HER2 loss in HER2‐positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research

Mechanisms of acquired resistance to trastuzumab‐based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post‐progression in patients receiving chemotherapy and trastuzumab for advanced HER2‐positive [immunohistochemistry (IHC) 3+ or 2+ with in‐situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over‐expression were defined as post‐trastuzumab IHC score <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post‐progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over‐expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over‐expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab‐based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti‐HER2 second‐line strategies in initially HER2‐positive disease.     

Antitumor activity of pan‐HER inhibitors in HER2‐positive gastric cancer

Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti‐human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti‐HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2‐positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan‐HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2‐amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin‐like growth factor‐1 receptor (IGF‐1R), were less sensitive to pan‐HER inhibitors. A combination therapy consisting of pan‐HER inhibitors and an IGF‐1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2‐amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF‐1R‐targeting therapy can overcome drug insensitiveness in HER2‐amplified gastric cancer.     

Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer

Background:

Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance.

Methods:

We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.

Results:

Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting.

Conclusions:

Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.     

The dual EGFR/HER‐2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN‐38

Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER‐2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN‐38, the active metabolite of irinotecan (CPT‐11), in colon and gastric cancer cell lines. Concentration‐dependent antiproliferative effects of both lapatinib and SN‐38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08–11.7 μM; SN‐38 range 3.6–256 nM). Lapatinib potently inhibited the growth of a HER‐2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER‐2 expression. The combination of lapatinib and SN‐38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN‐38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN‐38 when compared to SN‐38 treatment alone. Finally, the combination of lapatinib and CPT‐11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT‐11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas. © 2009 UICC     

EGFR / HER2 / HER3 expression in tumour and gefitinib treatment in Chinese patients with advanced non-small cell lung cancer

Objective: Biological markers performable in routine practice and able to predict the clinical outcome of advanced non-small cell lung cancer (NSCLC) treated with gefitinib are urgently needed.Methods: We analyzed EGFR / HER2 / HER3 primary tumour immunohistochemical expression in a prospective and consecutive series of 90 Chinese patients.Platinumpretreated patients received a 250 mg oral dose of gefitinib once daily until disease progression; EGFR / HER2 / HER3 tumour status was related with the clinical outcome in terms of response rate (RR), time to disease progression (TTP), and overall survival (OS).Results: A high expression (scores 2-3) of EGFR, HER2 and HER3 was verified in 16.7%, 43.3% and 21.1% of tumors, respectively.EGFR and HER3 status were not significantly related with response, while the HER2 overexpression result was significantly associated with a higher RR (35.9% vs.15.7%, P = 0.027).The RR in the 13 patients with both HER2 and HER3 expression was also significantly higher than in the other 77 patients (53.8% vs.22.1%, P = 0.036).EGFR / HER2 / HER3 status was not significantly correlated with TrP or OS.Conclusion: The HER2 immunohistochemical expression can play a role in the clinical management of Chinese patients with advanced NSCLC who are candidates for gefitinib therapy     

Trastuzumab‐based neoadjuvant therapy in patients with HER2‐positive breast cancer

Overexpression, or gene amplification, of the human epidermal growth factor receptor 2 (HER2) is evident in 20% to 25% of breast cancers. The biologic agent trastuzumab is an HER2‐targeted monoclonal antibody that inhibits the proliferation of tumor cells and induces tumor cell death through multiple mechanisms of action. Currently, trastuzumab is approved for use in the adjuvant and metastatic settings. Trials combining trastuzumab with neoadjuvant chemotherapy suggest that patients with HER2‐positive breast cancer also may benefit from preoperative trastuzumab. For this article, the author reviewed efficacy and safety data from key studies of patients who received neoadjuvant trastuzumab‐based therapy. Studies were identified from literature searches of publication and congress databases. The results of 3 large phase 3 trials (the M. D. Anderson Cancer Center neoadjuvant trastuzumab trial, the Neoadjuvant Herceptin [NOAH] trial, and the German Breast Group/Gynecologic Oncology Study Group “GeparQuattro” trial) demonstrated that, compared with chemotherapy alone, neoadjuvant trastuzumab plus chemotherapy significantly increased pathologic complete response rates to as high as 65%. Improvements in disease‐free, overall, and event‐free survival also were reported in the NOAH trial. In addition to demonstrated efficacy, a low incidence of cardiac dysfunction suggests that neoadjuvant trastuzumab is both effective and well tolerated. Similar results have been reported in a range of phase 2 studies using different trastuzumab‐based regimens. These encouraging data led the National Comprehensive Cancer Network to recommend treating patients who have operable, locally advanced, HER2‐positive breast cancer with neoadjuvant paclitaxel plus trastuzumab followed by 5‐fluorouracil, epirubicin, and cyclophosphamide plus trastuzumab. Cancer 2010. © 2010 American Cancer Society.     

