Abstract

Background

To determine whether human epidermal growth factor receptor 2 (HER2) status is an independent prognostic factor in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma.

Patients and methods

Formalin-fixed paraffin-embedded tumor samples from 381 metastatic gastric/GEJ cancer patients enrolled at Krankenhaus Nordwest and Memorial Sloan–Kettering Cancer Centers on six first-line trials of chemotherapy without trastuzumab were examined for HER2 by immunohistochemistry (IHC) and in situ hybridization (ISH). IHC 3+ or ISH-positive tumors were considered HER2 positive.

Results

Seventy-eight of 381 patients (20%) had HER2-positive disease. In the multivariate logistic model, there were significantly higher rates of HER2 positivity in patients with liver metastasis (liver metastasis 31%; no liver metastasis 11%; P = 0.025) and intestinal histology (intestinal 33%; diffuse/mixed 8%; P = 0.001). No significant differences in HER2 positivity were found between resections and biopsies or primaries and metastases. Patients with HER2-positive gastric cancer had longer median overall survival compared with HER2-negative gastric cancer patients (13.9 versus 11.4 months, P = 0.047), but multivariate analysis indicated that HER2 status was not an independent prognostic factor (hazard ratio 0.79; 0.44–1.14; P = 0.194).

Conclusions

Approximately 20% of Western patients with metastatic gastric cancer are HER2 positive. Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GEJ.

introduction

For breast cancer patients, human epidermal growth factor receptor 2 (HER2)-positive tumors are associated with significantly worse survival compared with tumors that do not overexpress HER2 [1–3]. Therapy with trastuzumab (HER2-directed monoclonal antibody) alters the natural history of HER2-positive breast tumors from a histologically aggressive disease to one with improved prognostic outcome [4]. Trastuzumab has been approved by the Food and Drug Administration (FDA) and the European Union and including this agent in association with systemic cytotoxic chemotherapy is the standard of care for patients with metastatic HER2-positive gastric and gastroesophageal (GE) junction adenocarcinoma, based on results of a randomized phase III trial demonstrating improved response and survival when trastuzumab is added to chemotherapy [5].

In the study of trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or GE junction cancer (ToGA) [5], 584 patients were randomly assigned to receive cisplatin and capecitabine alone or with trastuzumab. Those patients assigned to receive trastuzumab with chemotherapy had a significant improvement in overall survival [OS; 13.8 versus 11.1 months, hazard ratio (HR) 0.74; 0.6–0.91, P = 0.0046], progression-free survival (PFS; 6.7 versus 5.5 months), and response rate (Complete + Partial Response; 47 versus 35%). Notably, patients with strongly HER2-positive tumors (immunohistochemistry, IHC 2 +/FISH+ or IHC 3+) derived the greatest OS benefit with the addition of trastuzumab to chemotherapy (16.0 versus 11.8 months, HR 0.68; 0.5–0.83) [5].

The HER2 oncogene (also referred to as HER2/neu or ERBB-2) on chromosome 17q21, encodes a 185-kD transmembrane tyrosine kinase receptor that belongs to the epidermal growth factor receptor (EGFR) family comprised of EGFR/HER1, HER2, HER3, and HER4. HER2 activation plays a pivotal role in cell proliferation and survival, largely mediated through the RAS–MAPK pathway, and it inhibits cell death through the phosphatidylinositol 3′-kinase–AKT–mammalian target of rapamycin pathway. Although HER2 overexpression has been reported in a variety of solid tumors [6–12], anti-HER2 therapy is currently validated only in breast and gastric cancers.

The role of HER2 as a prognostic factor in gastric and GE junction adenocarcinoma remains controversial. Although some surgical series indicate that HER2 is a negative prognostic factor, associated with risk of increased serosal invasion, lymph node metastasis [13], and cancer-related death [14–25], others found no association with outcome and HER2 status in patients with gastric/GE junction cancer [26–33]. These studies consisted mainly of patients undergoing gastrectomies; data specific for prognostic significance in metastatic gastric cancer are lacking. To clarify the clinical relevance of HER2 status, this study examines the clinicopathologic characteristics and outcomes in a uniform population of Western patients with gastric/GE junction adenocarcinoma enrolled in first-line metastatic chemotherapy trials without trastuzumab.

patients and methods

patients

Stage IV gastric cancer patients with available tissue for HER2 testing were identified from a prospective database of six first-line trials of chemotherapy without trastuzumab (Figure 1). All patients had previously provided written informed consent for participation in protocol chemotherapy, including the use of their tissues for research. Prospectively captured patient clinical characteristics included sex, age, primary tumor location, stage, first-line, and if applicable, second-line chemotherapy, metastatic disease sites, and Lauren classification. The Memorial Sloan–Kettering (MSKCC) and Krankenhaus Nordwest Cancer Center Institutional Review Boards approved this study.

