THEMED ARTICLE y Gastrointestinal & Hepatopancreatobiliary Cancer

Review

Advances in biomarkers for esophageal cancer Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Washington University Library on 01/05/15 For personal use only.

Expert Rev. Anticancer Ther. 13(10), 1169–1180 (2013)

Vinayak Nagaraja and Guy D Eslick* The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Sydney, NSW, Australia *Author for correspondence: Tel.: +61 247 341 373 Fax: +61 247 343 432 [email protected]

Cancer of the esophagus is an aggressive disease with early lymphatic and hematogenous dissemination and at present often considered as one clinical entity because of their comparable increasing incidence, prognosis and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. Despite recent advances, treatment of upper gastrointestinal malignancies remains a significant challenge. Molecular pathology has revealed many molecular mechanisms of disease progression, which are related to prognosis. Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options. This review summarizes the rationale, preclinical evidence, retrospective clinical analyses and the interim clinical data pertaining HER2 therapy and many other molecular pathways. KEYWORDS: biomarkers • esophageal neoplasms • HER2 protein • survival

Background

The incidence and mortality from cancer of all types in the USA have decreased during the 1991–2006 timeframe [1]. However, the opposite is true for esophageal cancer. Its incidence and mortality continue to rise. In 2010, estimated new cases of esophageal cancer number 16,640 in the USA, whereas deaths total up to 14,500 [1]. The USA has seen an average increase of 20.6% per year in the incidence of adenocarcinoma of the esophagus since that time [2]. This translates into a 463 and 335% increased incidence in white males and females, respectively, between 1975 and 2004. Adenocarcinoma now accounts for 58% of all esophageal cancers in the USA. Total esophageal cancer incidence and mortality have been increasing among white men, stable among white women and decreasing in black men and women [3]. It is projected that there will be 16,470 new patients diagnosed with esophageal cancer and 14,280 deaths from it in 2008 [1]. Esophageal cancer is a highly lethal disease in which only one-third of patients present with resectable disease. Of this selected group, the average 5-year survival is only 35–45% [4]. Another consideration is our less-than-satisfactory ability to predict particular tumor’s response to neoadjuvant therapy. Targeted molecular therapy in upper gastrointestinal cancer has become www.expert-reviews.com

10.1586/14737140.2013.844953

an increasingly popular topic over the past few years. In part, this is due to rapid advances in our capability to characterize tumor biology. Human epidermal growth factor receptor gene HER-2/ neu (also known as c-erbB-2, now HER2) was recognized as an important prognostic factor in breast cancer in 1987 [5,6]. However, its role in other solid tumors is debatable [7,8]. HER2 (ErbB2) is a member of a family of transmembrane receptor tyrosine kinases ([HER1: EGF receptor], HER3 [ErbB3], HER4 [ErbB4]) that are involved in the regulation of cellular processes that control cell growth, survival, differentiation and migration [9]. Human epidermal growth factor receptor & esophageal cancer

The published frequency of HER2 overexpression in esophageal cancer ranges from 11 to 73% [10]. The relationship between HER2 overexpression and prognosis in operable esophagogastric cancer is controversial [10,11]. Some studies have suggested that HER2 overexpression is associated with poor survival in esophageal [12,13], whereas others have shown no association with prognosis [14–16]. Duhaylongsod et al. [17] and Yoon et al. [18] have stated that HER2+ improves survival compared with HER2–. The discrepancies among results can be due to factors such as patient definition, diagnostic methods and classification of HER2+.


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The prevalence rate of HER2+ among patients with squamous cell carcinoma (SCC) was significantly higher than that of esophageal adenocarcinoma (EAC). When comparing studies that have included both EAC and SCC, the difference of HER2+ between EAC and SCC is unclear. Hardwick et al. have analyzed HER2+ among EAC and SCC separately and have shown that SCC has a higher HER2+ prevalence than EAC [14]. On the other hand, Birner et al. have shown that EAC has a higher HER2+ rate than SCC [19]. The two remaining studies Stoecklein et al. [20] and Friess et al. [21] have combined the prevalence rate of HER2+ among EAC and SCC, and therefore the prevalence rates between the two groups were not defined. A recently published meta-analysis Chan et al. [22] has also examined HER2+ expression and amplification in esophageal cancer. This meta-analysis included 14 studies (322 [22%] HER2+ out of 1,464 patients). Five-year mortality was significantly higher in HER2-positive patients (odds ratio [OR]: 1.43, 95% CI: 1.04–1.95; p = 0.03). Analysis related to histological cell type demonstrated significantly higher 5-year mortality in HER2-positive squamous cell carcinoma (OR: 2.88, 95% CI: 1.34–6.17; p = 0.006) and adenocarcinoma (OR: 1.91, 95% CI: 1.15–3.17; p = 0.01). In the (ToGA trial) [23], HER2 overexpression was found in 22% of the cases in which 34% of the cases were of intestinal type of gastric cancer, 6% were of diffuse type and 20% were mixed histology. Nonetheless, survival of the HER2-positive patients in the control arm of the ToGA trial. HER2 positivity was found in 32 and 19% in gastroesophageal junction (GEJ) and gastric cancers. It has been suggested that poorer survival in HER2-positive patients with squamous cell carcinoma could be due to increased resistance to radiation therapy [24] and cisplatinum-based chemotherapy [25]. Moreover, the addition of trastuzumab in head-and-neck squamous cell carcinoma cell lines seemed to enhance the effect of irradiation [26]. Role of trastuzumab in esophageal cancer

