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The role of epidermal growth factor receptor in prognosis and treatment of gastric cancer Expert Rev. Gastroenterol. Hepatol. 8(1), 111–117 (2014)

Liu Hong*1,2‡, Yu Han2‡ and Lubi Brain3 1 State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China 2 Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China 3 The Sidney Kimmel Comprehensive Cancer Center, Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA *Author for correspondence: Tel.: +86 298 477 3974 Fax: +86 298 253 9041 [email protected]

Authors contributed equally

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Despite tremendous efforts to reduce deaths due to gastric cancer, it represents the second leading cause of cancer-related deaths worldwide. EGF receptor (EGFR) plays important roles in gastric carcinogenesis by regulation of cell cycle, angiogenesis and apoptosis. This review evaluates the functions, mechanisms and clinical uses of EGFR in gastric cancer. Although EGFR targeted single therapy shows limited effect, the combination of EGFR targeted agents with traditional chemotherapy regimens may bring about important progress in cancer therapy. More clinical trials should be performed to clarify both the prognostic and therapeutic value of EGFR in gastric cancer. KEYWORDS: epidermal growth factor receptor • gastric cancer • prognosis • target therapy

Gastric cancer is the third most prevalent malignancy and the second most common cause of cancer-related deaths worldwide [1]. Despite tremendous efforts which have promoted surgical techniques, the clinical outcomes remain poor in patients with advanced gastric cancer. Even after R0 resection of the tumor the overall recurrence rates are high. Thus, there is an urgent need for developing new chemotherapeutic drugs, including the molecular agents. Recently, some clinical trials have shown that EGF receptor (EGFR) target therapy was effective for many cancers, such as colon cancer and lung cancer [2–4]. EGFR belongs to the family of receptor tyrosine kinases ErbB, consisting of HER1/EGFR/ ErbB1, HER2/Neu/ErbB2, HER3/ErbB3 and HER4/ErbB4 [5]. The ErbB protein family plays a fundamental role in the development of many cellular processes, such as cell proliferation, apoptosis, angiogenesis and metastasis [6]. EGFR is abnormally expressed in a wide variety of solid malignancies, including gastric cancer [7]. High expression level of EGFR is associated with an increased risk of invasion or metastasis in solid tumors [7,8]. Inhibition of EGFR contributes to regulation of cell division, migration, angiogenesis and apoptosis in gastric cancer

10.1586/17474124.2014.844648

cells [9,10]. So far, the approaches of inhibiting the EGFR signaling pathway include monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) [11]. The anti-EGFR mAbs involve cetuximab, matuzumab, nimotuzumab, panitumumab, zalutumumab and ch806, while the anti-EGFR TKIs involve lapatinib, erlotinib and gefitinib. The expression of EGFR in gastric cancer

EGFR is overexpressed in various cancers, including breast, gastric, ovarian, colorectal, head and neck cancer [12,13]. Kim et al. have found that overexpression of EGFR occurred in 5–25% of gastric cancers [14]. Several studies have evaluated the association of EGFR expression with survival of gastric cancer patients (TABLE 1) [15–20]. Some studies have found that EGFR-positive status was significantly associated with worse outcomes of gastric cancer patients [15–17]. Inokuchi et al. have examined the expression of EGFR in 126 cases of gastric cancer patients who underwent a radical gastrectomy [15]. High expression of EGFR was found significantly related to distant metastasis and recurrence, as well as poor disease-specific survival. Terashima et al. have found that the overall

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Table 1. Summary of selected studies reporting EGF receptor expression and survival in gastric cancer. Study (year)

Ethnicity

Patients (n)

EGFR assay

HR

95% CI

Ref.

Inokuchi et al. (2011)

Mongoloid

126

Immunohistochemistry

1.7

0.74–3.80

[15]

Terashima et al. (2012)

Mongoloid

829

Immunohistochemistry

1.64

1.14–2.37

[16]

Lieto et al. (2008)

Caucasian

69

Immunohistochemistry

5.35

1.39–20.51

[17]

Atmaca et al. (2012)

Caucasian

357

Immunohistochemistry

0.85

0.57–1.13

[18]

Matsubara et al. (2008)

Mongoloid

87

Immunohistochemistry

0.99

0.63–1.57

[19]

Ja´come et al. (2013)

Caucasian

201

Immunohistochemistry

0.73

0.11–4.81

[20]

EGFR: EGF receptor; HR: Hazard ratio.

