gastric cancer is the fifth most common cancer worldwide , with an estimated occurrence of almost one million new cases every year , with half of the world total occurring in east asia . in terms of mortality , it remains one of the most common causes of cancer related mortality , only second to lung cancer , as less than 50% of patients are eligible for complete resection , and , in spite of recent progress , expected survival duration with palliative treatment barely exceeds 1 year . her2 amplification or overexpression is known to occur in approximately 15%-20% of patients with gastric cancer . the pivotal trastuzumab for gastric cancer ( toga ) trial   demonstrated that patients with her2-positive gastric or gastroesophageal junction ( gej ) cancer may benefit from trastuzumab , an anti - her2 monoclonal antibody . in the toga trial , patients assigned to receive trastuzumab in combination with chemotherapy showed significant improvement in overall survival ( os , 13.8 vs. 11.1 months ) , progression - free survival ( pfs , 6.7 months vs. 5.5 months ) , and overall response rate ( orr , 47% vs. 35% ) . in addition , an exploratory analysis demonstrated that patients with strong protein expression ( immunohistochemistry [ ihc ] 3[+ ] or ihc 2[+]/fluorescence in situ hybridization [ fish ] [ + ] ) were more likely to have favorable os with the addition of trastuzumab ( 16.0 months vs. 11.8 months ) . with these results , it is well - known that ethnicity matters in gastric cancer . not only in terms of epidemiology , histology , or pharmacodynamics , certain treatments which were effective for a western population did not show similar efficacy in an asian population , as in the avagast trial . in fact , in the subset analysis of the toga trial , os benefit was not observed in the asian population , while patients from america and europe did benefit from the treatment . in addition , according to the subset analysis of the toga trial , patients with diffuse - type cancer who seldom harbor her2 overexpression did not show os benefit from trastuzumab - based treatment . in the current study , we conducted a multicenter , retrospective analysis on her2-positive gastric cancer patients from 12 tertiary institutes in korea , who were treated with trastuzumab - based treatment in order to confirm whether the clinical outcomes are affected by asian ethnicity or histology , and to provide further understanding of the disease nature of her2-positive gastric cancer . patients diagnosed with her2-positive unresectable or metastatic gastric cancer from 2009 to 2014 were included in the analysis . the inclusion criteria were as follows : ( 1 ) a pathologically confirmed diagnosis of gastric cancer ; ( 2 ) her2 positivity confirmed according to the criteria used in the toga trial , that is , either ihc 3(+ ) or ihc 2(+)/fish ( + ) ; ( 3 ) treated with trasutuzumab - based chemotherapy as the first - line treatment . ( 4 ) complete medical records , including demographics , site of primary tumor , and pathologic reports . the study was approved by the institutional review board of the primary investigator s institute , samsung medical center . clinicopathologic parameters including age , sex , performance status , primary tumor site , lauren s classification , world health organization ( who ) histologic classification , measurability of lesions , methods for her2 confirmation , backbone chemotherapeutic regimen , and baseline laboratory findings were collected retrospectively from patients medical records . os was measured from the date of diagnosis of an unresectable or metastatic disease to the date of death or last follow - up , and pfs was measured from the date of diagnosis of a metastatic or unresectable disease to the date of progressive disease , death , or last follow - up . all survival parameters were calculated using the kaplan - meier method and were compared using a log - rank test . p - values less than 0.05 were considered statistically significant , and all p - values corresponded to two - sided significance tests . to assess whether higher her2/cep17 ratio affected pfs , patients were dichotomized according to good survival group ( median pfs  6 months ) versus poor survival group ( median pfs < 6 months ) . the optimal cutoff for her2/cep17 ratio for predicting a favorable pfs was determined