Figure 1

Consort diagram.

Figure 1

Consort diagram.

pathology review

Formalin-fixed paraffin-embedded (FFPE) tumor samples from 381 patients were evaluated for HER2 protein expression by IHC and gene amplification using FISH or dual-color HER2/chromosome 17 centromere silver in situ hybridization (SISH) assay. For each case, a corresponding hematoxylin–eosin section was reviewed to assess the sample adequacy. All tumors were reexamined by a gastrointestinal pathologist (LHT and LJT at MSKCC, HMA at Krankenhaus Nordwest) to confirm the histological subtype (diffuse versus intestinal versus mixed).

immunohistochemistry

IHC was carried out at the two institutions with the Ventana PATHWAY rabbit monoclonal antibody (clone 4B5; pre-diluted) on a BenchMark series automated stainer (Ventana, Tucson, AZ), following manufacturer's protocol. The 4B5 antibody is FDA approved for clinical HER2 testing in breast cancer. Antigen retrieval was carried out using CC1 (Cell Conditioning 1; citrate buffer pH 6.0; Ventana) for 30 min. The IHC results were interpreted using the scoring scheme proposed for gastric cancer by Hofmann et al. [34] (ToGA score) and Rüschoff et al. [35]: 0, no staining or membranous reactivity in <10% of tumor cells; 1+, weak, barely perceptible membranous reactivity in >10% of tumor cells; 2+, complete or basolateral membranous reactivity either nonuniform or weak in at least 10% of cells; and 3+, complete or basolateral membranous reactivity of strong intensity in ≥10% of cells. IHC was independently interpreted by two study pathologists (LHT, LJT) at MSKCC and by a pathologist (HMA) and a biologist trained in gastric cancer histology (DW) at Krankenhaus Nordwest.

insitu hybridization

FISH was carried out with the PathVysion HER2 DNA probe kit and procedure (Vysis/Abbott, Abbott Park, Illinois). The kit contains two fluorescently labeled DNA probes, LSI HER2 (labeled with SpectrumOrange), and CEP17 (chromosome 17 enumeration probe, labeled with SpectrumGreen).

Dual-color ISH was carried out according to the INFORM HER2 DNA and INFORM Chromosome 17 (Chr 17) probe kit (ultraVIEW SISH DNP Detection Kit and ultraVIEW RED ISH DIG Detection Kit) and procedure (Ventana/Roche). Both probes were labeled with dinitrophenol (DNP) and optimally formulated for use with the ultraVIEW SISH Detection kit. The HER2 and Chromosome 17 DNP labeled probes were visualized using rabbit anti-DNP primary antibody and the ultraVIEW Detection kit. For both FISH and ISH, the total numbers of HER2 and chromosome 17 signals were counted in at least 20 tumor cell nuclei in two different areas. The HER2/chromosome 17 ratios were interpreted in accordance with the ToGA FISH scoring scheme for HER2 testing in gastric and GE junction cancer as follows: <2.0, HER2 gene not amplified; ≥2.0, HER2 gene amplified [34]. Tumors showing 3+ protein expression or gene amplification were considered HER2 positive.

statistical analysis

PFS and OS were calculated by the Kaplan–Meier method, and statistical significance was analyzed using the log-rank test. To assess the univariate relationship between clinicopathologic variables and HER2 status (positive or negative), the Fisher's exact test was applied. Furthermore, Cox proportional hazard models and logistic regression models were used for the multivariate analyses concerning survival times and the association of HER2 status with clinicopathologic variables, respectively. All P values were two-sided, with P values <0.05 considered to indicate statistical significance.

results

patient characteristics

Supplemental Table S1 (available at Annals of Oncology online) summarizes patient characteristics. The cohort consists of 381 patients with stage IV adenocarcinoma of middle to distal stomach (50%) or GE junction (37%), with a similar number of Lauren's diffuse/mixed (46%) and intestinal tumors (48%). Lymph nodes were the most common site of metastatic disease (60%). The majority of samples were from primary tumors (86%) and were biopsy specimens (67%). Patients predominantly presented with metastatic disease (78%) and went on to receive three-drug combination chemotherapy (62%). None of the patients received trastuzumab or other anti-HER2 therapy in the first- or second-line setting. Fifty-one percent of patients received second-line chemotherapy (HER2-positive group, 60%; HER2-negative group, 49%).