HER2‐positive patients receiving trastuzumab treatment have a comparable prognosis with HER2‐negative advanced gastric cancer patients: A prospective cohort observation

The monoclonal antibody trastuzumab has brought survival benefit to patients with advanced gastric cancer (AGC) that have human epidermal growth factor receptor 2 (HER2) over expression or amplification. This study was designed to compare the clinical outcomes of HER2‐negative and HER2‐positive AGC patients with or without trastuzumab treatment. There were three groups of patients enrolled for analysis. Group A was 51 HER2‐positive AGC patients treated with trastuzumab and chemotherapy; group B was a matched control group of 47 HER2‐positive patients who received chemotherapy only; group C was a matched group of 251 HER2‐negative patients who received chemotherapy. All the patients were enrolled at Sun Yat‐sen University Cancer Center or Zhongshan Hospital, Fudan University between January 2010 and December 2012. The primary endpoint was overall survival (OS). The Kaplan‐Meier method and log‐rank test were used for survival analysis. The median duration of follow‐up was 13.5 months (range 5–18.6 months). The median OS of these three groups of patients was 14.8 months, 11.3 months and 14.4 months respectively (p < 0.001). The survival difference between group A and B was significant, p < 0.001. Similarly, there was significant difference between group B and C, p < 0.001. Moreover the survival between group A and C was comparable, p = 0.281. The median progression‐free survival for these three groups was 7.4, 6.0 and 7.2 months. Multivariate analysis confirmed that trastuzumab treatment was an independent prognostic factor in group A and B patients (p = 0.017). HER2 positive was an independent adverse prognostic factor in group B and C patients (p = 0.013).     

HER2 expression as a potential marker for response to therapy targeted to the EGFR

Since human epidermal growth factor receptor 2 (HER2) is known to participate with the epidermal growth factor receptor (EGFR) in mitogenic signalling, we hypothesised that HER2 overexpression might indicate responsiveness to EGFR targeted therapies. MCF7 breast cancer cells transfected with the HER2 gene were subcloned to establish a set of genetically related cell lines expressing graded levels of HER2 by immunoblot analysis. The subcloned cell lines and parental MCF7 cells were characterised by their growth characteristics, and cell by cell patterns of EGFR, HER2 and HER3 expression as well as levels of phosphorylated mitogen-activated protein kinase (MAPK) and AKT by laser scanning cytometry (LSC). Growth inhibition assays were used to characterise response to EGFR targeted therapy, and to determine the relationship between therapeutic response and levels of tyrosine kinase expression. The levels of growth inhibition of AG1478 and of the AG1478-trastuzumab combinations were correlated with levels of HER2 expression among the different cell lines. Among EGFR, HER2 and HER3, HER2 overexpression was the best single predictive marker, but combinations of two markers provided additional predictive information.     

HER2阳性胃癌的治疗研究进展

抗人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）的靶向治疗显著延长了HER2阳性晚期胃癌患者的生存期,抑制HER2通路已成为HER2阳性晚期胃癌一线治疗的基础策略。ToGA研究中的曲妥珠单抗联合5-Fu/卡培他滨及顺铂的化疗方案是HER2阳性晚期胃癌一线化疗的标准方案。后ToGA时代,曲妥珠单抗联合其它的多个化疗方案不仅在晚期胃癌的二线治疗和转化性治疗中有突出的疗效,而且在局部进展期胃癌的新辅助治疗中有望发挥更大的作用。目前胃癌抗HER2治疗的研究方向是开发新的抗HER2药物,以及与其它信号通路的靶向药物联合。动态的基因检测有助于明确抗HER2治疗耐药的分子生物学机制,目前的临床研究在克服耐药性方面已取得进展。本文就HER2阳性晚期胃癌治疗方面的最新进展及今后的研究方向进行综述,以期指导临床实践。      

Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib.     

