paid to HER2; however, the functions of HER3 and HER4 overexpression in GC are always ignored. The clinicopathological and prognostic roles of HER3 and HER4 in GC are controversial. In this study, a systematic review and meta-analysis was conducted to evaluate the use of HER3 or HER4 as a predictor of clinicopathology and survival time in GC patients. Methods Eligible studies were searched on PubMed, Ovid, Web of Science, and Cochrane databases through multiple search strategies. Data collection and statistical analysis were carried out by the Revman 5.3 software. The Newcastle-Ottawa scale was used to assess the quality of included studies. Accepted: August 1, 2016 Published: August 18, 2016 Results Copyright: © 2016 Cao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. A total of 448 studies about HER3 overexpression and GC, and 398 studies about HER4 overexpression and GC were searched. Of these, 5 eligible studies about HER3 including 1016 GC patients and 3 eligible studies about HER4 including 793 GC patients met the inclusion criteria. The results showed that HER3 and HER4 overexpression were significantly associated with depth of tumor invasion (OR = 0.44, 95%CI 0.29–0.67, P = 0.0002 and OR = 0.50, 95%CI 0.38–0.86, P = 0.007) and lymph node metastasis (OR = 0.40, 95% CI 0.20–0.77, P = 0.007 and OR = 0.57, 95%CI 0.38–0.86, P = 0.007), and HER3 overexpression reveals a tendency of later tumor node metastases (TNM) stage (OR = 0.50, 95% CI 0.22–1.15, P = 0.10) and predicts a worse survival time (RR = 0.71, 95%CI 0.61–0.84, P<0.00001), while HER4 overexpression had no correlation with TNM stage (OR = 0.60, 95%CI 0.20–1.78) and survival time (RR = 1.09, 95%CI 0.91–1.30). Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing Interests: The authors have declared that no competing interests exist. PLOS ONE | DOI:10.1371/journal.pone.0161219 August 18, 2016 1 / 14 HER3 and HER4 Over-Expression in GC Patients Conclusions This meta-analysis indicated that HER3 plays an essential role in the clinicopathology and prognosis of GC. However, HER4 may not be an ideal prognostic factor for GC. Introduction Gastric cancer (GC), one of the most common malignant tumors in the body, is the second cause of cancer-related deaths [1]. The early diagnosis rate of GC is low in Southeast Asia [2– 3]. Most GC patients are at an advanced stage of cancer or distant metastasis, and even through the palliative surgical treatment, the 5–year overall survival(OS) is still optimistic, with the median OS being less than 1 year [4]. The prognosis of patients with advanced GC who received several new chemotherapeutic regimens is not ideal [5]. Therefore, it is necessary to find a new prognostic biomarker that could prolong the survival time of GC patients. The human epidermal growth factor receptor (HER) family includes four members: epidermal growth factor receptor(EGFR)/HER1/ErbB1, HER2/ErbB2, HER3/ErbB3, and HER4/ ErbB4. Compared with EGFR and HER2, the functions of HER3 in GC are always ignored. HER3 is distinct from the other three HER family members [6] in that it lacks intrinsic tyrosine kinase activity. Due to this feature of HER3, it cannot activate the intracellular signaling pathway by forming a homodimer [7]. Nevertheless, it usually heterodimerizes with other HER family members, especially HER2; the most active heterodimer is the HER2/HER3 dimer, which can activate the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and the mitogen-activated protein kinase pathways in cancer [8–10]. As another member of HER family, HER4 overexpression in breast cancer is associated with significant worse survival in some studies [11–12], conversely, with better survival in other researches [13–14]. Several recent studies have reported that GC was closely linked with HER3 and HER4 expression [15–16]. Different researchers maintain different opinions on the associations of HER3 and HER4 with GC. Thus, several eligible studies were searched, and a systematic review was performed to evaluate the functions of HER3 and HER4 in GC. Methods Search strategy The electronic databases from PubMed, Ovid, Web of Science, and Cochrane from January 1990 to January 2016 were searched. The search terms were as follows: ("HER3" or "ErbB3" or "HER4" or "ErbB4" or "Human epidermal growth factor receptor") and ("gastric" or "stomach" or "cardia" or "gastrointestinal") and ("adenocarcinoma" or "carcinoma" or "cancer" or "tumour" or "neoplasm" or "tumor"). The full texts of the studies were read to find whether the studies met the inclusion criteria. Inclusion and exclusion criteria The inclusion criteria were as follows: (1) GC was identified, (2) HER3 or HER4 expression was evaluated by immunohistochemistry (IHC) assay, (3) information on clinicopathological parameters and OS was provided, (4)standards to assess the status of HER3 andHER4 was consistent in different studies, and (5) article was published in English or Chinese language. The exclusion criteria were as follows: (1) duplication, (2) reviews, (3) case reports, and (4) evaluation method was not IHC. PLOS ONE | DOI:10.1371/journal.pone.0161219 August 18, 2016 2 / 14 HER3 and HER4 Over-Expression in GC Patients Data extraction and quality assessment According to the data selection criteria, all relevant data was extracted from each eligible study independently by two investigators (Guo-dong Cao, Ke Chen). During the process of data extraction, disagreements should be discussed with all research team members until a consistent opinion was reached. The following data were extracted:first author’s name, year of publication, total number o (...truncated)