***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Trastuzumab , a monoclonal antibody against human epidermal growth factor receptor 2 ( HER2 ; also known as ERBB2 ) , was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer . METHODS ToGA ( Trastuzumab for Gastric Cancer ) was an open-label , international , phase 3 , r and omised controlled trial undertaken in 122 centres in 24 countries . Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation . Participants were r and omly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab . Allocation was by block r and omisation stratified by Eastern Cooperative Oncology Group performance status , chemotherapy regimen , extent of disease , primary cancer site , and measurability of disease , implemented with a central interactive voice recognition system . The primary endpoint was overall survival in all r and omised patients who received study medication at least once . This trial is registered with Clinical Trials.gov , number NCT01041404 . FINDINGS 594 patients were r and omly assigned to study treatment ( trastuzumab plus chemotherapy , n=298 ; chemotherapy alone , n=296 ) , of whom 584 were included in the primary analysis ( n=294 ; n=290 ) . Median follow-up was 18.6 months ( IQR 11 - 25 ) in the trastuzumab plus chemotherapy group and 17.1 months ( 9 - 25 ) in the chemotherapy alone group . Median overall survival was 13.8 months ( 95 % CI 12 - 16 ) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months ( 10 - 13 ) in those assigned to chemotherapy alone ( hazard ratio 0.74 ; 95 % CI 0.60 - 0.91 ; p=0.0046 ) . The most common adverse events in both groups were nausea  ( trastuzumab plus chemotherapy , 197 [ 67 % ] vs chemotherapy alone , 184 [ 63 % ] ) , vomiting ( 147 [ 50 % ] vs 134 [ 46 % ] ) , and neutropenia ( 157 [ 53 % ] vs 165 [ 57 % ] ) . Rates of overall grade 3 or 4 adverse events ( 201 [ 68 % ] vs 198 [ 68 % ] ) and cardiac adverse events ( 17 [ 6 % ] vs 18 [ 6 % ] ) did not differ between groups . INTERPRETATION Trastuzumab in combination with chemotherapy can be considered as a new st and ard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer . FUNDING F Hoffmann-La Roche Background Trastuzumab has been recently proposed as a treatment for patients with HER2-positive advanced/metastatic gastric cancer ( GC ) . Since most patients have inoperable disease at diagnosis , accurate assessment of HER2 status on biopsy specimens is essential to select the patients who may benefit from therapy . Aim The aim of this study is to establish whether HER2 status assessed on biopsy material could be reliable for treatment decisions using anti-HER2 agents . Methods The HER2 status was evaluated in 61 consecutive pairs of biopsy and surgical GCs sample s by immunohistochemistry and chromogenic in situ hybridization . Results The overall concordance of HER2 status between biopsy and surgical specimens was 91.8 % with a predictive positive value of 71.4 % and a negative predictive value of 94.4 % . Of five discordant cases , there were three negative and two positive false biopsy results . All the false negative cases showed heterogeneous expression of HER2 protein in surgical sample s. Two cases displayed overexpression of the receptors without corresponding gene amplification . Conclusions HER2 status as evaluated on biopsy sample s is a fairly good predictor of HER2 status of surgically-excised GCs . The most important influence for discordant results is tumor heterogeneity . However , HER2 overexpression , especially without coexisting gene amplification , may only be a temporary change in a tumor population . This may explain those cases with positive HER2 evaluation on biopsy material and a negative result on corresponding surgical specimen Background A recent r and omized controlled trial ( Trastuzumab for Gastric Cancer [ ToGA ] study ) established st and ard scoring criteria of human epidermal growth factor receptor 2 ( HER2 ) for gastric cancer and demonstrated the efficacy of trastuzumab for treating metastatic gastric cancer . The aim of the present study was to evaluate the frequency of HER2-positive cases by application of the st and ard criteria in patients with resectable gastric cancer and to examine the relationships between HER2 expression and prognosis , mucin phenotype , p53 status , and clinicopathological features . Methods A total of 213 patients were included in this retrospective study . All tumor sample s were examined for HER2 expression by immunohistochemistry ( IHC ) , HER2 amplification by in situ hybridization , and mucin and p53 expression by staining for CD10 , MUC2 , MUC5AC , MUC6 , and p53 . Results HER2-positive tumors were identified in 25 patients ( 11.7 % ) . HER2-positive cases were more frequently found in men , older patients , and in the intestinal histological type ( P = 0.0048 , 0.0309 , and < 0.0001 , respectively ) . Although no association was found between HER2 overexpression and mucin phenotype , the expression of CD10 and p53 was significantly correlated with HER2 positivity ( P = 0.0079 and 0.013 ) . The overall survival of HER2-negative and -positive patients was not significantly different . However , in patients with stage III/IV , overall survival was worse in HER2-positive patients ( P = 0.0149 ) . In a comparison between dual-color in situ hybridization ( DISH ) and fluorescence in situ hybridization ( FISH ) , four IHC2+/3 + cases that were DISH-positive were judged as negative by FISH . Conclusions Our study indicated that HER2 expression was less frequent in resectable gastric cancer than in metastatic gastric cancer . The impact of HER2 expression on survival was limited . DISH was superior to FISH for evaluating cases with limited HER2 expression Background HER2 status assessment is a prerequisite for the establishment of an appropriate treatment strategy in