In the ToGA trial [23], a crucial as well as the first randomized, controlled, Phase III trial for gaging the effectiveness of trastuzumab in adenocarcinoma of the stomach or GEJ, a total of 594 with locally advanced or metastatic HER2-overexpressing adenocarcinoma of the stomach or GEJ were randomized to receive trastuzumab plus chemotherapy or chemotherapy alone. Twenty two percent of patients out of more than 3,800 cases screened in 24 countries showed HER2 expression, with a good concordance rate between immunohistochemical (IHC) staining and FISH. The tumors were confirmed to be either HER2 gene amplified by FISH or protein overexpressing via IHC. The patients were included in the study only if the tumor was scored as 3+ on IHC or if it was 2+ on IHC and FISH positive Median overall survival (OS) was 13.8 months (95% CI: 12–16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10–13) in those assigned to chemotherapy alone (hazard ratio [HR]: 0.74; 95% CI: 0.60–0.91; p = 0.0046). Exploratory survival analyses in subgroups 1170

defined by IHC testing indicated that trastuzumab was most effective in prolonging survival in the IHC 3+ tumors and less effective in IHC 2+ tumors. However, the final exploratory survival analyses included only the HER2/neu FISH-positive patients. The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 (46%]) and neutropenia (157 [53%] vs 165 [57%]). Rates of overall Grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. In October 2010, the FDA granted approval for trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) for the treatment of patients with HER2-overexpressing metastatic gastric or GEJ adenocarcinoma who have not received previous treatment for metastatic disease [23]. Safran et al. [27] did a Phase I/II study (n = 19) of trastuzumab in combination with cisplatin and paclitaxel in locally advanced, HER2 overexpressing, esophageal adenocarcinoma. The ORR was 43% with an OS of 24 months. The 2-year survival was 50%. There was no significant cardiotoxicity related to trastuzumab. Several ongoing trials have the goal of evaluating trastuzumab in esophagogastric and/or gastric cancer in the first line in combination with chemotherapy or as a salvage agent in recurrent cancer. Other important prognostic markers in esophageal cancer E-cadherin expression & esophageal squamous cell carcinoma

The cadherins are a family of integral membrane glycoproteins, which are the prime mediators of cell–cell adhesion in normal cells. When cadherins are expressed, the inactivation of other CAMs has little or no effect. The members of the cadherin family are involved in adherens junctions and are components of desmosomes. E-cadherin plays an important role in the induction and maintenance of normal architecture in human tissues. The cytoplasmic domains of E-cadherin bind to the actin skeleton of the cell through catenins (a- and b-catenin) [28,29]. These catenins are closely related with the cadherins. Genetic alterations of the genes encoding the catenins (particularly b-catenin) lead to reduced cell–cell adhesivity. Apart from cell adhesion molecular function, b-catenin participates in Wnt signaling (Wnt proteins involve three intracellular signaling pathways) and activates oncogene transcription by complexing with T-cell factors and can influence the transcription of genes such as the cyclin D1 cell cycle regulator. The analysis of E-cadherin, acatenin and b-catenin expression in adenocarcinoma of the esophagus revealed that reduced expression of all three proteins correlated with decreased patient survival. The University of Hong Kong, Queen Mary Hospital, Hong Kong [30] investigated the association of s-Ecad with clinicopathological characteristics of patients with esophageal squamous cell carcinoma (ESCC) and its prognostic significance. Survival analysis showed that in patients who had surgical resection only, those Expert Rev. Anticancer Ther. 13(10), (2013)