and relapse-free survival rates were significantly lower in EGFRpositive gastric cancer patients than in negative ones [16]. Lieto et al. have found that the positive expression of EGFR was correlated with worse survival by both univariate and multivariate analyses [17]. On the contrary, several studies have demonstrated no significant correlation between EGFR expression and survival of gastric cancer patients [18–20]. Atmaca et al. have investigated the expression of EGFR in 57 cases of gastric cancer patients who received chemotherapy in four first-line trials [18]. The median overall survival was similar in gastric cancer patients with EGFRpositive tumors as compared with EGFR-negative ones. Overexpression of EGFR was not associated with drug resistance to chemotherapy in gastric adenocarcinoma. Matsubara et al. have investigated the clinical implications of EGFR in 87 cases of gastric cancer patients who underwent gastrectomy and subsequently received chemotherapy [19]. The EGFR expression did not significantly predict poor outcomes of patients. Ja´come et al. have investigated the prognostic role of EGFR expression in 201 cases of patients with gastric and esophagogastric junction adenocarcinoma [20]. The membrane and cytoplasmic expression of EGFR was 9 and 45%, respectively. The data revealed that EGFR did not have prognostic influence in the gastric cancer population. Taken together, the prognostic role of EGFR in gastric cancer remains unclear. Recent studies have showed that the polymorphisms of the EGFR gene might play important roles in the development of gastric cancer [21–23]. Zhang et al. have investigated the association between single nucleotide polymorphisms (SNP) of EGFR exons and risk of gastric cancer [21]. The variant rs2072454 T allele and TT genotype were significantly associated with an increased risk of gastric cancer. Han et al. have evaluated the association between the EGFR intron 1 CA repeat polymorphism and the treatment outcome of cetuximab plus modified leucovovin, 5-fluorouracil and oxaliplatin (FOLFOX6) chemotherapy in gastric cancer patients [22]. Patients with low CA repeats had longer progression-free survival and overall survival as compared with those having high CA repeats. Thus, the EGFR intron 1 CA repeat polymorphism might be a predictive biomarker of cetuximab efficacy in advanced gastric cancer. Moutinho et al. have investigated the structural alterations of the EGFR gene in 77 cases of gastric cancer patients [23]. The gastric cancer with alterations of EGFR 112

showed a significant increase of tumor size in comparison to wild-type EGFR cancers. Liu et al. have screened EGFR mutation in 58 cases of gastric adenocarcinoma using high resolution melting analysis [24]. Three EGFR missense mutations and 22 SNPs were identified. Becker et al. have analyzed the presence of EGFR mutations in 66 cases of gastric cancer patients [25]. No activating EGFR mutations were found, indicating that EGFR structural alterations were rare in gastric cancer. The role of EGFR in gastric cancer

EGFR plays a key role in many processes of tumor progression, such as cell proliferation, angiogenesis, invasion, migration, metastasis and apoptosis [6,7]. EGFR activation participates in intestinal differentiation of gastric cancer [26]. Hirao et al. have found that stable transfection of EGFR antisense could result in growth suppression of MKN28 gastric cancer cells in vitro and in vivo [27]. Jiang et al. have found that type II cGMP dependent protein kinase could inhibit EGFR-induced migration of gastric cancer cells [28]. EGFR consists of an extracellular domain, a short lipophilic transmembrane domain and an intracellular domain carrying tyrosine kinase activity. Ligand binding to the extracellular domain leads to EGFR activation, resulting in the phosphorylation of the intracellular tyrosine kinase initiating a series of intracellular signal pathways, including the PI3K-AKT, the Ras-MAPK pathway and the STAT signaling pathway [29,30]. The plasma membrane-bound EGFR signaling consists of the kinase-dependent and -independent modes of actions [31]. The kinase-independent functions are mediated by PLC-PKC/Ca2+, Ras-Raf-MEK-MAPK, Akt-mTOR and JAK2-STAT3. The kinase-independent functions are regulated by many genes, such as MAPK, mTOR, PUMA and SGLT1. The nuclear EGFR is implicated in a number of cellular processes, such as proliferation, DNA repair, metastasis and resistance to radiation and anti-cancer agents. Inhibition of EGFR can induce G0/G1 arrest of gastric cancer cells by decreasing the expression of phosphorylated retinoblastoma protein, phosphorylated GSK-3b, cyclin D1 and by increasing the expression of p21 and p27 [32]. Liao et al. have reported that inhibition of EGFR could lead to G0/G1 arrest of gastric cancer cells by downregulating cyclin D1, CDK2 and upregulating p27. Inhibition of EGFR could repress the Expert Rev. Gastroenterol. Hepatol. 8(1), (2014)