One hundred fifty-four patients (40%) received a three-drug regimen of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24-h infusion in combination with docetaxel 50 mg/m2 (FLOT) on day 1 every 2 weeks [36–38]; 45 patients (12%) received docetaxel 40 mg/m2, fluorouracil 400 mg/m2, leucovorin 400 mg/m2 on day 1, fluorouracil 1000 mg/m2/day × 2 days i.v. continuous infusion beginning on day 1, and cisplatin 40 mg/m2 on day 3 (modified DCF) or parent DCF, docetaxel 75 mg/m2, cisplatin 75 mg/m2, fluorouracil 750 mg/m2/day × 5, with prophylactic GCSF every 3 weeks [39]; and 38 patients (10%) received modified DCF with bevacizumab 10 mg/kg [40]. One hundred forty-four patients (38%) received a regimen of fluorouracil 2600 mg/m2 via 24-h infusion, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2 (FLO) every 2 weeks or fluorouracil 2000 mg/m2 via 24-h infusion, leucovorin 200 mg/m2 weekly, and cisplatin 50 mg/m2 every 2 weeks (FLP) [41].

HER2 positivity and correlation to clinicopathologic characteristics

Seventy-eight of 381 (20%) patients tested HER2 positive. Table 1 summarizes HER2 positivity rate by subgroup. The rate of HER2 positivity was similar between biopsies and surgical specimens (21% versus 19% P = 0.791), primary tumor and metastasis (21% versus 15% P = 0.447). The majority of HER2-positive tumors (77%) were Lauren's intestinal type, comprising 33% of all intestinal-type cases. By location, 45% of the HER2-positive tumors originated in the proximal region encompassing gastric cardia/GE junction (25% of all tumors at this location) and 43% in the gastric body and antrum (18% of tumors at this location). By metastatic disease site, of the patients with HER2-positive tumors, 72% had liver metastasis (31% of all patients with liver metastasis) and 20% had peritoneal disease (11% of all patients had peritoneal metastasis). HER2-positive tumors appeared to be more common in male than female patients (26% versus 10%, P = 0.002).

Table 1.

HER2 positivity by study subgroup

Characteristics Total, n = 381 HER2-positivitya, n (%) P univariate P multivariateb 
Female 125 12 (10)   
Male 256 66 (26) 0.002 0.091 
Age     
 ≥65 186 41 (22) 0.619 0.634 
 <65 195 37 (19)   
ECOG performance status     
 0–1 339 74 (22) 0.147 0.251 
 2 42 4 (9)   
Primary tumor location     
 Gastroesophageal junction 140 35 (25) 0.23 0.755 
 Mid to distal stomach 191 34 (18)   
 Not specified 50 9 (18)   
Disease status     
 Stage IV at diagnosis 296 66 (22) 0.211 0.264 
 Recurrent disease 78 11 (14)   
 Not specified   
Metastatic disease sites     
 Liver, present 181 56 (31)   
 Liver, not present 200 22 (11) 0.001 0.025 
 Lymph nodes, present 230 54 (23)   
 Lymph nodes, not present 151 24 (16) 0.160 0.320 
 Peritoneum, present 144 16 (11)   
 Peritoneum, not present 237 62 (26) 0.004 0.639 
Lauren classification     
 Diffuse/mixed 177 14 (8) <0.001 0.001 
 Intestinalc 184 60 (33)   
 Not specified 20 4 (20)   
Specimen used for HER2 testing     
 Biopsy 254 54 (21)   
 Surgical specimen 124 24 (19) 0.791 0.781 
 Not specified   
 Primary tumor 328 70 (21)   
 Metastatic lesion 48 7 (15) 0.447 0.762 
 Not specified 1 (25)   
Characteristics Total, n = 381 HER2-positivitya, n (%) P univariate P multivariateb 
Female 125 12 (10)   
Male 256 66 (26) 0.002 0.091 
Age     
 ≥65 186 41 (22) 0.619 0.634 
 <65 195 37 (19)   
ECOG performance status     
 0–1 339 74 (22) 0.147 0.251 
 2 42 4 (9)   
Primary tumor location     
 Gastroesophageal junction 140 35 (25) 0.23 0.755 
 Mid to distal stomach 191 34 (18)   
 Not specified 50 9 (18)   
Disease status     
 Stage IV at diagnosis 296 66 (22) 0.211 0.264 
 Recurrent disease 78 11 (14)   
 Not specified   
Metastatic disease sites     
 Liver, present 181 56 (31)   
 Liver, not present 200 22 (11) 0.001 0.025 
 Lymph nodes, present 230 54 (23)   
 Lymph nodes, not present 151 24 (16) 0.160 0.320 
 Peritoneum, present 144 16 (11)   
 Peritoneum, not present 237 62 (26) 0.004 0.639 
Lauren classification     
 Diffuse/mixed 177 14 (8) <0.001 0.001 
 Intestinalc 184 60 (33)   
 Not specified 20 4 (20)   
Specimen used for HER2 testing     
 Biopsy 254 54 (21)   
 Surgical specimen 124 24 (19) 0.791 0.781 
 Not specified   
 Primary tumor 328 70 (21)   
 Metastatic lesion 48 7 (15) 0.447 0.762 
 Not specified 1 (25)   