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with E-cadherin levels equal to or below the median value survived significantly longer than those with levels above the median (median survival 25.6 versus 14.1 months, p = 0.012). Multivariate analysis showed that pathological N stage, M stage, R category and serum E-cadherin level were significantly independent prognostic factors for ESCC patients who underwent surgery only. The hazard ratio for E-cadherin was 1.104 (95% CI: 1.026–1.187) and p = 0.008. Reduced E-cadherin expression detected by IHC could be a molecular marker to predict poor prognosis and poor differentiation degree in patients with EC, especially in patients with ESCC. Reduced E-cadherin expression is associated with other traditional clinicopathological features consisting of depth of tumor invasion, lymph node metastasis and clinical stage that allow the selection of patients eligible for pre- and post-neoadjuvant chemoradiotherapy.

of VEGF-C was found to be higher in Stage2B-4A tumors than in Stage0-2A tumors (p = 0.049). When the patients were divided into two groups according to their expression levels of VEGF-C (a group of 53 cases with high expression and a group of 53 cases with low expression), the patients with high VEGF-C expression had significantly shorter survival after surgery than the patients with low expression (p = 0.0065). Although univariate analysis showed that high expression of VEGF-C was statistically significant prognostic factor, this was not shown in multivariate analysis. In the subgroup of patients with Tis and T1 tumors, the expression of VEGF-C was higher in N1 tumors than in N0 tumors (p = 0.029). The survival rate of patients from the high expression group (n = 10) was lower than that in the low expression group (n = 11) and all the patients in the low VEGF-C expression group survived.

VEGF

EGF receptor

Expression of VEGF, one of the most potent sources of angiogenesis, has been shown to be responsible for the development and maintenance of a vascular network that promotes tumor growth and metastasis for a wide range of human tumors and human cell lines [31]. VEGF is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa. In healthy humans, VEGF promotes angiogenesis in embryonic development and is important in wound healing in adults. VEGF is a key mediator of angiogenesis in cancer, and angiogenesis is essential for cancer development and growth [32]. Moreover, a large and growing body of evidence indicate that VEGF expression is associated closely with poor prognosis in patients with cancer [33–35]. Of the 73 ESCC patients studied by Medical School of University of Southeast of China [36], 39 cases (53.4%) were strongly positive for VEGF-C. Six cases (8.2%) were negative and 28 cases (38.4%) revealed unclear weak reactions. All 34 cases were included in the negative group (46.6%). VEGFC expression correlated with histological grade (p = 0.005), depth of tumor invasion (pT) (p = 0.021), lymph node metastasis (pN) (p = 0.002) and lymphatic invasion (p = 0.008). The median OS of 39 patients who had positive staining for tumor cell VEGF-C and 34 patients who had negative staining were 10.4 months (95% CI: 6.9–13.9 months) and 28.5 months (95% CI: 12.6–44.4 months), respectively (p = 0.003). In univariate analysis by log-rank test, histological grade, pN, stage, lymphatic invasion and VEGF-C were significant prognostic factors (p = 0.047, 0.007, 0.018, 0.002 and 0.003, respectively). In multivariate analysis, high VEGF-C expression (p = 0.0451) maintained its independent prognostic influence on OS, as well as pN status (p = 0.0029). Nagoya City University Graduate School of Medical Sciences [37] reported that high expression of VEGF-C was detected in most of the KYSE cell lines, especially KYSE410, yet, in an esophageal normal epithelium cell line, Het-1A, VEGF-C was not detected. In the clinical specimen, the expression of VEGF-C in the cancerous tissue was higher than in the corresponding noncancerous esophageal mucosa (p = 0.026). The expression