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

Receptor tyrosine kinase MET (c‐MET) has received considerable attention as a potential target for gastric cancer (GC) therapy and a number of c‐MET inhibitors have been developed. For successful drug development, proper preclinical studies especially using patient derived cancer cell lines are very important. We profiled MET and MET‐related characteristics in 49 GC cell lines to utilize them as models in preclinical studies of GC. Forty‐nine cell lines were analyzed for genetic, biological, and molecular status to characterize MET and MET‐related molecules. Four c‐MET inhibitors were tested to elucidate the dependency on MET pathway in the 49 GC cell lines. Six of 49 cell lines were MET amplified with overexpression of c‐MET and p‐MET. The variants of MET were not associated with c‐MET expression or amplification. Hs746T showed an exon 14 deletion in conjunction with MET amplification. The cell lines were divided into 6 MET amplified, 2 c‐MET overexpressed, 2 hepatocyte growth factor (HGF) overexpressed, and 39 MET‐negative subgroups. Except tivantinib, the c‐MET inhibitors showed higher inhibition (%) in MET amplified than in MET nonamplified cell lines that MET amplified cell lines showed MET pathway dependency. However, the c‐MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. Well‐characterized cell lines are very important in studying drug development. Our 49 GC cell lines had various characteristics of MET and MET‐related molecules and MET pathway dependency. These provide a promising platform for development of various RTK inhibitors including c‐MET inhibitors.     

Impact of HER2 and EGFR gene status on gefitinib-treated patients with nonsmall-cell lung cancer

We previously examined the relationship between epidermal growth factor receptor (EGFR) status and clinical outcomes of nonsmall-cell lung cancer (NSCLC) patients treated with gefitinib. In our study, we additionally examined HER2 status and investigate the impact of genetic status as predictors in Japanese NSCLC patients treated with gefitinib. The HER2 copy number status was determined by fluorescence in situ hybridization assay and mutation of HER2 exon 20 was determined by direct sequencing in 74 patients to investigate the relationship between molecular statuses including HER2 and EGFR and the clinical outcomes of patients treated with gefitinib. The high HER2 copy number was identified in 32 (43.2%) of 74 NSCLC patients and no HER2 exon 20 mutations were found. The high HER2 copy number was significantly associated with the sensitivity to gefitinib (p = 0.0045) and a prolonged progression-free survival (PFS) (p = 0.0089) in a univariate analysis, but not in a multivariate analysis. Multivariate analyses exhibited that the drug-sensitive EGFR mutation was an independent predictive factor of a better sensitivity to gefitinib (OR = 41.9, p = 0.002), prolonged overall survival (HR = 0.32, p = 0.019) and PFS (HR = 0.31, p = 0.0045). The high EGFR copy number might have a weak association with better response and prognosis without statistical significance. In conclusion, the drug-sensitive EGFR mutation, rather than HER2 and EGFR copy numbers, is a determinant of favorable clinical outcomes in gefitinib-treated patients with NSCLC, although the high HER2 copy number, to some extent, may influence the gefitinib effect.     

HER2过表达对胃癌预后的影响及其临床应用

人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)的过度表达与胃癌的侵袭、转移和复发有一定的相关性。目前HER2的表达对胃癌的预测价值存有争议。当前的治疗指南已经把检测胃癌中HER2状态作为标准化操作。ToGA研究是胃癌治疗的一项里程碑,其结果奠定了曲妥珠单抗在HER2阳性胃癌患者中的治疗地位。本文就近年HER2基因在胃癌中的表达、检测及其靶向治疗等相关研究进展作一概述。     

DS‐8201a,a new HER2‐targeting antibody–drug conjugate incorporating a novel DNA topoisomerase I inhibitor,overcomes HER2‐positive gastric cancer T‐DM1 resistance

Anti‐HER2 therapies are beneficial for patients with HER2‐positive breast or gastric cancer. T‐DM1 is a HER2‐targeting antibody–drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T‐DM1 resistance. DS‐8201a is a new ADC incorporating an anti‐HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan‐derivative topoisomerase I inhibitor (DXd). DS‐8201a has a drug‐to‐antibody‐ratio (DAR) of 8, which is higher than that of T‐DM1 (3.5). Owing to these unique characteristics and unlike T‐DM1, DS‐8201a is effective against cancers with low‐HER2 expression. In the present work, T‐DM1‐resistant cells (N87‐TDMR), established using the HER2‐positive gastric cancer line NCI‐N87 and continuous T‐DM1 exposure, were shown to be susceptible to DS‐8201a. The ATP‐binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87‐TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T‐DM1 sensitivity. Therefore, resistance to T‐DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS‐8201a inhibited the growth of N87‐TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS‐8201a relative to T‐DM1 compensates for increased efflux. Notably, N87‐TDMR xenograft tumor growth was prevented by DS‐8201a. In conclusion, the efficacy of DS‐8201a as a treatment for patients with T‐DM1‐resistant breast or gastric cancer merits investigation.     

