Recently, several meta-analyses have been published regarding the role of human epidermal growth factor receptor 2 (HER2) oncogene in gastric and oesophageal cancer. HER2 encrypts for a 185 KD transmembrane glycoprotein receptor with intracellular tyrosine kinase activity and is positioned at the long arm of human chromosome 17 (17q12) (1), and was first discovered in breast cancer and has become an important prognostic factor (2,3). Since the advent and the success of adjuvant medical therapy for HER2-positive breast cancer in the form of trastuzumab there has been increasing interest in the development of similar therapies in other solid organ malignancies. It has been assessed in various other solid organ malignancies including gastric cancer (4), oesophageal cancer (5), colorectal cancer (6-8), osteosarcoma (9), ovarian cancer (10,11), prostate cancer (12), lung cancer (13), pancreatic cancer (14), bladder cancer (15), and uterine cancer (16). In gastric and oesophageal cancer the incidence of HER positive tumours range from 4% to 53% (17) and 9% to 64% (18). However, multiple observational studies have been inconsistent with regards to its correlation with survival. A major breakthrough in targeted therapy in gastric cancer was the ToGA trial (19). This multicentre randomized trial of 594 gastric cancer patients demonstrated an increase of 2.7 months in the median overall survival (OS) with trastuzumab and a recent meta-analysis (20) of randomized control trials suggested an improvement in overall and progression free survival with the addition of trastuzumab to chemotherapy. The most important issue is that some of the subsequent meta-analyses published produce conflicting results. This review aims to summarize the meta-analytic evidence for the association between HER2 in gastric and oesophageal cancer.
The search strategy involved the major computer databases, including Medline, PubMed, EMBASE and Current Contents (January 1983 to November 2014). The search methodology involved using combinations of the following keywords: HER2, gastric cancer/carcinoma/ adenocarcinoma, stomach cancer, meta-analysis, systematic review, oesophageal cancer/carcinoma/adenocarcinoma/squamous cell carcinoma. Additional manual searches were made using the reference lists from the selected articles to retrieve other papers relevant to the topic. No language restriction was placed on any of the literature searches.
We included studies that met the following inclusion criteria:
- Meta-analyses and systematic reviews on the role of HER2 in gastric and oesophageal cancer.
The original search strategy retrieved 140 citations (Figure 1). The abstracts were reviewed and after applying the inclusion and exclusion criteria, articles were selected for full-text evaluation. Of the articles selected, only 9 studies (4,5,17,18,21-25) met full criteria for analysis and are summarised in Table 1. The years of publication ranged from 2011 to 2014.
HER2 and gastric cancer
There have been six systematic reviews published so far regarding the role of HER2 in gastric cancer (4,17,21-23,25). Most of the studies were from China (Table 1). A recent meta-analysis of eight studies (22) reported that HER2 had significant predictive ability for estimating OS with a hazard ratio (HR: 1.43; 95% CI: 1.09-1.88) and was associated with moderate heterogeneity (I2=52.90, P=0.038) and no publication bias (P=0.256). Similarly, Wang et al. (4) included 4,342 gastric cancer cases which suggested that HER2 was poor prognostic feature with a HR of 1.59 (95% CI: 1.20-2.12) and was associated with moderate heterogeneity (I2=48.10, P=0.019) and no publication bias (P=0.081). Liang et al. (21) suggested that HER2 overexpression was linked with Bormann type (I + II), well differentiated, intestinal type, lymph node metastasis, venous invasion, and lymphovascular invasion. Nevertheless, it had no relationship with depth of invasion, tumour size and stage. On the contrary, HER2 was significantly associated with patients’ OS. A recent multicentre study consisting of 1,148 gastric cancer patients who underwent gastrectomy in eleven institutes across Japan found HER2 overexpression to be an important predictive factor in patients with any stage of operable gastric cancer (26).
