**3. Pancreatic cancer**

#### **3.1 Introduction**

Pancreatic cancer has the worst prognosis of all gastrointestinal malignancies with the mortality approaching the incidence (Buxbaum & Eloubeidi, 2010)(Bünger et al., 2011). Late clinical presentation, intrinsic biological aggressiveness, and resistance to conventional chemotherapy and radiotherapy represent the predominant reasons for its poor prognosis (Pizzi et al., 2009). This demonstrates an urgent demand for improved screening tools for early detection (Buxbaum & Eloubeidi, 2010)(Bünger et al., 2011). While surveillance is performed in individuals with genetic syndromes, hereditary pancreatitis, and a strong family history there are no clear guidelines for those with clinical risk factors like diabetes mellitus, tobacco use, and chronic pancreatitis (Buxbaum & Eloubeidi, 2010). Pancreatic ductal adenocarcinoma is the most commonly diagnosed pancreatic neoplasm, and reported to be the forth or fifth leading cause of cancer death in Western countries. Diagnosis of pancreatic cancer at early stages is crucial because successful surgical resection remains the only possibility of cure (Ansari et al., 2011). Only 10-30% of pancreatic tumor patients are operated on with curative intent. The expected 5-year survival rate of R0 resected patients with additional adjuvant chemotherapy is about 4-26%. In contrast, for the remaining patients who present with unresectable UICC stage III and IV carcinomas, no curative therapy is available. These patients have median survival times of 8-12 months (stage III) and 5-8 months (stage IV), respectively (Bünger et al., 2011). In addition, early-stage pancreatic cancer is usually clinically silent, and symptoms only become apparent after the tumor invades surrounding tissues or metastasis to distant organs. Therefore, most persons who present with symptoms attributable to pancreatic cancer have advanced disease (Vincent et al., 2011).

The Holy Grail for pancreatic cancer investigators is to identify early markers, which predict the development of pancreatic cancer, uncover early resectable disease, and guide therapy (Buxbaum & Eloubeidi, 2010).

Potential molecular markers are sought in the pancreatic tissue, juice as well as other body fluids including serum and urine. An important consideration is that pancreatic tumor cells and secreted molecules are found in markedly higher concentrations in the pancreas and pancreatic juice compared to serum. Additionally, molecules and proteins in the serum are overwhelmed by high concentrations of albumin, transferrin, and immunoglobulins (Buxbaum & Eloubeidi, 2010).

Both hypothesis driven and high throughput searches for molecular markers to predict disease, early diagnosis, and treatment response are underway. Challenges include differentiation of cancer from chronic inflammatory disease of the pancreas and achieving reproducible results among diverse patients. Minimally invasive methods including endoscopic ultrasound guided fine needle aspiration (EUS-FNA) to acquire tissue may facilitate these important efforts (Buxbaum & Eloubeidi, 2010). This method enabled not only accurate diagnosis, but also the collection of cancer tissue before surgery or chemotherapy even in inoperable cases. Evaluation of the expression status of multiple molecules within the FNA specimen will lead to the establishment of individualized therapeutic strategies based on the prediction of prognosis or response to chemotherapy (Hamada & Shimosegawa, 2011).