using receiver operating characteristic ( roc ) curve analyses , and further evaluation was performed using the area under the curve ( auc ) . patients diagnosed with her2-positive unresectable or metastatic gastric cancer from 2009 to 2014 were included in the analysis . the inclusion criteria were as follows : ( 1 ) a pathologically confirmed diagnosis of gastric cancer ; ( 2 ) her2 positivity confirmed according to the criteria used in the toga trial , that is , either ihc 3(+ ) or ihc 2(+)/fish ( + ) ; ( 3 ) treated with trasutuzumab - based chemotherapy as the first - line treatment . ( 4 ) complete medical records , including demographics , site of primary tumor , and pathologic reports . the study was approved by the institutional review board of the primary investigator s institute , samsung medical center . clinicopathologic parameters including age , sex , performance status , primary tumor site , lauren s classification , world health organization ( who ) histologic classification , measurability of lesions , methods for her2 confirmation , backbone chemotherapeutic regimen , and baseline laboratory findings were collected retrospectively from patients medical records . os was measured from the date of diagnosis of an unresectable or metastatic disease to the date of death or last follow - up , and pfs was measured from the date of diagnosis of a metastatic or unresectable disease to the date of progressive disease , death , or last follow - up . all survival parameters were calculated using the kaplan - meier method and were compared using a log - rank test . p - values less than 0.05 were considered statistically significant , and all p - values corresponded to two - sided significance tests . to assess whether higher her2/cep17 ratio affected pfs , patients were dichotomized according to good survival group ( median pfs  6 months ) versus poor survival group ( median pfs < 6 months ) . the optimal cutoff for her2/cep17 ratio for predicting a favorable pfs was determined using receiver operating characteristic ( roc ) curve analyses , and further evaluation was performed using the area under the curve ( auc ) . the median age of patients was 60 years ( range , 27 to 85 years ) and 118 patients ( 70.2% ) were male . regarding the location of the primary tumor , 161 cases ( 95.8% ) were stomach cancer and seven cases ( 4.2% ) were gej cancer . as many pathologists in korea do not interpret lauren s classification with biopsied specimens , only 78 cases had been confirmed using lauren s classification , and among them , 44 ( 56.4% ) , 22 ( 28.2% ) , and 12 cases ( 15.4% ) were found to be intestinal - type , diffuse - type , and mixed - type cancer , respectively . however , who histologic classification was confirmed in all cases , with 14 ( 8.3% ) , 63 ( 37.5% ) , 75 ( 44.6% ) , and 11 cases ( 6.5% ) found to be well - differentiated , moderately - differentiated , poorly - differentiated tubular adenocarcinoma , and signet ring cell carcinoma , respectively . in terms of methods for her2 confirmation , in 129 patients disease was confirmed by ihc 3(+ ) , and by ihc 2 - 3(+)/fish ( + ) in 59 patients whose median value of her2/cep17 ratio was 3.34 ( range , 2.09 to 20.00 ) . other details are described in table 1 . regarding the backbone regimen of the trastuzumab - based therapy , 145 patients ( 86.3% ) had received capecitabine plus cisplatin , 14 patients ( 8.3% ) had received 5- fluorouracil ( 5-fu ) plus cispaltin , and nine patients had received other agents . median number of cycles was six ( range , 1 to 62 ) for both trastuzumab and chemotherapy . tumor responses were as follows : 12 ( 7.1% ) complete response , 73 ( 43.5% ) partial response , 48 ( 28.6% ) stable disease , 17 ( 10.1% ) progressive disease , and 18 ( 10.7% ) cases were not evaluable , resulting in 50.6% of orr ( table 2 ) . with a median follow - up duration of 32.9 months ( 95% confidential interval [ ci ] , 30.0 to 35.8 ) , median pfs was 10.2 months ( 95% ci , 8.7 to 11.7 ) , and median os was 18.5 months ( 95% ci , 16.4 to 50.6 ) . considering that asian patients usually achieve approximately 12 months of os and 6 months of pfs , the numerical data of the current study may suggest that even in an asian population , trastuzumab - based therapy could be beneficial for patients with her2-positive gastric cancer . patients with well - differentiated and moderately - differentiated tubular adenocarcinoma were categorized as the well - differentiated histologic ( wdh ) group , and poorly - differentiated tubular adenocarcinoma and signet ring cell carcinoma as poorly - differentiated histologic ( pdh ) group . consequently , 77 ( 45.8% ) and 86 ( 51.2% ) patients were classified as the wdh and pdh group , respectively . the median pfs of the wdh group was slightly longer than that of the pdh group , which did not reach statistical significance ( 11.5 months [ 95% ci , 8.1 to 14.9 ] vs. 8.9 months [ 95% ci , 7.2 to 10.6 ] , p=0.16 ) ( fig . however , the median os of two groups was significantly different ; 19.0 months ( 95% ci , 14.2 to 23.8 ) for the wdh group ; 14.6 months ( 95% ci , 11.9 to 17.3 ) ( p=0.025 ) for the pdh group ( fig . 2 ) . again , in numerical perspectives , these data of pdh patients , that is , pfs of 8.9 months and os of 14.6 months , are better than the data from the typical asian trial , which might suggest that even patients of pdh could benefit from trastuzumab - based therapy . other than histologic differentiation , eastern cooperative oncology group ( ecog ) status and serum albumin level were associated with survival ( table 3 ) . roc analysis was performed for 59 patients who were confirmed as fish ( + ) if a certain her2/cep17 ratio could predict favorable pfs for trastuzumab - based treatment . higher ratios ( 3 or higher and 4 or higher ) were not associated with prolonged pfs ( table 4 ) . the median age of patients was 60 years ( range , 27 to 85 years ) and 118 patients ( 70.2% ) were male . regarding the location of the primary tumor , 161 cases ( 95.8% ) were stomach cancer and seven cases ( 4.2% ) were gej cancer . as many pathologists in korea do not interpret lauren s classification with biopsied specimens , only 78 cases had been confirmed using lauren s classification , and among them , 44 ( 56.4% ) , 22 ( 28.2% ) , and 12 cases ( 15.4% ) were found to be intestinal - type , diffuse - type , and mixed - type cancer , respectively . however , who histologic classification was confirmed in all cases , with 14 ( 8.3% ) , 63 ( 37.5% ) , 75 ( 44.6% ) , and 11 cases ( 6.5% ) found to be well - differentiated , moderately - differentiated , poorly - differentiated tubular adenocarcinoma , and signet ring cell carcinoma , respectively . in terms of methods for her2 confirmation , in 129 patients disease was confirmed by ihc 3(+ ) , and by ihc 2 - 3(+)/fish ( + ) in 59 patients whose median value of her2/cep17 ratio was 3.34 ( range , 2.09 to 20.00 ) . regarding the backbone regimen of the trastuzumab - based therapy , 145 patients ( 86.3% ) had received capecitabine plus cisplatin , 14 patients ( 8.3% ) had received 5- fluorouracil ( 5-fu ) plus cispaltin , and nine patients had received other agents . median number of cycles was six ( range , 1 to 62 ) for both trastuzumab and chemotherapy . tumor responses were as follows : 12 ( 7.1% ) complete response , 73 ( 43.5% ) partial response , 48 ( 28.6% ) stable disease , 17 ( 10.1% ) progressive disease , and 18 ( 10.7% ) cases were not evaluable , resulting in 50.6% of orr ( table 2 ) . with a median follow - up duration of 32.9 months ( 95% confidential interval [ ci ] , 30.0 to 35.8 ) , median pfs was 10.2 months ( 95% ci , 8.7 to 11.7 ) , and median os was 18.5 months ( 95% ci , 16.4 to 50.6 ) . considering that asian patients usually achieve approximately 12 months of os and 6 months of pfs , the numerical data of the current study may suggest that even in an asian population , trastuzumab - based therapy could be beneficial for patients with her2-positive gastric cancer . patients with well - differentiated and moderately - differentiated tubular adenocarcinoma were categorized as the well - differentiated histologic ( wdh ) group , and poorly - differentiated tubular adenocarcinoma and signet ring cell carcinoma as poorly - differentiated histologic ( pdh ) group . consequently , 77 ( 45.8% ) and 86 ( 51.2% ) patients were classified as the wdh and pdh group , respectively . the median pfs of the wdh group was slightly longer than that of the pdh group , which did not reach statistical significance ( 11.5 months [ 95% ci , 8.1 to 14.9 ] vs. 8.9 months [ 95% ci , 7.2 to 10.6 ] , p=0.16 ) ( fig . however , the median