HER2/neu基因扩增和蛋白表达与晚期胃癌患者预后的关系

背景与目的:有证据表明胃癌患者HER2/neu过表达与预后不良及高侵袭性相关,本研究旨在探求HER2/neu表达与晚期胃癌患者临床特征,尤其是与生存期的关系。方法:回顾性分析2006～2008年中国医学科学院肿瘤医院收治的83例晚期胃癌患者的临床资料。应用免疫组化(IHC)和荧光原位杂交(FISH)法检测83例患者的HER2/neu表达情况。数据分析采用SPSS13.0统计软件,生存分析应用Kaplan-Meier法,生存率比较采用log-rank检验。结果:83例患者中位年龄60岁,男女比例为2.95:1。存在HER2/neu蛋白过表达(2+和3+)和基因扩增的患者分别为25例(30.1%)和29例(34.9%)。存在HER2/neu蛋白过表达和基因扩增的晚期胃癌患者往往预后不佳。无HER2/neu基因扩增的晚期胃癌患者中位生存期12.6个月,而有基因扩增者中位生存期仅5.5个月。结论:HER2/neu的表达情况对判断晚期胃癌预后有一定临床意义。     

Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody‐“decoy” strategy

MET, a master gene sustaining “invasive growth,” is a relevant target for cancer precision therapy. In the vast majority of tumors, wild‐type MET behaves as a “stress‐response” gene and relies on the ligand (HGF) to sustain cell “scattering,” invasive growth and apoptosis protection (oncogene “expedience”). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti‐MET antibody (MvDN30) inducing “shedding” (i.e., removal of MET from the cell surface), with a “decoy” (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF‐sequestering ability. To avoid antibody/decoy interaction—and subsequent neutralization—we identified a single aminoacid in the extracellular domain of MET—lysine 842—that is critical for MvDN30 binding and engineered the corresponding recombinant decoyMET (K842E). DecoyMET^K842E retains the ability to bind HGF with high affinity and inhibits HGF‐induced MET phosphorylation. In HGF‐dependent cellular models, MvDN30 antibody and decoyMET^K842E used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell “scattering.” The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In a preclinical model, built by orthotopic transplantation of a human pancreatic carcinoma in SCID mice engineered to express human HGF, concomitant treatment with antibody and decoy significantly reduces metastatic spread. The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand‐dependent MET activation, providing proof of concept in favor of combined target therapy of MET “expedience.”     

HER2 and gastric cancer: a novel therapeutic target for trastuzumab

HER2 protein overexpression by immunohistochemistry (IHC) and/or erB2 gene amplification by in situ hybridization (ISH) was detected in 4-28% of gastric or gastro-oesophageal junction (GOJ) cancers. Most studies have shown that HER2-overexpressing gastric cancers were worse prognosis. Trastuzumab is a humanized monoclonal antibody directed against HER2 with known efficacy in patients with HER2+ early or metastatic breast cancer. The international randomized trial ToGA study showed the superiority of the combination of trastuzumab with chemotherapy doublet fluoropyrimidine (5-FU or capecitabine) plus cisplatin (FP) every three weeks compared with chemotherapy alone in terms of overall survival : 13.8 versus 11.1 months (HR: 0.74, 95% CI: 0.60-0.91, P = 0.0046) in HER2+ advanced gastric cancers. The benefit was even greater in the subgroup with HER2 overexpression (16% of the screened population) as defined by IHC3+ or IHC2+ confirmed by positive ISH test. Trastuzumab plus FP chemotherapy has become the standard treatment for patients with HER2+ non-pretreated metastatic adenocarcinoma of the stomach or GOJ cancer. All these cancers should be tested for HER2 on paraffin block resection or biopsy specimens of the primary tumour or metastases. Endoscopic gastric biopsies should be multiple. The IHC should be the initial test. The standardized immunohistochemical scoring system differs from that recommended for breast cancer given the heterogeneity of HER2 expression and the frequency of incomplete membranous staining in gastric cancers. Equivocal IHC2+ tumours should be tested by ISH with two tools: fluorescence in situ hybridization (FISH) or bright field in situ hybridization (SISH). The perspectives are the assessment of trastuzumab in the perioperative and adjuvant setting, the development of novel anti-HER2 drugs and research into mechanisms of resistance and predictive molecular markers.