EGFR & gastric cancer

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invasion and angiogenesis of SGC-7901 cells by inhibiting them from secreting MMP-2, MMP-9 and VEGF [33]. Caruso et al. have found that protease-activated receptor-2 activation could promote EGFR transactivation in gastric cancer cells [34]. Dan et al. have investigated the crosstalk between EGFR and integrin-mediated signal transduction pathways in human gastric adenocarcinoma cells [35]. EGF could activate FAK and p130cas phosphorylation, while fibronectin could activate ERK general phosphorylation. The effect of EGFR mAbs and TKIs on gastric cancer cells

Cetuximab, an IgG1 anti-EGFR mAb, can bind specially to the extracellular domain of EGFR on both normal and tumor cells, thus competitively inhibiting the binding of EGF [36]. Cetuximab is the first anti-EGFR antibody to be approved by the US FDA since 2004 for treating squamous cell carcinomas and colorectal cancer. High EGFR expression and low levels of receptor activation are associated with cetuximab responsiveness in gastric cancer cells [37,38]. Hara et al. have investigated the anti-tumor effect of cetuximab in gastric cancer cells [39]. Cetuximab could significantly inhibit tumor growth of MKN-28 cells in nude mice. This anti-tumor activity was significantly enhanced by treating it with IL-2, which could expand NK cells. Zhang et al. have found that cetuximab could effectively inhibit the growth of gastric cancer xenografts in nude mice, and could trigger its apoptosis [40]. Cetuximab cannot significantly reduce cell viability and proliferation in EGFR-positive/K-ras mutated gastric cancer cells [41]. Hypoxia is recognized as an important factor contributing to cancer development and drug resistance. Cetuximab can enhance the effect of oxaliplatin on hypoxic gastric cancer cell lines [42]. Combination treatment of cetuximab and oxaliplatin resulted in a significant reduction in the expression of activated phosphorylated AKT, ERK1/2, p-BAD and VEGF in both normoxia and hypoxia. Fukuda et al. have investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and cetuximab in gastric cancer cells [43]. The combination of cetuximab and S-1 resulted in significantly higher antitumor activity than cetuximab or S-1 alone [43,44]. Panitumumab is one human mAb (IgG2) specific to EGFR. Pertuzumab in combination with trastuzumab can significantly enhance anti-tumor activity in HER2-positive human gastric cancer xenograft models [45]. Combining pertuzumab with trastuzumab can promote cell growth inhibition and apoptosis by inhibiting EGFR-HER2 heterodimerization and the phosphorylation of their downstream factors. Lapatinib is a dual TKI targeting EGFR and HER-2. Lapatinib can inhibit the growth of SNU-216 and NCI-N87 gastric cancer cells [14]. Lapatinib can induce G1 cell cycle arrest by down-regulation of cMyc and induction of p27 [14]. Shiraishi et al. have found that lapatinib could inhibit growth of gastric cancer through trastuzumab-mediated cellular cytotoxicity [46]. The combination of lapatinib and trastuzumab was highly synergistic for inhibiting cell growth and increasing apoptosis of gastric cancer cells [47]. In vivo studies showed that the www.expert-reviews.com

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combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone. LaBonte et al. have evaluated the therapeutic effect of lapatinib in combination with SN-38, the active metabolite of irinotecan, on gastric cancer cells [48]. The combination of lapatinib and SN-38 led to enhanced cell cycle arrest and the induction of apoptosis. Lapatinib combined with 5-fluorouracil, cisplatin, oxaliplatin or paclitaxel could also show a synergistic effect [14]. Shibata et al. have found that Y-box-binding protein-1 (YB-1) could contribute to lapatinib sensitivity in gastric cancer cells [49]. Erlotinib and gefitinib are two small oral molecules of the TKIs class that inhibits EGFR autophosphorylation and signal transduction. The anti-tumor effect of gefitinib is due to the effective inhibition of HER2-driven constitutive activation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway [50]. Gefitinib can inhibit SN38-triggered EGF signals and IL-8 production in gastric cancer cells [51]. The acquired resistance to gefitinib is due to the constitutive activation of Ras/MAPK pathway [50]. Zhu et al. have found that DARPP-32 could promote resistance of gastric cancer cells to gefitinib by promoting interaction between EGFR and ERBB3 and activating phosphatidylinositol-3-kinaseAKT signaling [52]. Overexpression of DARPP-32 in MKN-28 cells could block gefitinib-induced apoptosis, while reduced expression of DARPP-32 could increase the sensitivity of gastric cancer cells to gefitinib. Inhibition of the EGFRassociated tyrosine kinase by genistein led to a dose-dependent growth inhibition of gastric cancer cells [53]. The combined inhibitors of EGFR and the other member of the EGFR family may show synergistic anti-tumor effects in gastric cancer cells. Nam et al. have evaluated the effects and mechanisms of PF00299804, a pan-HER inhibitor, in gastric cancer [54]. PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells in vitro and in vivo. The combination of PF00299804 with other molecular-targeted agents, including trastuzumab, CP751871 (an IGF1R inhibitor), PD0325901 (an ERK1/2 inhibitor) and PF04691502 (a PI3K/ mTOR inhibitor), produced synergistic effects. EGFR target therapy in gastric cancer patients