os of two groups was significantly different ; 19.0 months ( 95% ci , 14.2 to 23.8 ) for the wdh group ; 14.6 months ( 95% ci , 11.9 to 17.3 ) ( p=0.025 ) for the pdh group ( fig . in numerical perspectives , these data of pdh patients , that is , pfs of 8.9 months and os of 14.6 months , are better than the data from the typical asian trial , which might suggest that even patients of pdh could benefit from trastuzumab - based therapy . other than histologic differentiation , eastern cooperative oncology group ( ecog ) status and serum albumin level were associated with survival ( table 3 ) . roc analysis was performed for 59 patients who were confirmed as fish ( + ) if a certain her2/cep17 ratio could predict favorable pfs for trastuzumab - based treatment . higher ratios ( 3 or higher and 4 or higher ) were not associated with prolonged pfs ( table 4 ) . although several combinations have been introduced in treatment of unresectable or metastatic gastric cancer patients , their prognosis remains poor . as a significant interest in targeted therapies has emerged , a number of targeted agents have been evaluated in gastric cancer . however , most of them fell short of success [ 7 - 9 ] , and trastuzumab is the only agent with a known predictive biomarker and proven efficacies . clinical efficacy of ramucirumab and apatinib was recently demonstrated in refractory gastric cancer patients ; however , their predictive biomarkers have not been found . her2 is a member of the epidermal growth factor receptor family which promotes cell proliferation and inhibits apopapoptosis , and its overexpression has been described in various human malignancies . trastuzumab , a recombinant humanized anti - her2 monoclonal antibody , was first developed as a targeted agent for her2-positive breast cancer , and its unprecedented successes heralded the era of target therapy and relevant biomarkers in the field of oncology . as the carcinogenic roles of her2 in gastric cancer had been suggested , a randomized phase iii trial commenced to assess the clinical efficacy and safety of trastuzumab , which was followed by a great success . not only the nationwide screening policies , epidemiology , pathogenesis , anatomic location or dominant histology , treatment modalities including surgical approaches and adjuvant treatment also differ between asian and western countries . in addition , several pharmacokinetic studies demonstrated that efficacy and tolerability of fluoropyrimidine , a major antineoplastic agent in management of gastric cancer , differ between asian and western people . owing to these factors , the clinical outcomes of asian gastric cancer patients are superior to those of western patients . therefore , mindfulness of ethnicity is important in managing patients and in planning clinical trials as well . given that her2 overexpression is frequently found in gej and intestinal - type cancer , her2 overexpression rate might be lower in asians , who tend to have distal and diffuse - type cancers . however , several series of surveys demonstrated that her overexpression rate was not low in asians . as prevalence of gastric cancer is high in asia , many gastric cancer trials have been conducted with asians . in the toga trial , among 584 patients , 319 ( 54.6% ) were asians , and , as described above , asians per se , were not associated with os benefit with trastuzumab - based treatment . however , this could result from the fact that asian gastric cancer patients already have sufficient survival outcomes with chemotherapy alone , probably due to subsequent treatment which may attenuate the impact of effective combinations as shown in the avagast trial . the benefit of trastuzumab - based therapy in asians might be suggested in two recent asian trials . in a japanese study , 53 patients were treated with trastuzumab combined with s-1 plus cisplatin , and their median pfs and os were estimated as 7.8 months and 16.0 months . and , in a korean study , 55 patients treated with trastuzumab combined with capecitabine and oxaliplatin ( xelox ) showed a median pfs of 9.8 months and a median os of 21.0 months . along with these data , our retrospective analysis showed a median pfs and os of 10.2 months and 18.5 months , respectively ( table 5 ) . considering that asians usually achieve pfs of 5 to 6 months and os of 12 