**1. Introduction**

48 Biomarker

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> Personalized cancer medicine based on genetic profiling of individual tumors is regarded as the treatment strategy of the future. The targeted drugs for the treatment of cancer have rapidly developed. However, our understanding (at the molecular level) of the precise role that potential targets have in tumorigenesis, and the survival dependence of tumors on these components, has not progressed at the same rate (De Roock et al., 2011). Since patient selection for therapy remains problematic, there has been an increasing interest in biomarkers of cancer risk in predicting future patterns of disease. In the broadest sense, a biomarker is any biological, chemical, or biophysical indicator of an underlying biological process. From a medical perspective, a biomarker is a physiological characteristic that is indicative of health and disease. A cancer biomarker has been defined as "a molecular, cellular, tissue, or process-based alteration that provides indication of current, or more importantly, future behavior of cancer" (Hayes et al., 1996). Cancer biomarkers are employed across the entire healthcare spectrum from the cancer biological research laboratory to patient monitoring in the clinic. Clinical applications include disease risk stratification, chemoprevention, disease screening, diagnosis and prognosis/prediction, treatment planning and monitoring, and posttreatment surveillance. Cancer biomarkers have contributed greatly to our current understanding of the heterogeneous nature of specific cancers and have led to improvements in treatment outcomes. However, full adoption of cancer biomarkers in the clinic has been slow to date, and only a limited number of cancer biomarker products are currently in routine use (http://www.insightpharmareports.com/reports\_report.aspx?r=559&id=78452). Two primary challenges in developing cancer biomarkers are the discovery of candidate markers and the validation of those candidates for specific uses. The discovery process depends on the technologies available, and their sensitivity and specificity, to investigate the complex biochemistry of health and disease in order to identify differences that can be detected consistently in diverse populations. The validation process is also arduous and costly, often

<sup>\*</sup> Corresponding Author

Biomarkers in Gastrointestinal Cancer: Focus on Colon, Pancreatic and Gastric Cancer 51

Although hundreds of these markers have been proposed in the last 2 to 3 decades, the current reality is that no molecular marker, other than the *KRAS* gene in the case of epidermal growth factor receptor (EGFR)-targeted therapy for metastatic disease, has made

EGFR is a receptor tyrosine kinase belonging to the HER-family. When activated, EGFR phosphorylates and activates other intracellular proteins that affect cell signaling pathways, (Harding & Burtness, 2005) cellular proliferation, and control of apoptosis and angiogenesis (Figure 1) (Tedesco et al., 2004)(Harding & Burtness, 2005). EGFR has been implicated in colorectal tumorigenesis, tumor progression, and metastasis, as reviewed in Lockhart and Berlin (Lockhart et al., 2005)(Ng & Zhu, 2008). Overexpression of EGFR has been described in up to 65%–70% of human colon tumors and has been associated with the progression of CRC to a more advanced stage (Ng & Zhu, 2008). Therefore, EGFR not only represents a possible prognostic marker in the adjuvant setting of primary tumors but primarily a rational molecular target for a new class of anticancer agents, especially in the setting of metastatic CRC (mCRC) (Scartozzi et al., 2006a)(Scartozzi et al., 2006b)(Overman & Hoff,

it into clinical practice (Duffy & Crown, 2008)(De Roock et al., 2009).

Fig. 1. EGFR signaling pathways and its main transduction pathways.

In preclinical studies, it was found that the inhibition of EGFRs had antitumor activity, and available data suggests synergy with both chemotherapy and radiotherapy (Rivera et al.,

2007).

requiring collection of or access to many patient samples with extensive clinical annotation and long-term follow-up. In addition, a biomarker must be validated for each specific application for which it will be used. There must be convincing evidence that a surrogate endpoint accurately predicts the clinical endpoint of interest or in the case of screening, a test must have sufficient sensitivity, specificity, and positive predictive value to accurately identify a disease in the general population (US National Academy Press, Institute of Medicine (U.S.). Committee on Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment, 2007). Rapidly growing insights in the molecular biology of cancer and recent developments in gene sequencing, global gene expression profiling or genome wide analysis have led to high expectations for the identification, validation and assessment of cancer biomarkers alongside the established "standards of care" for cancer diagnosis and treatment.

In this review, the most promising biomarkers in gastrointestinal cancer are discussed, focusing on the epidermal growth factor receptor (EGFR)-pathway in colon cancer, the serum biomarkers, the glucose transporter (GLUT) receptors, and human equilibrative nucleoside transporter 1 in pancreatic cancer and HER2 in gastric tumors.