aHER2 positivity defined as IHC 3+ or FISH/SISH ≥2.0 HER2: chromosome 17.

bLogistic regression model.

cHer2 was positive in 27 of 88 (31%) gastroesophageal junction intestinal-type tumors and 27 of 78 (35%) mid to distal stomach intestinal-type tumors.

ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2.

Bold values indicate statistical significance.

In a multivariate logistic regression model (Table 2), HER2 positivity was strongly associated with histological subtype (intestinal versus diffuse; P = 0.001) and liver metastasis (yes versus no; P = 0.025), whereas the association with anatomic location (P = 0.755), sex (P = 0.091), and presence of peritoneal metastasis was not statistically significant (P = 0.639).

Table 2.

Multivariate overall survival analysis

Characteristics Hazard ratio (95% CI) P 
HER2 positive versus HER2 negative 0.79 (0.44 to 1.14) 0.194 
Male versus female 1.55 (1.25 to 1.85) 0.004 
Age ≥65 versus <65 1.19 (0.93 to1.46) 0.192 
ECOG performance status 2 versus 0–1 1.94 (1.56 to 2.33) <0.001 
Therapy with two-drug versus three-drug combination 1.40 (1.12 to1.68) 0.021 
Stomach versus gastroesophageal junction 1.09 (0.78 to 1.41) 0.565 
Stage IV at diagnosis versus recurrent disease 1.22 (0.89 to1.55) 0.22 
Liver metastasis, yes versus no 1.21 (0.91 to 1.51) 0.21 
Peritoneal metastasis, yes versus no 1.60 (1.29 to 1.91) 0.003 
Intestinal versus diffuse/mixed 0.75 (0.43 to 1.07) 0.083 
Characteristics Hazard ratio (95% CI) P 
HER2 positive versus HER2 negative 0.79 (0.44 to 1.14) 0.194 
Male versus female 1.55 (1.25 to 1.85) 0.004 
Age ≥65 versus <65 1.19 (0.93 to1.46) 0.192 
ECOG performance status 2 versus 0–1 1.94 (1.56 to 2.33) <0.001 
Therapy with two-drug versus three-drug combination 1.40 (1.12 to1.68) 0.021 
Stomach versus gastroesophageal junction 1.09 (0.78 to 1.41) 0.565 
Stage IV at diagnosis versus recurrent disease 1.22 (0.89 to1.55) 0.22 
Liver metastasis, yes versus no 1.21 (0.91 to 1.51) 0.21 
Peritoneal metastasis, yes versus no 1.60 (1.29 to 1.91) 0.003 
Intestinal versus diffuse/mixed 0.75 (0.43 to 1.07) 0.083 

ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2.

Bold values indicate statistical significance.

