EGFR expression as a predictive marker in esophageal squamous cell cancer: Review article

， ， Y

(1.Department of Oncology，Zhongda Hospital，Southeast University，Nanjing 210096，China;2.Department of Pediatrics，Zhongda Hospital，Southeast University，Nanjing 210096，China;3.Department of Oncology，Oncology Hospital，Hefei City，Hefei 230031，China)

1 Introduction

Esophageal carcinoma is one of the most common malignancies in China， and squamous cell carcinoma(SCC) is the main histological type[1]. The incidence of esophageal cancer varies considerably with geographical location.According to GLOBOCAN 2008 cancer of the esophagus is the 8th leading cause of cancer death worldwide and about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these， 56% of the cases and 64% of the deaths occurred in the economically developing world[2].The majority of esophageal cancers are squamous cell or adenocarcinoma. In the United States， an estimated 17，990 cases of esophageal cancer will be diagnosed in 2013，and 15，210 deaths are expected from the disease[3]. In the highest- risk area， stretching from Northern Iran through the central Asian republics to North- Central China(often referred to as the "esophageal cancer belt")， 90 percent of cases are SCC[4]. SCC of the esophagus has been increasing in certain Asian countries such as China and Taiwan， probably as a result of increases in tobacco and alcohol consumption[5]. Despite advances in surgical and perioperative treatment， the prognosis of esophageal cancer remains poor. Half of the patients are unresectable or present with metastases at diagnosis， with a 5- year survival rate of about 2.8% and 17.1% in metastatic and locally advanced disease， respectively[6].A recent meta analysis came to the conclusion that combined neoadjuvant chemo radiation confers a significant improvement in overall survival and local tumor control and the benefit for patient with ESCC[7]. However， concerns exist regarding its impact on surgical safety and morbidity and its feasibility after chemoradiation. Several phase-III trials found higher postoperative mortality and/or morbidity in patients given neoadjuvant CRT[8- 9]. A study by Bosset et al. demonstrated improved recurrence- free survival， but significantly higher postoperative mortality. It did not show benefit to overall survival[9]．

It has been well established that only patients with a complete pathological response to neoadjuvant therapy will have a significant survival benefit. The prognosis of patients who do not respond to neoadjuvant therapy appears to be inferior to that of patients who had surgery alone[10]. These data suggest the need for predictive markers to allow tailored(radio- ) chemotherapy to increase the number of complete pathological responses following neoadjuvant approaches. Definitive CRT only improves the treatment results in patients whose tumors show chemoradiosensitivity.If the tumor does not show chemoradiosensitivity the patient would waste valuable time， experience severe toxicity， and lose an opportunity to have potentially curative surgery[11]. Therefore， if markers that allow the prediction of response to CRT are found， it would be possible to select potential responders and the adverse effects of the treatment could be avoided in non responders. It would spare risk of postoperative comp-lications. The molecular biomarker like the epidermal grow-th factor receptor(EGFR) over expression has been studied as possible predictive factors in esophageal cancer[12]. Since it has been reported that epidermal growth factor receptor(EGFR)[13]is related to the progression of esophageal SCC， these molecules are candidates for molecular targeted the-rapy.

1.1 Epidermal Growth Factor Receptor(EGFR)

In late 1970s， EGFR was first isolated and then postulated to be similar to the v- erb- B oncogene protein sequence[14]. EGFR(ERBB1) is a member of the ERBB receptor tyrosine kinase family that includes ERBB2(HER- 2)， ERBB3， and ERBB4[15]. EGFR， also known as HER1 or ErbB， is a 170 kDa receptor transmembrane glycoprotein encoded by 28 exons located on chromosome 7p12. There are three functional domains of EGFR:an extracellular domain(containing of two EGF binding sites); a hydrophobic transmembrane domain and a cytoplasmic domain(tyrosine kinase(TK) and additionally a carboxyl autophosphorylation region)[16]．

The binding of ligands， including EGF or transforming growth factor- alpha(TGF-α) to the EGFR results in increased DNA synthesis and stimulates the growth and proliferation of various cells[17]. Beside of its natural ligands EGF or TGF-α， the EGFR can be activated by irradiation[18]. Ligand binding and irradiation results in homodimerisation of two EGFR molecules or in heterodimerisation of an EGFR molecule with another member of the ErbB receptor family(fig 1). After dimerisation and internalisation， autophosphorylation of the intracellular tyrosine kinase(TK) domain occurs[19]， which may activate different intracellular signal transduction pathways．

A major signaling route is the ras- raf- MAPK pathway， resulting in increased cell proliferation. Another important pathway activates PI3K- AKT， regulating not only cell cycle progression but also cell survival[20]. The function of EGFR can be blocked using monoclonal antibodies(mAb) or tyrosine kinase inhibitors(TKI).