A few of clinical trials have been performed to evaluate the effect of EGFR target therapy in gastric cancer patients (TABLE 2). Chan et al. have carried out a multicenter Phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma [55]. Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab. No patients were taken off study due to cetuximab related adverse events. Although well tolerated, cetuximab had minimal clinical activity, with the progression-free survival and overall survival of 1.6 and 3.1 months, respectively. Lordick et al. have evaluated the efficacy and safety of cetuximab combined with modified FOLFOX6 as first-line treatment in advanced gastric cancer [56]. Totally 52 cases of patients received cetuximab 400 mg m(-2) at week 1 followed by weekly infusions of 250 mg m(-2) combined with FUFOX. The most common grade 3/4 toxicities were diarrhea (33%) 113

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Hong, Han & Brain

and skin toxicity (24%). The response rate was 65%, and four patients showed complete responses. Time to progression and overall survival was 7.6 months and 9.5 months, respectively. Combined treatment of EGFR inhibitors and chemotherapeutic drugs led to better outcomes of gastric cancer patients as compared with single EGFR target therapy. The mechanisms need to be investigated in future. Wainberg et al. have evaluated the efficacy of mFOLFOX6 and erlotinib in 33 cases of patients with metastatic or advanced esophageal or gastro-esophageal junction cancers [57]. The most common grade 3/4 toxicities were diarrhea (24%), nausea/vomiting (11%), peripheral neuropathy (8%) and skin rash (8%). There were two complete responses and 15 partial responses. Median progression-free survival and overall survival was 5.5 months and 11.0 months, respectively. Iqbal et al. have performed a Phase II trial of lapatinib as first-line therapy in 47 cases of patients with advanced or metastatic gastric cancer [58]. Lapatinib was administered to patients at a dose of 1500 mg orally daily for 28 days. The grade four toxicities were cardiac ischemia/infarction (2%), fatigue (2%) and emesis (2%). One treatment-related death was due to CNS ischemia. Although lapatinib was well tolerated, only four patients (9%) had a confirmed partial response. Median (95% CI) time to treatment failure was 1.9 (1.6–3.1) months and overall survival was 4.8 (3.2–7.4) months. Bamias et al. have carried out a randomized Phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in 147 cases of patients with gastric cancer [59]. The most common grade 3/4 toxicities were neutropenia (9%) and diarrhea (7 %). After a median follow-up of 53.7 months, no differences in overall and disease-free survival were found between the two arms. Waddell et al. have performed a randomized, open-label Phase III trial of epirubicin, oxaliplatin and capecitabine with or without panitumumab treatment in patients with untreated, metastatic or locally advanced esophagogastric adenocarcinoma [60]. Totally 553 eligible patients were randomly allocated to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day

1 and capecitabine 1250 mg/m(2) per day on days 1–21) or EOC plus panitumumab. The grade 3/4 toxicities were diarrhea (17%), neutropenia (13%), rash (11%), mucositis (5%) and hypomagnesaemia (5%). The median overall survival in 278 patients allocated EOC plus panitumumab was 8.8 months. Addition of panitumumab to EOC chemotherapy did not increase overall survival of patients. The unsatisfactory clinical effect of anti-EGFR therapy may be due to drug resistance. The EGFR copy number variation and mutation are closely related to drug sensitivity [61]. Resistance to anti-EGFR therapy may arise from activating mutations of RAS, BRAF, PIK3CA and inactivating mutations of PTEN. Analysis of the gene status of KRAS, BRAF, PIK3CA, PTEN, MEK and AKT can provide clues to clinical response of EGFR target therapy. Expert commentary