correlation between HER2 status and survival

A total of 297 deaths (78%) had occurred at the time of analysis, with median follow-up for surviving patients of 18.2 months (range 3.3–44.1). Patients with HER2-positive disease had a longer OS than HER2-negative patients (13.9 months versus 11.4 months; log-rank test P = 0.047; Figure 2). The median PFS was almost identical in the two groups (6.5 versus 6.4 months; log-rank test P = 0.889). When analyzed in subgroups divided by histology, similar differences in OS according to HER2 status were seen in the intestinal group (HER2 positive versus negative, 15 versus 12 months; P = 0.067) but not in the diffuse group (HER2 positive versus negative, 9 versus 11 months; P = 0.70; Figure 3). Similar distributions of OS according to HER2 status were also observed when the survival analysis was adjusted for use of docetaxel (yes or no; P = 0.053) and the type of platinum used (oxaliplatin or cisplatin; P = 0.075). Results were also similar when tumors of mixed type histology were analyzed within the intestinal group or were excluded from the analysis (data not shown). In the multivariate analysis, including HER2 status, age, sex, performance status, two- versus three-drug chemotherapy, histologic subtype, liver metastasis, peritoneal metastases, type of sampling, and disease status, HER2 status was not an independent predictor of OS (HR 0.792; P = 0.194; Table 2). In the multivariate analysis, an Eastern Cooperative Oncology Group performance status of zero or one, the absence of peritoneal carcinomatosis, female gender, and three-drug chemotherapy were significantly associated with longer survival time.

Figure 2

Kaplan-Meier curves for (A) progression free survival (PFS) and (B) overall survival (OS) for patients with HER2-positive (n = 78) and HER2-negative (n = 303) disease. Although the difference was significant in the univariate analysis (log-rank test p = 0.047), HER2 status was not an independent prognostic factor in the multivariate HR 0.79 (95% Cl; 0.44 to 1.14; p = 0.194).

Figure 2

Kaplan-Meier curves for (A) progression free survival (PFS) and (B) overall survival (OS) for patients with HER2-positive (n = 78) and HER2-negative (n = 303) disease. Although the difference was significant in the univariate analysis (log-rank test p = 0.047), HER2 status was not an independent prognostic factor in the multivariate HR 0.79 (95% Cl; 0.44 to 1.14; p = 0.194).

Figure 3

Kaplan-Meier curves for overall survival by HER2 status in patients with (A) intestinal and (B) diffuse (mixed) type of histology.

Figure 3

Kaplan-Meier curves for overall survival by HER2 status in patients with (A) intestinal and (B) diffuse (mixed) type of histology.

discussion

In gastric cancer, overexpression and amplification of HER2, first described more than two decades ago [42, 43], occur in 20%–30% of intestinal and <10% of diffuse/signet ring gastric cancers [5, 15, 34]. In our cohort of 381 metastatic gastric cancer patients treated in first-line trials of chemotherapy without trastuzumab, 20% of tumors were HER2 positive. Unlike breast cancer, HER2 positivity was associated with longer OS (13.9 versus 11.4 months, HR 0.792; P = 0.047) on univariate analysis. This prognostic value disappeared in multivariate analysis (P = 0.194). We also found no impact of HER2 status on PFS, indicating that HER2 overexpression is not associated with more aggressive tumor biology or with resistance to chemotherapy in gastric and GE junction adenocarcinoma. Likewise, a series of patients with resected disease [26–33], including three recent studies [28, 32, 44], concluded that HER2 is not an independent prognostic factor in localized esophagogastric cancer. Terashima et al. conducted a biomarker analysis of 829 patients enrolled in the ACTS-GC study, a randomized phase III trial, of adjuvant treatment with S-1 after D2 dissection for locally advanced gastric cancer [45]. This large biomarker study showed that HER2 status was not associated with the OS or relapse-free survival in either the surgery alone group or the S-1 group [32]. Yoon et al. [28] examined a cohort of 713 patients with resected esophageal adenocarcinoma and also demonstrated that HER2 status is not associated with adverse survival. Kunz et al. [44] reported on 169 patients with radical resection of esophagogastric cancer and found that HER2 status or primary tumor site did not correlate with patient survival.

In the phase III ToGA study [5], the median OS of HER2-positive patients on the standard arm (i.e. non-trastuzumab arm) was 11.1 months [5] similar to historic comparisons with other phase III studies in metastatic gastric cancer, supporting our finding that HER2 is not a negative prognostic factor in esophagogastric cancer [46, 47]. Although HER2 is not a negative prognostic factor in gastric cancer, this is not a reflection on its value as a predictive marker. The ToGA study marks a significant milestone in the development of targeted agents in metastatic gastric cancer.

Our analysis is based on a large and uniform cohort of Western patients with metastatic gastric cancer, all treated with standardized chemotherapy in a clinical trial. HER2 testing was carried out and reviewed by referenced pathologists, with other clinical and pathological characteristics captured prospectively in research databases. Unlike other studies, our cohort consists solely of patients with stage IV disease with well annotated chemotherapy data available on all of our patients, and none received trastuzumab in the first- or second-line setting.

