Cáncer de páncreas: alteraciones genéticas, cambios morfológicos y sus implicaciones terapéuticas / Pancreas cancer: genetic alterations, morphological changes and its therapeutic implications

Resumen El cáncer de páncreas es una enfermedad mortal, principalmente porque se descubre muy tarde y es muy resistente a la quimioterapia y radioterapia. El tipo más común de cáncer de páncreas (más del 90%) se desarrolla a partir de las células exocrinas del páncreas y se denomina adenocarcinoma ductal pancreático (ACDP). Se han reconocido tres lesiones precursoras de cáncer de páncreas ductal: neoplasia intraepitelial pancreática (PanIN), neoplasia papilar-mucinosa intraductal (NPMI) y neoplasia quística mucinosa (NCM). Uno de los primeros eventos genéticos implicados en la patogénesis de ACDP es una mutación en el punto de activación en el oncogén KRAS, una mutación conductora oncogénica que se encuentra en más del 90% de todos los cánceres de páncreas. Además, se ha informado que hasta un 10% de los cánceres de páncreas están asociados con el historial familiar. Aunque la causa es multifactorial, el tabaquismo y la historia familiar son dominantes. Existe heterogeneidad morfológica en muchos cánceres humanos, pero parece ser un hallazgo particularmente común en ACDP. La cirugía solo es posible en 15-20% de los casos: tumores confinados al páncreas con posible afectación ganglionar local no muy extensa y que no produce afectación vascular o está limitada.

Abstract Pancreatic cancer is a deadly disease, mainly because it is generally discovered very late and it is very resistant to chemotherapy and radiation therapy. The most common type of pancreatic cancer (over 90%) develops from the exocrine cells of the pancreas and is named pancreatic ductal adenocarcinoma (PDAC). Three precursor lesions of ductal pancreatic cancer have been recognized: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary-mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). One of the earliest genetic events involved in PDAC pathogenesis is an activating point mutation in the KRAS oncogene, an oncogenic driver mutation found in more than 90% of all pancreatic cancer. In addition, it has been reported that up to 10% of pancreatic cancer is associated with family history. Although the cause is multifactorial, cigarette smoking and family history are dominant. Morphological heterogeneity exists in many human cancers, but seems to be a particularly common finding in PDAC. Surgery is only possible in 15-20% of cases: tumors confined to the pancreas with possible local nodal involvement not very extensive and that do not produce vascular involvement or is limited.

Inherited pancreatic cancer.

Pancreatic cancers arise through a series of genetic events both inherited and acquired. Inherited genetic changes, both high penetrance and low penetrance, are an important component of pancreatic cancer risk, and may be used to characterize populations who will benefit from early detection. Furthermore, pancreatic cancer patients with inherited mutations may be particularly sensitive to certain targeted agents, providing an opportunity to personalized treatment. Family history of pancreatic cancer is one of the strongest risk factors for the disease, and is associated with an increased risk of caners at other sites, including but not limited to breast, ovarian and colorectal cancer. The goal of this chapter is to discuss the importance of family history of pancreatic cancer, and the known genes that account for a portion of the familial clustering of pancreatic cancer.

Is screening for pancreatic cancer in high-risk groups cost-effective? - Experience from a Danish national screening program.

OBJECTIVE: Pancreatic cancer (PC) is the fourth leading cause of cancer death worldwide, symptoms are few and diffuse, and when the diagnosis has been made only 10-15% would benefit from resection. Surgery is the only potentially curable treatment for pancreatic cancer, and the prognosis seems to improve with early detection. A hereditary component has been identified in 1-10% of the PC cases. To comply with this, screening for PC in high-risk groups with a genetic disposition for PC has been recommended in research settings. DESIGN: Between January 2006 and February 2014 31 patients with Hereditary pancreatitis or with a disposition of HP and 40 first-degree relatives of patients with Familial Pancreatic Cancer (FPC) were screened for development of Pancreatic Ductal Adenocarcinoma (PDAC) with yearly endoscopic ultrasound. The cost-effectiveness of screening in comparison with no-screening was assessed by the incremental cost-utility ratio (ICER). RESULTS: By screening the FPC group we identified 2 patients with PDAC who were treated by total pancreatectomy. One patient is still alive, while the other died after 7 months due to cardiac surgery complications. Stratified analysis of patients with HP and FPC provided ICERs of 47,156 US$ vs. 35,493 US$ per life-year and 58,647 US$ vs. 47,867 US$ per QALY. Including only PDAC related death changed the ICER to 31,722 US$ per life-year and 42,128 US$ per QALY. The ICER for patients with FPC was estimated at 28,834 US$ per life-year and 38,785 US$ per QALY. CONCLUSIONS: With a threshold value of 50,000 US$ per QALY this screening program appears to constitute a cost-effective intervention although screening of HP patients appears to be less cost-effective than FPC patients.