Gastric cancer is one of the most common malignancies worldwide. Treatment effects of advanced gastric cancer are unsatisfactory, and novel therapeutic approaches are much needed. Overexpression of EGFR is commonly found in human gastric cancer. The positive expression of EGFR may be related with poor survival of gastric cancer. EGFR plays important roles in tumor growth, metastasis, angiogenesis and apoptosis of gastric cancer by regulation of many signal pathways, such as PLC-PKC/Ca2+, Ras-Raf-MEK-MAPK, Akt-mTOR and JAK2-STAT3. EGFR plays an important role in gastric carcinogenesis by mediating many genes, such as cyclin D1, p21, p27, CDK2, MMP-2 and VEGF. Inhibition of EGFR leads to growth inhibition, cell cycle arrest and angiogenesis inhibition of gastric cancer cells, indicating that EGFR blockade strategy may serve as a promising therapy for the treatment of EGFR-overexpressed gastric cancer. Several clinical trials have investigated the effect of anti-EGFR inhibitors on patients with advanced gastric cancer. Although well tolerated, anti-EGFR inhibitor administered as a single agent has minimal clinical activity. Anti-EGFR therapy can be combined with other chemotherapeutic drugs, such as leucovovin, 5-fluorouracil and oxaliplatin, so as to increase the response rate of gastric cancer patients.

Table 2. The selected clinical trials of anti-EGF receptor therapy in gastric cancer. Study (year)

Cancer type

Phase

Patients (n)

Regimens

Overall response rate (%)

CT identifier

Ref.

Chan et al. (2011)

EGJA or GC

II

35

Cetuximab

3

00130689

[55]

Lordick et al. (2010)

GC

II

52

Cetuximab plus FOLFOX

65

00402412

[56]

Wainberg et al. (2011)

EA, GEJA

II

33

Erlotinib plus FOLFOX

51.5

00591123

[57]

Iqbal et al. (2011)

GC

II

47

Lapatinib

9

00103324

[58]

Bamias et al. (2010)

GC

III

147

Platinum/docetaxel plus RT verse RT

N/A

308272

[59]

Waddell et al. (2013)

EGJA

III

553

Panitumumab plus EOC verse EOC

N/A

00824785

[60]

CT identifier: ClinicalTrials.gov identifier; EA: Esophageal adenocarcinoma; EGJA: Esophagogastric junctional adenocarcinoma; EOC: Epirubicin, oxaliplatin and capecitabine; FOLFOX: Leucovovin, 5-fluorouracil and oxaliplatin; GC: Gastric cancer; N/A: Not applicable; RT: Radiotherapy.

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EGFR & gastric cancer

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Many questions remain to be answered: What is the prognostic value of EGFR in resectable and metastatic gastric cancer? What is the mechanism of resistance toward anti-EGFR therapy? How to improve the effect of anti-EGFR therapy for gastric cancer patients? A great challenge is to identify the right set of patients that may benefit from anti-EGFR therapy. More randomized clinical trials are needed to evaluate the effect of combined therapy of antiEGFR inhibitors and other anti-cancer agents. Five-year view

More investigations should be performed along the following avenues that are likely to lead to exciting results. Identification of the prognostic value of EGFR in gastric cancer. Although several studies have investigated the clinical value of EGFR expression in gastric cancer patients, whether high EGFR expression can predict poor survival remains unclear [15– 17]. The findings of these studies are basing on a small sample size of patients. No data are achieved on the basis of Negroid. Furthermore, the expression of EGFR is only detected in tumor samples, instead of serum. Larger populations of samples need to be collected for further evaluation of the relation between EGFR expression and outcome of gastric cancer patients. The combined detection of EGFR and other molecules may be considered as an effective strategy for predicting prognosis of gastric cancer. Identification of the mechanisms of EGFR in gastric cancer. We are still in the early stage of understanding the molecular mechanisms of EGFR in cancer development and progression. In different tumor cells, EGFR can regulate diverse pathways and cause various phenotypes. Continued basic studies are warranted to gain more mechanistic insights into EGFR-mediated signaling pathways in gastric cancer. It will help the researchers to understand why anti-EGFR treatment are effective for inhibiting the growth of gastric cancer cells, but not effective for prolonging the survival of gastric cancer