A conflicting analysis published by Bengami et al. examined HER2 IHC and FISH in 221 gastric carcinoma surgical specimens using tissue microarray (TMA). Although only 15 samples were HER2 positive, of which only 11 samples were included in the survival analysis (8%), HER2 was suggested to be a negative prognostic factor (17 versus 40 months survival, P = 0.23) [16]. Similar studies that demonstrated HER2 as a negative prognostic factor in resected esophagogastric cancer also use TMA [14–25]. These results must be considered as problematic owing to the known variability of TMA quality and HER2 overexpression in esophagogastric cancers [48–50]. It is also important to note that these studies did not consider special scoring recommendations for gastric cancer.

Earlier series described a wider range of HER2 positivity in gastric cancer from 9% to 53% [19, 24], which can be attributed to differences in antibodies used and scoring system for IHC, variation in tumor location (proximal versus distal), histology (diffuse versus intestinal), stage, and geographic distribution (Asia versus United States/Europe). The series from Japan and Korea report a HER2 positivity rate of 8%–13% [32, 51]. On the other hand, our report correlates with HER2 positivity rate in the ToGA study [5, 15, 34] and confirms that HER2-positive tumors are more common among proximal/GE junction cancers (25%) and tumors of Lauren intestinal histology (33%). Because clinicopathologic variables are interrelated (e.g. intestinal histology is more common in the GE junction and is more often associated with liver metastasis than diffuse histology), we carried out a logistic regression model. This showed that intestinal histology and the presence of liver metastases were independently associated with positive HER2 status.

HER2 testing by IHC is reported to be distinct from breast cancer IHC testing because of the secretory nature of gastric epithelium, resulting in higher frequency of incomplete membranous staining (basolateral only) [34]. As a result, these tumors would be scored ‘negative’ by IHC while in fact they may be FISH positive [34]. Based on these findings, we used the modified HER2 scoring system proposed by Hofmann et al. in 2008 (used in the ToGA) and Rüschoff et al. [35] in 2010, which considers basolateral staining as positive. Alternatively, the new ASCO/CAP HER2 scoring guidelines for breast cancer may be used as long as it is recognized that the basolateral pattern of immunoreactivity can make it difficult to assign an IHC score in gastric cancer [52].

Gastric cancer is a heterogeneous disease that subdivides into proximal/GE junction, diffuse/signet ring type, and distal gastric cancer. Each subtype is associated with unique epidemiology and gene expression profile [37]. Our study supports the idea of substantial molecular differences between histologic tumor types, which may develop through different molecular alterations, by demonstrating that HER2 amplification is extremely rare in diffuse gastric carcinoma, associated with abnormal E-cadherin expression [31, 53, 54] and CDH1 gene mutations [55], and that HER2 expression is more often found in gastric carcinomas that spread to the liver. An improved understanding of the biology of gastric cancer, including a better recognition and delineation of gastric cancer subtypes, will significantly improve the ability to define and explore the benefits of novel molecularly targeted therapies in this disease.

Our study demonstrates that HER2 amplification or overexpression is not a prognostic marker in gastric and GE junction carcinoma. The implication of this finding is that the impact of HER2 on gastric cancer is different than in breast cancer. Whether this is due to gastric cancer-specific epigenetic or genetic influences on HER2 biology or simply that the poor survival of gastric cancer masks the potential prognostic influence of HER2 positivity is not known. However, what is clear is that common genetic drivers of malignancy must be taken in context of the underlying disease. Disease-specific insights into HER2 biology may therefore be necessary to improve HER2 targeting in this disease.

funding

This study was supported in part by Roche Pharma, Germany and Ventana Medical Systems Inc. (Tucson AZ).

disclosure

YYJ: Boehringer Ingelheim, Gentech; MAS: Sanofi Aventis; SEA: Roche Pharma, Sanofi Aventis, Novartis Pharma. All other authors have declared no conflicts of interests.

acknowledgements

The Institute of Clinical Research at Krankenhaus Nordwest University Cancer Center, Frankfurt and the Memorial Sloan–Kettering Cancer Center, New York designed this study and carried out all tests and evaluations. The Institute of Clinical Research has received partial funding from Roche Pharma, Germany and Ventana Medical Systems Inc. (Tucson AZ). However, the funder had no role in the conduct of the study or collection, analysis, and interpretation of the data. The funder also had no role in writing or reviewing this manuscript. Presented in part at the ASCO Annual Meeting, Chicago, IL, June 3–7, 2011.

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