Some authors have claimed that adenocarcinomas arising in association with Barrett esophagus (intestinal-type mucosaassociated adenocarcinomas) have a better prognosis than those arising in a background of gastric/cardiac-type mucosa (cardiac-type mucosa-associated adenocarcinomas) [38,39]. This has led to the assertion that intestinal-type mucosa-associated adenocarcinoma is biologically different from cardiac-type mucosa-associated adenocarcinoma. Nevertheless, some groups maintain that cardiac type mucosa-associated adenocarcinomas are simply large tumors that have overgrown pre-existing short-segment Barrett esophagus, rather than comprising a separate entity [40], and that prognostic differences between intestinal-type and cardiac-type mucosa-associated adenocarcinomas are due to early detection of tumors on surveillance endoscopy [41]. Common gastric tumors classified as intestinal type are more likely to be HER2 positive (16–34%) than diffuse (2–7%) or mixed (5–20%) types [42–44]. The reason for the selective overexpression of HER2 in intestinal-type gastric cancers is complex and needs further investigation. The association of HER2 with a specific type suggests that intestinaland diffuse-type gastric cancers develop along different molecular pathways and supports earlier studies showing distinct patterns of genetic alterations in gastric cancers of differing histopathologic features. [45]. EGF receptor (EGFR), also known as HER-1, is a transmembrane protein with intrinsic tyrosine kinase activity. Binding of specific ligands, such as EGF and TGF-a, results in the homodimerization of EGFR or in heterodimerization with another member of the EGFR family of receptors. In turn, this homodimerization or heterodimerization stimulates phosphorylation of the intracellular tyrosine kinases on the receptor, leading to the activation of various downstream signal–transduction pathways that ultimately regulate cell proliferation, migration, adhesion, differentiation and survival [46]. Elevated levels of EGFR have been identified in nondysplastic intestinal metaplasia [47–49]. EGFR amplification is more highly associated with cardiac-type mucosa-associated adenocarcinoma. EGFR has also been linked to high-grade tumors and poor survival [50–52].

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EGFR amplification could be construed to be a later event in more advanced cancers. However, even when comparing only large tumors, EGFR amplification was significantly more frequent in cardiac-type mucosa-associated adenocarcinomas than in intestinal-type mucosa-associated adenocarcinomas. Taken together with the other immunophenotypic differences between intestinal- and cardiac-type mucosa-associated adenocarcinomas, this suggests that different pathways are involved in carcinogenesis of the two types of adenocarcinoma arising in the vicinity of the esophagogastric junction [53]. MD Anderson Cancer Centre [54] investigated EGFR expression in 103 patients. EGFR was expressed in 33 of 103 adenocarcinomas (32%) and was correlated with higher pathologic tumor (T) classification (p = 0.02), the presence of lymph node metastasis (p = 0.01) and higher pathologic tumor, lymph node, metastasis classification (p = 0.02). EGFR expression also was correlated with shorter disease-free and OS in univariate analyses (p = 0.001 and p = 0.004, respectively), and there was a trend toward correlation between EGFR expression and shorter disease-free survival in multivariate analyses (p = 0.07 and p = 0.08). The results demonstrated that EGFR expression in esophageal adenocarcinomas was correlated with advanced pathologic tumor classification and lymph node metastasis. EGFR expression also was correlated with poor disease-free and OS, but that correlation was not independent of T classification. EGFR expression in esophageal adenocarcinomas was correlated with higher tumor stage, lymph node metastasis and poor disease-free and OS in patients who underwent esophagectomy. These findings suggest that EGFR expression is correlated with poor prognostic factors and may be used to predict patient outcomes. Anti-EGFR monoclonal antibodies

Cetuximab (Erbitux, ImClone Systems, NY, USA) is a partially humanized murine IgG1 monoclonal antibody that blocks the binding of protein ligands to the EGFR and its activation [55]. Various other proposed mechanisms of action of cetuximab include receptor internalization through endocytosis and immune-mediated mechanisms including antibody-dependent cytotoxicity, complement-dependent cytotoxicity and complement-dependent cell-mediated cytotoxicity [56]. Anti-EGFR tyrosine kinase inhibitors

Gefitinib (Iressa, AstraZeneca Pharmaceuticals, London, UK) is an oral small molecule tyrosine kinase inhibitor (TKI). Cleveland Clinic Taussig Cancer Institute [57] assessed the efficacy of gefitinib in combination with cisplatin/5-FU and RT (n = 80) to chemo-RT alone (n = 93) in a Phase II trial of patients with locoregionally advanced esophagus and gastroesophageal junction cancer. There was a trend toward improved 3-year OS rates in favor of gefitinib arm (40 vs 28%; p = 0.07). Toxicity profiles were similar in both the arms. In another Phase II study, gefitinib was evaluated in the second-line setting in 28 patients [58]. The partial response rate was 3% and stable disease in 28%. The time to progression 1172

and OS were 2.0 and 5.5 months, respectively. There was a no significant trend toward improved outcome in patients with high EGFR expression compared with low EGFR expression (time to progression: 5.1 months versus 1.8 months and OS: 7.8 months versus 2.8 months) [59]. We await the results of ongoing Phase III trials that are exploring the addition of cetuximab to induction concurrent chemoradiotherapy in patients with locoregionally advanced esophageal cancer, both in the preoperative and definitive treatment settings, such as the ongoing RTOG 0436 trial that compares definitive induction concurrent chemoradiotherapy with or without cetuximab in patients with esophageal cancer. Insulin-like growth factor 1