Review

patients [57,58]. Understanding the regulatory network of EGFR in gastric cancer will also help to identify novel therapeutic targets. Identification of novel targets for EGFR-based therapy. So far, the known anti-EGFR agent is limited effective for treatment of gastric cancer. The identification of new targets in EGFR mediated signal pathways is necessary for developing novel approaches of target therapy. Further analysis of targets is also urgent for predicting response to anti-EGFR therapy or conferring sensitivity to chemotherapy. A careful evaluation of the safety of novel anti-EGFR agents is necessary before they can be applied clinically. Although anti-EGFR therapy seems to be well tolerated for treating gastric cancer, many challenges still exists, including long-term safety. Long time followup study is needed to investigate whether the effective therapeutic outcome is achieved without any unanticipated side effects. Identification of the strategy of combination therapy. Anti-EGFR therapy can improve the efficacy of current chemotherapeutics for cancer patients. Mono-therapy with anti-EGFR agents is believed to be less toxic, but less efficient either. The combination of EGFR targeted agents with traditional chemotherapeutic drugs basing on a patient’s molecular profile may deliver better responses. Further randomized controlled trials will be required to evaluate the therapeutic efficacy of gastric cancer patients with different mode of combination therapy. Financial & competing interests disclosure

This paper was supported in part by grants from the National Natural Scientific Foundation of China (81100714, 81171923), the Foundation of Shaanxi Province Science and Technology research (2012KJXX-20), and the Top Ph.D. Foundation of China (201075). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Despite tremendous efforts have promoted therapeutic approaches, the clinical outcomes remain poor in patients with advanced gastric cancer. • High expression of EGF receptor (EGFR) may predict poor survival of gastric cancer patients. The prognostic value of EGFR remains controversial. • Inhibition of EGFR may suppress cell growth, angiogenesis and metastasis of gastric cancer cells. • EGFR targeted single therapy shows limited effect for gastric cancer patients. • Combination treatment of epidermal growth factor receptor targeted agents and other cytotoxic agents may increase the therapeutic response rate of gastric cancer patients.

cancer. Discov. Med. 11(57), 95–105 (2011).

References Papers of special note have been highlighted as: • of interest •• of considerable interest 1

2

Smyth EC, Cunningham D. Targeted therapy for gastric cancer. Curr. Treat. Options Oncol. 13(3), 377–389 (2012). Yarom N, Jonker DJ. The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal

www.expert-reviews.com

3

Weickhardt AJ, Price TJ, Chong G et al. Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. J. Clin. Oncol. 30(13), 1505–1512 (2012).

4

Welsh JW, Komaki R, Amini A et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J. Clin. Oncol. 31(7), 895–902 (2013).

5

Patel R, Leung HY. Targeting the EGFR-family for therapy: biological challenges and clinical perspective. Curr. Pharm. Des. 18(19), 2672–2679 (2012).

115

Review 6

Troiani T, Martinelli E, Capasso A et al. Targeting EGFR in pancreatic cancer treatment. Curr. Drug Targets. 13(6), 802–810 (2012).

18

Atmaca A, Werner D, Pauligk C et al. The prognostic impact of epidermal growth factor receptor in patients with metastatic gastric cancer. BMC Cancer 12, 524 (2012).

28

Jiang L, Lan T, Chen Y et al. PKG II Inhibits EGF/EGFR-Induced Migration of Gastric Cancer Cells. PLoS One 8(4), e61674 (2013).

7

Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin. Ther. Targets. 16(1), 15–31 (2012).

19

Matsubara J, Yamada Y, Hirashima Y et al. Impact of insulin-like growth factor type 1 receptor, epidermal growth factor receptor, and HER2 expressions on outcomes of patients with gastric cancer. Clin. Cancer Res. 14(10), 3022–3029 (2008).

29

Klein S, Levitzki A. Targeting the EGFR and the PKB pathway in cancer. Curr. Opin. Cell Biol. 21(2), 185–193 (2009).

30

Merlo V, Longo M, Novello S, Scagliotti GV. EGFR pathway in advanced non-small cell lung cancer. Front. Biosci. (Schol. Ed.). 3, 501–517 (2011).

31

Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 318(2), 124–134 (2012).

32

Liao G, Wang Z, Zhang N, Dong P. Dominant negative epidermal growth factor receptor inhibits growth of human gastric cancer cells by inducing cell cycle arrest and apoptosis. Cancer Biother. Radiopharm. (doi:10.1089/cbr.2012.1399) (2013) (Epub ahead of print).

33

Liao G, Wang Z, Zhao L, Zhang N, Dong P. Inhibitory effects of cytoplasmic-domain substituted epidermal growth factor receptor on growth, invasion and angiogenesis in human gastric cancer cells. Mol. Med. Rep. 3(2), 287–294 (2010).

34

Caruso R, Pallone F, Fina D et al. Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation. Am. J. Pathol. 169(1), 268–278 (2006).

35

Dan L, Jian D, Na L, Xiaozhong W. Crosstalk between EGFR and integrin affects invasion and proliferation of gastric cancer cell line, SGC7901. Onco Targets Ther. 5, 271–277 (2012).