to 13 months with the first - line fluoropyrimidine and platinum combinations , these numerical data imply that asians may also benefit from trastuzumab - based therapy in the same manner with western people . however , prospective head - to - head comparative analyses are warranted in order to confirm the efficacy of trastuzumab - based therapy in this unique population . gastric cancer can be categorized according to two distinct histologic subtypes , intestinal and diffuse , which are distinct in their microscopic and gross appearance , epidemiology , pathogenesis , and prognosis . among them , diffuse - type gastric cancer is associated with poor response to treatment and early relapse , thereby a worse survival . in the current study , we used who classification as a substitute for lauren s classification , as many pathologists in korea do not interpret lauren s classification with endoscopic specimens due to fear of misreading , yet a high concordance between two systems has been observed . compared to the patients with wdh , the patients with pdh showed worse clinical outcomes in both pfs ( 8.9 months vs. 11.5 months , p=0.16 ) and os ( 14.6 months vs. 19.0 months , p=0.025 ) . as these data are not head - to - head comparisons , it is difficult to make a firm conclusion whether patients with pdh can benefit from trastuzumab - based therapy or not . nonetheless , considering the numerical clinical data usually reported in asians , our data may imply that even patients harboring pdh cancer could benefit from trastuzumab - based therapy , although the degree is somewhat limited compared to patients with wdh . in the perspective of frequency of her2 overexpression or amplification , it is more commonly found in intestinal - type cancer than diffuse - type cancer . in the toga trial , 51 out of 584 patients ( 8.7% ) had diffuse - type cancer , and in the logic trial , the differential became even more remarkable ; 3.9% of patients ( 19/487 ) had diffuse - type cancer . this dominance of intestinal - type cancer in the two trials looks suitable considering its disease nature . however , in our cohort , the number of patients with pdh ( n=86 , 51.2% ) was slightly higher than that of patients with wdh ( n=77 , 45.8% ) . several large studies from asia demonstrated that diffuse - type or poorly - differentiated cancer was more predominant . although these types of gastric cancer do not harbor her2 overexpression very often , out - numbering of patients could draw the results . similar to our finding , in the tytan trial , which recruited her2-positive gastric cancer patients confined to asia , only 43% of patients had intestinal - type gastric cancer . a her2/cep17 ratio was recently suggested as a novel predictive marker for trastuzumab - based treatment . in a spanish trial , 66 fish positive patients were evaluated and her2/cep17 higher than 4.7 was identified as the cutoff value for prolonged os . in another report by ock et al . , a her2/cep17 ratio of 4.48 clearly discriminated clinical outcomes . in our study , however , we failed to find optimal discriminating values for favorable pfs . this could have resulted from the small number of samples , and our fish data did not come from a single laboratory . this could draw somewhat inconsistent interpretation regarding the favorable tumor response , such as complete or partial responses . however , as we assessed pfs and os , we believe the validity of the conclusive data and rather , it may reflect real world clinical outcomes . although the backbone regimens are varied , most of them ( 98.2% ) are the combination of fluoropyrimidine ( 5-fu and capecitabine ) and platinum ( cisplatin , oxaliplatin ) which have similar efficacies and can be used interchangeably . and , as we focused on the efficacy of the treatment , the current analysis does not provide ethnic or histologic difference of safety issue . in conclusion , despite the result of subset analysis of the toga trial , we might conclude that irrespective of ethnicity or histologic subtypes , patients with her2-positive gastric cancer can benefit from trastuzumab - based chemotherapy . further analysis to find predictive biomarkers for these patients should be continued and ethnic difference and histologic subtypes should be considered for future clinical trials on gastric cancer patients .