1.2 Expression of EGFR and its clinical significance

The EGFR is constitutively expressed in many normal epithelial tissues， including the skin and hair follicle. Over expression of EGFR， as wild type or with mutations， occurs in many types of human tumors， including esophageal(92%)，head and neck(90%)， colorectal(72%)， prostate(65%)， bladder(65%)， ovarian(60%)， cervical(60%)， pancreatic(89%)， renal cell(50%)， and lung(50%) cancers. The EGFR signal transduction network plays an important role in various tumorigenic processes， including cell cycle， progression，angiogenesis，and metastasis，as well as protection from apoptosis[15].EGFR seems not only to be a prognostic but also a predictive factor in patients with esophageal cancer．

1.3 EGFR as a prognostic marker

EGFR over expression is common in esophageal carcinoma[21]and correlates with extensive disease， lymph node metastases[22]， resistance to chemo- or radiotherapy[23]， and is may be indicative of a poor progn-osis[24]. It correlates with deeper invasion of the tumor， intravascular invasion， and risk of local relapses. In 1999 a study by Inada et al showed that intratumoral EGFR protein expression is significantly correlated with the depth of tumor invasion， the number of lymph node metastases and survival rate[13].In 2006 Gibault et al. found that diffuse EGFR staining was significantly related to higher local recurrence and lower overall survival in a subgroup of patients of poor outcome who had received postoperative adjuvant treatment， suggesting EGFR protein expression to be an important prognostic factor in patients with esophageal cancer[21]. Recently， in 2011， Meta analysis by Yu et.al also concluded that over- expression of EGFR might play an important role in the progression of ESCC， and it might be useful as a predictive marker in clinical practice[25].

1.4 EGFR as a predictive marker for CRT sensitivity

In the last two decades many researches evaluating EGFR expression and its predictive significance in chemoradiotherapy in ESCC have been done with conflicting results. In earlier studies by Hickey et al and Gibson et al in 1994 and 2003 respectively， EGFR over expression could not predict the response in patients with esophageal cancer receiving neoadjuvant CRT[23，12].A study by Miyazono et al in 2004 also didn′t show any predictivity to response to their hospital based neoadjuvant chemoradiotherapy protocol[26]. However， a study by Gotoh et al in 2006 showed that EGFR positive patients have higher complete response than EGFR negative patients suggesting EGFR expression has significant correlation with the sensitivity to CRT[27]. It was followed by many studies including Sarbia et al and Ressiot et al. which could not establish EGFR as predictive marker[28- 29].But in last five years various individual studies have been done in China. A study by Qiang et al in 2009 showed correlation between EGFR expression level and predictive sensitivity to CRT for esophageal cancer[30]. Furthermore， another Chinese study by Huang et al. in 2011 also suggested EGFR may help to predict the response of tumor to CRT in ESCC[31]. But another study by Yoon et al. did not show any predictive significance in treatment response in patient with ESCC after definitive concurrent CRT[32]. In 2012 studies by Yamamoto et al. and Marina Schena et al had again had contradictory results[33- 34]. In a different study by Chen EGFR expression using immunohistochemestry was shown to be effective way to predict the efficacy of CRT plus Cetuximab regimen in ESCC[35]．

2 Conclusion

Summarizing the status of clinical studies， it can be firmly concluded that over expression of the EGFR is associated with poor prognosis.However its predictive role has yet to be defined for targeted therapy. Researches on EGFR as predictor for chemotherapeutic sensitivity in ESCC are still few. EGFR plays an important role in signal transduction network in various tumorigenic processes， including cell cycle progression， angiogenesis， and metastasis， as well as protection from apoptosis. With recent advances in drug development， there are new possibilities to use anti EGFR targeted therapy .And the ability to predict likely responders to chemoradiotherapy， based on immunocytochemical assessment of pretreatment biopsies would be a major advancement in the management of patients with squamous cell esophageal carcinoma. In future， further multicenter clinical research trials should be done to establish EGFR as predictive marker for novel targeted therapies in ESCC.

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