36

Norguet E, Dahan L, Seitz JF. Targetting esophageal and gastric cancers with monoclonal antibodies. Curr. Top. Med. Chem. 12(15), 1678–1682 (2012).

37

Heindl S, Eggenstein E, Keller S et al. Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines. J. Cancer Res. Clin. Oncol. (doi:10.1007/s00432-011-1128-4) (2012) (Epub ahead of print).

38

Kneissl J, Keller S, Lorber T et al. Association of amphiregulin with the cetuximab sensitivity of gastric cancer cell lines. Int. J. Oncol. 41(2), 733–744 (2012).

39

Hara M, Nakanishi H, Tsujimura K et al. Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer

8

Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Korea University on 01/02/15 For personal use only.

Hong, Han & Brain

9

Berg M, Soreide K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. Discov. Med. 14(76), 207-–214 (2012). Liakakos T, Fatourou E, Ziogas D, Lykoudis E, Roukos DH. Targeting VEGF, EGFR, and other interacting pathways for gastric cancer-promises and reality. Ann. Surg. Oncol. 15(10), 2981–2982 (2008).

10

Smyth EC, Cunningham D. Targeted therapy for gastric cancer. Curr. Treat. Options Oncol. 13(3), 377–389 (2012).

11

Okines A, Cunningham D, Chau I. Targeting the human EGFR family in esophagogastric cancer. Nat. Rev. Clin. Oncol. 8(8), 492–503 (2011).

12

Ettinger DS. Clinical implications of EGFR expression in the development and progression of solid tumors: focus on non-small cell lung cancer. Oncologist 11(4), 358–373 (2006).

14

Kim JW, Kim HP, Im SA et al. The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett. 272(2), 296–306 (2008).

15

Inokuchi M, Murayama T, Hayashi M et al. Prognostic value of co-expression of STAT3, mTOR and EGFR in gastric cancer. Exp. Ther. Med. 2(2), 251–256 (2011).

16

Terashima M, Kitada K, Ochiai A et al. Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin. Cancer Res. 18(21), 5992–6000 (2012). Lieto E, Ferraraccio F, Orditura M et al. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann. Surg. Oncol. 15(1), 69–79 (2008).

116

Ja´come AA, Wohnrath DR, Scapulatempo Neto C et al. Prognostic value of epidermal growth factor receptors in gastric cancer: a survival analysis by Weibull model incorporating long-term survivors. Gastric Cancer. (doi:10.1007/ s10120-013-0236-z) (2013) (Epub ahead of print).

21

Zhang J, Zhan Z, Wu J et al. Association among polymorphisms in EGFR gene exons, lifestyle and risk of gastric cancer with gender differences in Chinese han subjects. PLoS One 8(3), e59254 (2013).

22

Han SW, Oh DY, Im SA et al. Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6. Cancer Sci. 101(3), 793–799 (2010).

Garcı´a I, Vizoso F, Martı´n A et al. Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann. Surg. Oncol. 10(3), 234–241 (2003).

13

17

20

23

Moutinho C, Mateus AR, Milanezi F, Carneiro F, Seruca R, Suriano G. Epidermal growth factor receptor structural alterations in gastric cancer. BMC Cancer 8, 10 (2008).

24

Liu Z, Liu L, Li M et al. Epidermal growth factor receptor mutation in gastric cancer. Pathology. 43(3), 234–238 (2011).



The paper is focusing on epidermal growth factor receptor mutation in gastric cancer.

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Becker JC, Mu¨ller-Tidow C, Stolte M et al. Acetylsalicylic acid enhances antiproliferative effects of the EGFR inhibitor gefitinib in the absence of activating mutations in gastric cancer. Int. J. Oncol. 29(3), 615–623 (2006).

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Sakamoto N, Oue N, Sentani K et al. Liver-intestine cadherin induction by epidermal growth factor receptor is associated with intestinal differentiation of gastric cancer. Cancer Sci. 103(9), 1744–1750 (2012). Hirao T, Sawada H, Koyama F et al. Antisense epidermal growth factor receptor delivered by adenoviral vector blocks tumor growth in human gastric cancer. Cancer Gene Ther. 6(5), 423–427 (1999).

Expert Rev. Gastroenterol. Hepatol. 8(1), (2014)

EGFR & gastric cancer

xenografts through antibody-dependent cellular cytotoxicity. Cancer Sci. 99(7), 1471–1478 (2008). 40

Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Korea University on 01/02/15 For personal use only.