Current concepts suggest that centrally deposited fat, so-called visceral adipose tissue, is more metabolically active than peripheral subcutaneous fat and a more significant fuel for the association with dysmetabolism and related problems including cancer [60]. The insulin-like growth factor (IGF) axis is thought to play a role in the link between obesity and cancer [61]. The observation that insulin resistance is associated with an increased risk of cancer has led to the hypothesis that this may be mediated through the IGF axis [62,63]. Insulin resistance leads to reduced levels of IGF-binding proteins and results in a subsequent increase in free IGF-1 [64]. Prospective studies have shown a relationship between circulating IGF-1 and the risk of developing prostate, breast, colorectal and other cancers [62]. The IGF-1 receptor (IGF-1R) plays a role in the establishment and maintenance of cellular transformation [65], and the receptor or its ligands may be overexpressed in human tumors [66,67]. Its action may protect against apoptosis and favors invasion and metastasis [68,69]. Howard et al. [70] stated that 91% of patients with esophageal adenocarcinoma expressed leptin receptor (ObR), 95% expressed adiponectin receptors 1 (AdipR1) and 100% expressed adiponectin receptors 2 (AdipR2). Relative expression of ObR was upregulated in 67%, and AdipR1 and AdipR2 were downregulated in 55 and 68%, respectively, relative to the calibrator sample. Upregulated ObR and AdipR2 expressions were significantly associated with anthropometric and radiological measures of obesity. Upregulated ObR was associated with advanced tumor and node category (p = 0.036 and p = 0.025, respectively) and upregulated AdipR2 with nodal involvement (p = 0.037). Studies in vitro support a role for the IGF axis in esophageal adenocarcinoma progression. Blockade of the IGF-1R leads to apoptosis [71] and IGF-1 stimulates proliferation [72]. In esophageal cancer, overexpression of IGF-1R has been associated with the malignant progression of Barrett’s esophagus to adenocarcinoma [73]. Trinity College [74] reported that higher IGF-1 receptor (IGF-1R) protein expressions were observed in SCC cells compared with esophageal adenocarcinoma cells; however, only adenocarcinoma cell lines significantly increased proliferation in response to IGF-1 (p < 0.01). Serum IGF-1 levels were highest in esophageal adenocarcinoma patients (p < 0.01) and higher in viscerally obese versus nonobese (p < 0.05) patients. In Expert Rev. Anticancer Ther. 13(10), (2013)

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resected esophageal cancer, increased expression of IGF-1R was observed in the tumor and invasive edge compared with tumor-associated stroma (p < 0.05), which coincided with increased CD68+ cells in stromal tissue surrounding invasive tumor edge (p < 0.01). A total of 220 patients were studied by Donohoe et al. [75]. Total and free IGF-1 levels were significantly increased in the serum of viscerally obese patients. Gene expression analysis revealed a significant association between obesity status and both IGF-1R (p = 0.021) and IGF-1 (p = 0.031) in tumors. Tissue microarrays analysis demonstrated that IGF-1R expression in resected tumors was significantly higher in viscerally obese patients than in those of normal weight (p = 0.023). Disease-specific survival was longer in patients with negative IGF-1R expression than in those with IGF-1R-positive tumors (median 60.0 vs 23.4 months; p = 0.027). This highlights the relationship between IGF axis with visceral obesity and a probable impact on the biology of esophageal adenocarcinoma through its receptor. Studies are ongoing with other novel agents targeting insulin-like growth factor receptor, its ligand IGF-1 and telomerase enzyme [76].

Review

or favorable clinical outcome (log-rank test: OS, p = 0.4660; DFS, p = 0.3468). In the present study, the patients with high nuclear ERb immunoreactivity were significantly associated with shorter survival or adverse clinical outcome (log-rank test: OS, p = 0.0017; DFS, p = 0.0005). Results of univariate analysis (TABLE 1) demonstrated that pathological stage (OS, p = 0.0003; DFS, p = 0.0006), ERb status in the nucleus of carcinoma cells (OS, p = 0.0025; DFS, p = 0.0010), tumor size (OS, p = 0.0485; DFS, p = 0.0366) and infiltration type (OS, p = 0.0200; DFS, p = 0.0416) were all significant prognostic factors for OS and/or DFS in 90 ESCC examined in our study. A subsequent multivariate analysis did reveal that ERb status (OS, p = 0.0010; DFS, p = 0.0007) was an independent prognostic factor for OS and DFS of these patients, as well as pathological stage (OS, p = 0.0019; DFS, p = 0.0091) and infiltration type (OS, p = 0.0185; DFS, p = 0.0328). Future perspective would be if a confirmed link might provide support for ERb to be used as a target for therapy or as a prognostic marker. Survivin & ESCC