gastric cancer . Gastric cancers are very heterogeneous and separate evaluations of gene amplification and protein expression lead to uncertainties in localizing distinct clones and are time consuming . This study evaluates the equivalence of the novel method combining both gene and protein platforms on one slide . Methods Immunohistochemistry ( IHC ) and HER2 dual-colour silver in situ hybridization ( SISH ) as single methods ( IHC/SISH ) and gene-protein platform combining both methods on one slide ( gene/protein ) were performed in r and omly collected 100 cases of gastric adenocarcinoma . Results of IHC/SISH were compared with gene/protein staining . Results 96 of 100 sample s were assessable . In the gene/protein staining , pathologists were able to assess gene amplification and consequent protein expression at the single cell level . In comparison trials , gene amplification was observed in 14.6 % by both , conventional SISH and gene/protein platform ( agreement 100 % ; Kappa-coefficient κ = 1.0 ) . Protein expression scores by IHC were 70.8 % ( 0 ) , 10.4 % ( 1 + ) , 9.4 % ( 2 + ) , and 9.4 % ( 3 + ) . Protein expression by gene/protein method were : 70.8 % ( 0 ) , 11.5 % ( 1 + ) , 7.3 % ( 2 + ) and 10.4 % ( 3 + ) of patients . There were complete concordances in IHC assessment of cases with score 0 ( 100.0 % ; κ = 1 ) . High concordances are shown in score 1 + ( 98.96 % ; κ = 0.947 ) and 3 + ( 96.88 % ; κ = 0.825 ) cases and good concordances in 2 + cases ( 95.83 % ; κ = 0.728 ) . Conclusions This novel combined platform has the advantage of being able to evaluate both gene and the protein status in the same cancer cell and may be of particular interest for research and patient ’s care . Article categoryDisease Biomarker Background In the Trastuzumab for GAstric cancer ( ToGA ) study , trastuzumab plus chemotherapy improved median overall survival by 2.7 months in patients with human epidermal growth factor receptor 2 (HER2)-positive [ immunohistochemistry ( IHC ) 3+/fluorescence in situ hybridization-positive ] gastric/gastroesophageal junction cancer compared with chemotherapy alone ( hazard ratio 0.74 ) . Post hoc exploratory analyses in patients expressing higher HER2 levels ( IHC 2+/fluorescence in situ hybridization-positive or IHC 3 + ) demonstrated a 4.2-month improvement in median overall survival with trastuzumab ( hazard ratio 0.65 ) . The ToGA study provides the largest screening data set available on HER2 overexpression/amplification in this indication . We further analyzed correlation(s ) of HER2 overexpression/amplification with clinical and epidemiological factors . Methods HER2-positivity was analyzed by histological subtype , tumor location , geographic region , and specimen type . Exploratory efficacy analyses were performed . Results The HER2-positivity rate was 22.1 % across analyzed tumor sample s. Rates were similar between European and Asian patients ( 23.6 % vs. 23.9 % ) , but higher in intestinal- vs. diffuse-type ( 31.8 % vs. 6.1 % ) , and gastroesophageal junction cancer versus gastric tumors ( 32.2 % vs. 21.4 % ) . Across all IHC scores , variability in HER2 staining ( ≤30 % stained cells ) was observed in almost 50 % of cases , with increasing rates in lower IHC categories , and did not affect treatment outcome . The polysomy rate was 4 % . Conclusions HER2 expression varies by tumor location and type . All patients with advanced gastric or gastroesophageal junction cancer should be tested for HER2 status , preferably using IHC initially . Due to the unique characteristics of gastric cancer , specific testing/scoring guidelines should be adhered to Goals : To evaluate the HER-2/neu protein level by immunohistochemistry ( IHC ) and its gene amplification by fluorescence in situ hybridization ( FISH ) in gastric cancer sample s , and the relevance to the prognosis of gastric cancer patients . Study : HER-2/neu overexpression and gene amplification were examined with semiquantitative st and ardized IHC in 775 formalin-fixed paraffin-embedded gastric cancer sample s , and 252 of these cases were analyzed with FISH .  Results : Of the 775 gastric cancer sample s examined by IHC  , a total of 88 ( 11 % ) cases were positive for HER-2/neu overexpression at a score of 3 + ; another 44 ( 6 % ) cases were equivocal with a score of 2 + ; and the rest 643 ( 83 % ) cases were negative scored as 0/1 + . Intestinal-type and early-stage cancers exhibited higher rate of HER-2/neu overexpression than those of diffuse/mixed-type and advanced cancers ( P<0.05 ) . Intestinal-type and early-stage cancers with HER-2/neu overexpression also exhibited short 5 year survival rates ( 21 % vs. 47 % , P=0.027 ; 29 % vs. 60 % , P=0.037 ) than HER-2/neu-negative cases , but not in the diffuse/mixed-type and advanced stage cancers . By FISH analysis , it was shown that 70 % ( 60/86 ) of IHC 3 + had HER-2/neu gene amplication . In contrast , only 14 % ( 6/43 ) of IHC 2 + cases , and 2.5 % ( 3 ) of the 120 cases with IHC 0/1 + r and omly selected showed HER-2/neu gene amplification . Conclusions : HER-2/neu overexpression may be used as an independent prognostic factor for intestinal-type and early-stage gastric cancer patients . IHC 3 + and 2 + cases should be further detected by FISH to assess HER-2/neu gene status . Patients with HER-2/neu amplification also might constitute potential c and i date s for targeted therapy with trastuzumab It has been reported that HER2 expression is different in gastric and breast cancers , and a gastric cancer scoring system 
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Conclusions Our results showed that HER2 IHC was well concordant with ISH in HER2 IHC score 0/1 + or 3 + .
Although this meta- analysis showed higher diagnostic accuracy of HER2 IHC , more detailed criteria for HER2 IHC score 2 + cases will be required to predict HER2 status