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Zhang J, Ji J, Yuan F et al. EGFR-blockade by antibody Cetuximab inhibits the growth of human gastric cancer xenograft in nude mice and its possible mechanism. Zhonghua Zhong Liu Za Zhi. 31(2), 85–89 (2000). Hotz B, Keilholz U, Fusi A, Buhr HJ, Hotz HG. In vitro and in vivo antitumor activity of cetuximab in human gastric cancer cell lines in relation to epidermal growth factor receptor (EGFR) expression and mutational phenotype. Gastric Cancer. 15(3), 252–64 (2012). Luo HY, Wei W, Shi YX et al. Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines. Oncol. Rep. 23(6), 1735–1745 (2010). Fukuda K, Saikawa Y, Takahashi M et al. Antitumor effect of cetuximab in combination with S-1 in EGFR-amplified gastric cancer cells. Int. J. Oncol. 40(4), 975–982 (2012).

48

LaBonte MJ, Manegold PC, Wilson PM et al. The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. Int. J. Cancer. 125(12), 2957–2969 (2009).

49

Shibata T, Kan H, Murakami Y et al. Y-box binding protein-1 contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells. Mol. Cancer Ther. 12(5), 737–746 (2013).

Review

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Lordick F, Luber B, Lorenzen S et al. Cetuximab plus oxaliplatin/leucovorin/5fluorouracil in first-line metastatic gastric cancer: a phase II study of the arbeitsgemeinschaft internistische onkologie (AIO). Br. J. Cancer. 102(3), 500–505 (2010).

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One clinical trial about anti-EGFR therapy plus traditional chemotherapy in gastric cancer.

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Wainberg ZA, Lin LS, DiCarlo B et al. Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. Br. J. Cancer. 105(6), 760–765 (2011).

50

Yokoyama H, Ikehara Y, Kodera Y et al. Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis. Br. J. Cancer 95(11), 1504–1513 (2006).



51

Kishida O, Miyazaki Y, Murayama Y et al. Gefitinib (“Iressa”, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. Cancer Chemother. Pharmacol. 55(4), 393–403 (2005).

One clinical trial about EGFR target therapy in cancer of the oesophagus and gastro-oesophageal junction.

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Zhu S, Belkhiri A, El-Rifai W. DARPP-32 increases interactions between epidermal growth factor receptor and ERBB3 to promote tumor resistance to gefitinib. Gastroenterology 141(5), 1738–1748 (2011).

Iqbal S, Goldman B, Fenoglio-Preiser CM et al. Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann. Oncol. 22(12), 2610–2615 (2011).



One clinical trial about lapatinib therapy in gastric cancer.

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Bamias A, Karina M, Papakostas P et al. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother. Pharmacol. 65(6), 1009–1021 (2010).

52

Kobunai T, Watanabe T, Fukusato T. Antitumour activity of S-1 in combination with cetuximab on human gastric cancer cell lines in vivo. Anticancer Res. 31(11), 3691–3696 (2011). Yamashita-Kashima Y, Iijima S, Yorozu K et al. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin. Cancer Res. 17(15), 5060–5070 (2011).

53

Piontek M, Hengels KJ, Porschen R, Strohmeyer G. Antiproliferative effect of tyrosine kinase inhibitors in epidermal growth factor-stimulated growth of human gastric cancer cells. Anticancer Res. 13(6A), 2119–2123 (1993).

60

Shiraishi K, Mimura K, Izawa S et al.; Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity. Gastric Cancer. (2012) (Epub ahead of print).

54

Nam HJ, Ching KA, Kan J et al. Evaluation of the antitumor effects and mechanisms of PF00299804, a pan-HER inhibitor, alone or in combination with chemotherapy or targeted agents in gastric cancer. Mol. Cancer Ther. 11(2), 439–451 (2012).

Waddell T, Chau I, Cunningham D et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 14(6), 481–489 (2013).



Wainberg ZA, Anghel A, Desai AJ et al. Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin. Cancer Res. 16(5), 1509–1519 (2010).

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Chan JA, Blaszkowsky LS, Enzinger PC et al. A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma. Ann. Oncol. 22(6), 1367–1373 (2011).

One clinical trial about panitumumab therapy in esophagogastric cancer.

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Wei X. Mechanism of EGFR-related cancer drug resistance. Anticancer Drugs 22(10), 963–970 (2011).

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One clinical trial about EGFR target therapy in gastric cancer.

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The role of epidermal growth factor receptor in prognosis and treatment of gastric cancer.

Despite tremendous efforts to reduce deaths due to gastric cancer, it represents the second leading cause of cancer-related deaths worldwide. EGF rece...
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