Estrogen receptor

Estrogens, the primary female sex hormones, are mechanistically linked to aspects of cancer risk and cancer development. A connection between estrogen-activated signaling and carcinogenesis in many organs including mammary glands [77], ovaries and colon [78] has been clearly defined, although it is unclear whether a similar connection exists for the esophagus and esophageal adenocarcinoma in particular. Furthermore, estrogen is actively involved in the regulation of metabolism in adipose tissues [79], and it can be synthesized locally by activated aromatase in adipocytes in both men and women [80]. Therefore, it seems reasonable to consider that estrogens might contribute toward the gender difference for esophageal adenocarcinoma. Involvement of estrogen signaling in regulation of adipose tissue metabolism indicates a possible connection between the effects of estrogen and male obesity – one of the main risk factors for esophageal adenocarcinoma. A recent article from Japan [81] examined the status of estrogen receptor (ER)a and ERb in 90 Japanese ESCC patients. ERa and ERb immunoreactivity was detected in the nuclei of ESCC cells (41.1 and 97.8%, respectively). Correlation between the status of ERb immunoreactivity and clinicopathological variables in 90 ESCC patients There was a statistically significant positive association between ERb H score and tumor differentiation (p = 0.0403) and TNM-pM (LYM) (p = 0.0164). There was also a weak but statistically significant positive correlation between the ERb H score and Ki67/MIB1 LI (p = 0.0497, r = 0.207). No significant association was detected between ERb immunoreactivity and age, gender, tumor size, depth of tumor invasion, presence of lymph node metastasis, TNM stage, lymphatic invasion, venous invasion or infiltrative growth pattern of the patients examined in the present study. The patients with positive nuclear ERa immunoreactivity in carcinoma cells were by no means associated with better survival www.expert-reviews.com

Survivin forms an inhibitor of apoptosis protein and is necessary for anti-apoptotic function [82]. In a mix of both squamous and adenocarcinomas of the esophagus surviving immunostaining was detected in 95% of the tumors. The level of expression and the number of proliferating cells was related with each other. Hsu et al. [83] demonstrated that higher expression of survivin may be related to tumor progression and it is an independent risk factor for poor survival time of ESCC. Survivin may be a satisfactory biomarker to be applied in clinic to predict the prognosis of ESCC. Cyclooxygenase-2

After the discovery of cyclooxygenase (COX-2) enzyme in 1988, a growing body of genetic studies suggests its association with many oncogenetic processes including decreased apoptosis, increased proliferation, angiogenesis and invasiveness [84–86]. Overexpression of COX-2 has been documented in head and neck, breast, lung, colon, gastric, pancreatic and prostate cancers [87–93]. Epidemiological studies and clinical trials indicate that long-term use of nonsteroidal anti-inflammatory drugs could decrease the incidence of certain malignancies, including colorectal, esophageal, breast, lung and bladder cancers [94]. According to Prins et al. [95], high COX-2 expression was observed in 39 (26.5%) esophageal adenocarcinomas and was associated with poor cancer-specific survival (p = 0.022). In multivariate analysis, high COX-2 expression (HR: 1.65; 95% CI: 1.04–2.61; p = 0.034) was associated with OS. In patients with T3 tumors, COX-2 expression was an independent prognostic factor for cancer-specific survival (HR: 1.81: 95% CI: 1.10–2.95; p = 0.019). As said by Kagoshima University [96], COX-2 expression was significantly correlated with depth of invasion and tumor stage (p = 0.03 and p = 0.04, respectively). The 5-year survival rate of patients decreased significantly with increased expression of COX-2 (p = 0.005). Multivariate 1173

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Table 1. HER2 expression and amplification in esophageal cancer. Study (year)

Continent

Yoon et al. (2012)

North America

713

IHC, FISH

EAC

[18]

Australia

89

IHC, SISH

EAC

[16]

North America

116

IHC, CISH

EAC

[15]

Reichelt et al. (2007)

Europe

255

IHC, FISH

EAC

[11]

Hardwick et al. (1997)

Europe

127

IHC

EAC and SCC

[14]

Duhaylongsod et al. (1995)

North America

42

IHC

EAC

[17]

Sauter et al. (1993)