A robust publication from Gu et al. (23) included only publications that classified HER2 expression based on ToGA criteria (27). This study demonstrated that relapse-free survival (RFS) as well as OS was not related to HER2 expression. The heterogeneity among the studies was low to moderate. The pooled odds ratio (OR) for HER2 positivity was linked to being male (OR: 2.31; 95% CI: 1.59-3.36), well/moderately differentiated tumour (OR: 5.32; 95% CI: 3.95-7.17), and for intestinal-type tumour (OR: 5.55; 95% CI: 4.01-7.67). Jørgensen et al. (25) published a systematic review with 12,749 patients which suggested HER2 positive tumours were associated with poor survival, serosal invasion, lymph node metastases and distant metastases. Finally, Chua et al. (17) published an excellent review of 49 studies. Out of which 35 studies reported the influence of HER2 overexpression on survival. Among these only two studies stated considerably longer OS in patients with HER2 overexpression and 13 studies reported significantly poorer OS in patients with HER2 overexpression.
HER2 and oesophageal cancer
The role of HER2 has also been well investigated in oesophageal cancer. Chan et al. (18) reviewed the effect of HER2 expression in surgically resectable oesophageal carcinoma which included 1,464 patients. The 5-year mortality rate was considerably greater in HER2-positive patients with an OR of 1.43 (95% CI: 1.04-1.95). However, there was significant heterogeneity among the studies and publication bias was evident. The effect of HER2 positivity was greater in squamous cell carcinoma (OR: 2.88; 95% CI: 1.34-6.17; I2=0.00; P=0.52) compared to adenocarcinoma (OR: 1.91; 95% CI: 1.15-3.17; I2=78.00; P=0.001) with respect to 5-year mortality. A recent meta-analysis of 2,319 oesophageal cancer patients of all stages demonstrated that HER2 positive tumours survived 7 months less than HER2 negative tumours (5), however, this was not statistically significant.
Gastric and oesophageal cancers result in 700,000 and 386,000 deaths every year respectively (28). HER2 plays an important role in the aggressiveness and progression of gastric (21,29) and oesophageal cancer (18). The overall direction of the meta-analyses for gastric cancer (4,17,21-23) suggests HER2 as a poor prognostic factor and is associated with poor OS. However, Gu et al. (23) published that RFS and OS were not related to HER2 expression. Gu et al. (23) included only publications that classified HER2 expression based on ToGA criteria making the analysis robust (27). As per Hofmann et al. (27) the definition for HER2 positivity was reclassified from IHC 2+ or 3+ or amplification in FISH to IHC 3+ or IHC 2+ and hence the conclusion from Gu et al. (23) were significantly different from the other meta-analyses. HER2 positive tumours are more likely to be well differentiated, intestinal-type, with lymphovascular invasion and more common in men. As far as oesophageal cancer is concerned (5,18), HER2 positive tumours have negative impact on survival and have a higher 5-year mortality rate.
Strengths and limitations
Gu et al. (23) searched the multiple databases including PubMed, EMBASE, Scopus, Medline between the dates Jan 2008 to Nov 2013 only, a significant drawback of the meta-analysis. Similarly, Chen et al. (22) searched only from 2007-May 1, 2013. Chen et al. (24), Chua et al. (17), and Chan et al. (18) explored only one or two databases for studies. The search strategy could explain the variability in the number of studies included among the meta-analyses and the inconsistency of the ORs for the various outcomes and heterogeneity among the meta-analyses. Gu et al. (23) did not describe a search strategy was and manual searches were not stated openly. Publication language in these meta-analyses was restricted to English only which introduces a language bias (17,21-23,25).
A strict inclusion/exclusion criterion was lacking in Gu et al. (23). The publication bias in these meta-analyses (18,23) was assessed by visual examination of the funnel plot which was unsuitable as the number of studies were less than ten and this was acknowledged only by Chan et al. (18). Inverse variance (IV) random-effects model was utilized in this meta-analysis which does not consider both within- and between-study variations (23) and Chen et al. (22) used fixed effects model. The authors suggest that the DerSimonian and Laird random-effects model (30) should be utilised to obtain a more accurate estimate and the confidence interval. Lastly, only three meta-analyses (17,21,23) performed stratified analysis according to the clinicopathological parameters of tumours this could be due to insufficient information acquired from the included studies.
It is essential for a good meta-analysis to have a through database search (preferably multiple) and avoid language bias. With the available data the authors suggest that future prospective studies should use ToGA criteria (27) to assess the HER2 status and large studies are the need of the hour to confirm the evidence. HER2 status clearly plays a key role in the pathogenesis of gastric and oesophageal carcinomas. Targeted therapy towards this subgroup (despite variable frequency and association with survival) would offer a mortality benefit and improve survival.
Disclosure: The authors declare no conflict of interest.
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