***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 Resected specimens of 288 primary stomach cancers ( 175 early cases and 113 advanced cases ) and recurrent tumors or biopsy specimens of 21 recurrent or inoperable metastatic stomach cancers were examined immunohistochemically for expression of c-erbB-2  oncogene product . c-erbB-2 protein-positive staining was detected in 6.9 , 15.9 and 28.6 % of early , advanced and recurrent or inoperable metastatic stomach cancers , respectively , the difference being significant ( p < 0.005 ) . Four patients with advanced cancer showed positive staining in metastatic lymph nodes but not in the primary tumors . The results of tissue immunostaining were compared with c-erbB-2 protein levels in sera of the patients measured by an enzyme-linked immunosorbent assay . The levels of this oncogene product were consistently low in the sera of most of the patients with primary stomach cancers , regardless of whether or not c-erbB-2 protein was expressed in the tumor . However , in the recurrent or inoperable metastatic stomach cancers , 5 of 6 patients with c-erbB-2 protein-positive tumors showed elevated levels of c-erbB-2 protein in the serum . After following up c-erbB-2 protein levels in the sera of 3 patients during the period of chemotherapy against recurrent or inoperable metastatic disease , we found that the levels increased only in the late stage . These results suggest that , in stomach cancer , c-erbB-2 protein is likely to be excreted into the serum at a relatively late stage , reflecting systemic spread of the disease PURPOSE The c-erbB-2 gene ( encoding the protein p185 ) is overexpressed in diverse human cancers and has been implicated to be of prognostic value in gastric cancer . Recent studies suggest a role of p185 in tumor progression by specifically promoting the invasive capacity of tumor cells . Therefore , the present study was conducted with the following three objectives : ( 1 ) to support the prognostic value of c-erbB-2 in gastric cancer in a large prospect i ve series using a monoclonal antibody and a highly sensitive immunohistochemical method ; ( 2 ) to determine the association of c-erbB-2 expression with the expression of invasion-related genes ; and ( 3 ) to perform the first overall multivariate analysis including c-erbB-2 and the invasion-related tumor-associated protease systems . PATIENTS AND METHODS In a consecutive prospect i ve series of 203 gastric cancer patients ( median follow-up , 42 months ) , expression of c-erbB-2 and a panel of tumor-associated proteases and inhibitors by tumor cells were evaluated semiquantitatively ( score 0 to 3 ) and analyzed for correlation ( chi(2 ) test , Bonferroni-corrected ) . Kaplan-Meier survival analysis and multivariate Cox analysis were performed to determine the relative prognostic impact of c-erbB-2 and the invasion-related parameters . RESULTS Kaplan-Meier analysis ( log-rank statistics ) revealed a significant association of increasing expression of c-erbB-2 with shorter disease-free ( P = . 0023 ) and overall survival ( P = .0160 ) . High amounts of p185 were significantly associated with a high expression of urokinase-type plasminogen activator ( uPA ) ( P < .010 ) , uPA-receptor ( P = .030 ) , type-1 plasminogen activator inhibitor ( PAI ) ( P < .010 ) , type-2 PAI ( P = .021 ) , cathepsin D ( P = .036 ) , matrix metalloproteinase-2 ( P = . 024 ) , alpha-1-antichymotrypsin ( P = .025 ) , and alpha-2-macroglobulin ( P = .017 ) . Multivariate analysis considering these proteases/protease inhibitors , in addition to alpha-1-antitrypsin , tissue plasminogen activator , plasminogen , alpha-2-antiplasmin , and antithrombin III , and established prognostic parameters revealed that , in addition to surgical curability , pT stage , pN stage , and PAI-1 , c-erbB-2 is an independent prognostic factor for overall survival of curatively resected patients ( n = 139 ; P = .049 ; relative risk , 1.54 ; 95 % confidence interval , 1.08 to 1.67 ) and all patients ( P = .028 ; relative risk 1.33 ; 95 % CI , 1.28 to 1.38 ) . CONCLUSION c-erbB-2 is confirmed as a new independent , functional prognostic parameter for overall survival in gastric cancer , even when a panel of invasion-related factors , including the strong prognostic parameter PAI-1 , are considered . The significant correlation of p185 with several tumor-associated proteases supports the hypothesis that c-erbB-2 is a promoter of invasion and metastasis . This strongly suggests that c-erbB-2 may be a promising target for anti-invasive therapy in gastric cancer Amplification of the HER2 gene and over-expression of the HER2 protein in gastric cancer have been shown in a large number of studies . HER2 positivity can be detected in approximately 20 % of patients , which is a characteristic associated with poor prognosis . Pre clinical in vitro and in vivo studies have demonstrated that both trastuzumab and lapatinib are effective in different gastric cancer models and have thus lead to the initiation of clinical studies . In the first phase III study , the ToGA trial , HER2-positive patients with advanced gastroesophageal and gastric adenocarcinoma were r and omized to receive 5-fluorouracil/capecitabine and cisplatin either alone or in combination with trastuzumab . A statically significant gain in overall survival was seen in the patients who received the combined treatment of trastuzumab and chemotherapy . It is expected that the encouraging results from the ToGA trial will have an immediate impact on the management of patients and that routine HER2 testing of patients with advanced gastric cancer will be initiated within a relatively short period of time Using a prospect ively acquired data base of 290 patients with advanced gastric adenocarcinoma , the prognostic significance of serum levels of carcinoembryonic antigen ( CEA ) ( 237 patients ) , alphafeto protein ( AFP ) ( 164 patients ) , beta-human chorionic gonadotrophin ( beta HCG ) ( 165 patients ) , CA19 - 9 ( 64 patients ) and CA125 ( 104 patients ) and tissue staining for C-erb B-2 ( 160 patients ) and beta HCG ( 160 patients ) was investigated . Serum was taken prior to 5-fluorouracil (5FU)-based chemotherapy and immunohistochemistry was performed on diagnostic specimens . In the univariate analysis , tumour markers of poor prognosis were CEA > or = 5 micrograms/l ( P = 0.01 ; median survival ( MS ) 42 versus 35 weeks ) , serum beta HCG > or = 4 U/l ( P = 0.02 ; MS 42 versus 25 weeks ) , CA125 > or = 35 U/ml ( P = 0.03 ; MS 43 versus 31 weeks ) and CA125 > or = 350 U/ml ( P = 0.001 ; MS 42 versus 17 weeks ) . Other significant factors were poor performance status , the presence of metastases and poorly differentiated tumour histology . Tumours markers of poor prognosis in the multivariate analysis were serum beta HCG > or = 4 IU/l [ hazard ratio ( HR ) 1.7 ; 95 % confidence interval ( CI ) 2.8 - 1.1 ] and CA125 > or = 350 U/ml ( HR 2.2 ; CI 4.2 - 1.2 ) . There was a degree of subgroup variability in this model but , in general , other factors correlating with a poor survival were poor performance status , metastases and poorly differentiated tumour histology . This is the largest prognostic study of each tumour marker in advanced disease and demonstrates that serum beta HCG and CA125 in gastric cancer prior to chemotherapy do convey an independent poor prognosis which may reflect not just tumour burden but aggressive biology 
    Output:
    
Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown , suggesting that HER2 overexpression and /or amplification is a molecular abnormality that might be linked to the development of gastric cancer