North America

14

IHC

EAC

[117]

Langer et al. (2011)

Europe

142

IHC, FISH

EAC

[12]

North America

39

IHC

EAC and SCC

[21]

Asia

66

IHC, FISH

SCC

[118]

Stoecklein et al. (2008)

Europe

107

FISH

EAC and SCC

[20]

Polkowski et al. (1999)

Europe

41

IHC

EAC

[119]

South America

185

IHC, FISH

SCC

[120]

Asia

142

IHC

SCC

[121]

Birner et al. (2011)

Europe

330

IHC

EAC and SCC

[19]

Wei et al. (2007)

Europe

40

IHC

SCC

[122]

Tanaka et al. (1997)

North America

32

IHC

EAC and SCC

[123]

Brien et al. (2000)

North America

63

ISH

EAC

[10]

Europe

62

IHC

EAC

[124]

Asia

145

IHC, FISH

SCC

[125]

Flejou et al. (1994)

Europe

66

IHC

EAC and SCC

[13]

Bizari et al. (2006)

South America

40

IHC, FISH

SCC

[126]

Europe

176

IHC, FISH

EAC and SCC

[127]

Thompson et al. (2011)

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Hu et al. (2011)

Friess et al. (1999) Mimura et al. (2005)

Sato-Kuwabara et al. (2009) Yamamoto et al. (2012)

Nakamura et al. (1994) Zhan et al. (2012)

Schoppmann (2011)

Cases

regression analysis indicated COX-2 expression as an independent prognostic factor for ESCC. University of California published [97] a meta-analysis including nine studies with 1,813 patients, there was 43% risk reduction of developing esophageal cancer with these agents. However, the Chemoprevention for Barrett’s Esophagus Trial [98] a Phase IIb multicenter randomized placebo-controlled trial did not find any difference in the primary outcome – change from baseline to 48 weeks of therapy in the proportion of biopsy specimens with dysplasia in the celecoxib and placebo arms. COX-2 might be a potential therapy target for and work as a prognostic factor.

Test method

Histology

Ref.

patients with an elevated CRP level in the serum have a worse survival [99–102]. Nakatsu et al. [100] assessed tumoral CRP expression in resected specimens of tumor tissue by immunohistochemistry and demonstrated that 59% of the study participants (43/73) were positive for tumoral CRP expression, and the remaining 41% (30/73) were negative. Patients expressing tumoral CRP showed significantly poorer survival and recurrence rates. A multivariate analysis showed that tumoral CRP expression was an independent factor contributing to the likelihood of a poor outcome and is a potentially useful indicator that could enable more personalized cancer treatment in the future.

C-reactive protein & ESCC

C-reactive protein (CRP) is a prototype acute phase protein and is synthesized in hepatocytes in response to inflammatory changes, but can also be expressed by cancer cells. CRP can be detected in serum and its expression can be induced by a proinflammatory cytokine (especially IL-6), which also acts as a growth factor in cancers. In esophageal cancer, 1174

SOX2 & ESCC

Sox2 is an important member of the Sox gene family. Sox (SRY box) genes have been identified through their homology to the high mobility group (HMG) box (79 amino acids) of sex-determining factor SRY [103–106]. The Sox genes encode transcription factors that interact with DNA through their highly Expert Rev. Anticancer Ther. 13(10), (2013)

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Mitochondria

Review

Bcl-2

Bax

TG F-β R

Cyt C

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TGF-β

p53

p16

DNA-damage

Caspase 8 Caspase 9

p21

Smad4 Apoptosis Changes in gene expression

Cyclin D1 PCNA cdk4

Bad

Rb

Integrin NF-κB

E-cadherin

Cyt C

Cyclin E PCNA cdk2

Phospho Rb

Mitochondria

Cell proliferation Akt pathway

B-catenin APC MMP NF-κB

Bcl-2 COX-2 EGFR

MMP

VEG

F-R

VEG

EGF TGF-α

F

Figure 1. Relationship between the diverse prognostic factors in patients with adenorcarcinoma of the esophagus. Reproduced with permission from [128].

conserved HMG domain [107,108]. The Sox genes are expressed in a wide variety of tissues and play important roles in the regulation of organ development and cell-type specification [104,106]. They also have a crucial function in embryonic stem cell (ESC) development [109]. Wang et al. [110] established that Sox2 expressions were significantly associated with higher histological grade (p < 0.001 for both factors), indicating their correlation to dedifferentiation in these tumors, and a significant correlation between increasing levels of Sox2 immunostaining and decreasing survival for the patients (p < 0.001) was observed. After being stratified by histological grade, Sox2 expressions were still significantly associated with unfavorable OS (p = 0.008 and p = 0.003, respectively). The role of Sox2 in esophageal carcinogenesis evidences further studies. OCT4 & ESCC

OCT4, also known as OCT3, belongs to the Pit-Oct-Unc (POU) transcription factor family [111]. The POU family of transcription factors can activate the expression of their target www.expert-reviews.com

genes through binding the octameric sequence motif with an AGTCAAAT consensus sequence [112,113]. The expression of this gene is necessary for the maintenance of pluripotentiality in ESCs and primordial germ cells and is downregulated in all differentiated cells in vitro as well as in vivo [113]. According to Zhou et al., Oct4 protein was expressed in 93.7% of the ESCC samples and was not expressed in normal esophageal mucosa [114]. The overexpression of Oct4 in ESCCs suggests that it is a potential target for ESCC therapy. Oct4 could be a useful tumor marker in an IHC panel designed to differentiate between ESCC and esophageal mucosa. Expression of Oct4 in tumorospheres might indicate the presence of a population of ECSCs, and its expression in xenograft tumors suggests that Oct4 is also associated with tumor metastasis. Among 153 specimens from the department of Oncology at Zhengzhou University [115], 105 (68.7%) were negative or weakly positive for OCT4 staining; 21 (13.7%) were moderately positive and 27 (17.6%) were strongly positive. Higher expression level of OCT4 was significantly associated with higher histological 1175

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grade (p < 0.001) and poor clinic outcome (p < 0.001). The role of Oct3/4 in esophageal carcinogenesis, especially in consideration of tumor cell stemness, merits further studies.

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Expert commentary

The HER2 pathway is crucial for cancer cell survival, and its overexpression is seen in some cancer types. Targeting of this pathway has been applied to the therapy of breast and esophagogastric cancers. Despite contemporary developments, management of upper gastrointestinal malignancies remains a major challenge. Targeting HER2 molecule, trastuzumab, in combination with chemotherapy is the standard approach at present for the therapy of advanced HER2/neu-overexpressing upper gastrointestinal adenocarcinomas. As far as other prognostic markers are concerned, molecular cancer research has generated an immense amount of information concerning the progression of adenocarcinoma of the distal esophagus. Molecular prognostic factors are still not included in prognostic models such as the TNM classification. Drug development has already been transformed with the identification and ability to direct treatment at specific molecular targets (e.g., COX-2, VEGF and TKIs). In esophageal cancer, these novel-targeted treatments are in its infancy although many Phase I trials are currently being conducted [116].

Five-year view

The main reason for this is that molecular biological research is rapidly evolving, and an astonishing number of biomarkers have been described, but sufficiently large studies about the prognostic value of one specific gene or protein are still lacking. In the near future, the targeting of major signaling pathways (e.g., mitogenactivated protein kinase signaling), the targeting of multiple molecules together and the discovery of new pathways associated with tumor progression and dissemination will enhance the therapeutic options of patients with this type of cancer and will give clinicians the ability, to not only give (neo)adjuvant chemo radiotherapy on the basis based on the prognostic information, but also to tailor individually targeted therapy based on molecular biology. It is likely that therapeutic intervention at the level of genes and molecules with great prognostic power and its signaling pathways will have the largest impact on long-term survival. Financial & competing interests disclosure

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • In the Western world, there has been an alarming rise in the incidence and prevalence of adenocarcinoma during recent decades. • Cancer of the esophagus shows multiple genetic alterations, which indicate that progression of cancer is a multistep complex process with many different alterations. • Targeted molecular therapy in upper gastrointestinal cancer has become an increasingly popular topic over the past few years. • A bewildering number of biomarkers have been described. Many genes and molecules have prognostic impact (EGFR, Her-2/Neu, survivin, estrogen, Cox-2, E-cadherin, OCT4, SOX2, IGF-1 and CRP). • Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options. • Drug development has already been transformed with the identification and ability to direct treatment at specific molecular targets (e.g., COX-2, HER2, VEGF and tyrosine kinase inhibitors). • It is likely that therapeutic intervention at the level of genes and molecules with great prognostic power and its signaling pathways will have the largest impact on long-term survival. • In future, gene expression analysis with microarrays may reveal important prognostic information and the discovery of new genes and molecules associated with tumor progression and dissemination will enhance prognostication and offers adjuvant therapeutic options.

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Expert Rev. Anticancer Ther. 13(10), (2013)