Biomarkers in pancreatic and other periampullary cancers - some familiar and one new

AbstractBackground: Adenocarcinomas arising in the area around the papilla of Vater are referred to as periampullary adenocarcinomas and are of four different anatomical origins: pancreas, distal bile duct, ampulla and duodenum. These heterogeneous tumors are usually divided into two morphological subtypes, pancreatobiliary type (PB-type) and intestinal type (I-type), which provides more important prognostic information than tumor origin. In general, the prognosis for patients with these tumors is dismal, and treatment options are few. Therefore, there is an urgent need to gain further knowledge about the biology of these cancers, with the aim to improve patient survival. A way forward is through the identification of prognostic and predictive biomarkers, which was the overall aim of this thesis. Methods: The studies were based on a retrospective consecutive cohort of 175 patients with surgically resected periampullary adenocarcinomas (paper I-IV), and a retrospective cohort comprising 186 patients with surgically resected pancreatic cancers (paper IV). From primary tumors and selected lymph node metastases, tissue microarrays were constructed and used for immunohistochemical assessment of expression of podocalyxin-like protein (PODXL), members of the human epidermal growth factor receptor (HER) family, and mismatch repair (MMR) proteins. PODXL is a new and promising biomarker candidate and its interplay with epidermal growth factor receptor 1 (EGFR) was also analyzed in vitro. Results: Overexpression of PODXL in tumor cell membranes was significantly higher in PB-type than in I-type tumors, and an independent factor of poor prognosis for patients with I-type tumors. In addition, it was demonstrated that patients with I-type tumors displaying high PODXL expression benefited from adjuvant chemotherapy. In contrast, patients with PB-type tumors with high EGFR expression who received adjuvant gemcitabine had an adverse prognosis. HER2 overexpression was seen in 6% of I-type tumors, and was strongly associated with HER2 gene amplification. MMR deficiency (dMMR) was more frequent in I-type compared to PB-type tumors, and a prognostic factor for long-term survival in patients with the former type. Patients with PB-type tumors displaying dMMR did not seem to benefit from adjuvant chemotherapy. There was a significant correlation and synergistic adverse prognostic impact between PODXL and EGFR expression in both study cohorts. Silencing of PODXL in a human pancreatic cancer cell line led to reduced levels of EGFR, but not vice versa.Conclusions: These results suggest that the poor prognosis associated with PODXL overexpression may be reversed by adjuvant treatment in patients with I-type periampullary tumors, and that high EGFR expression and dMMR are negative predictors of response to adjuvant chemotherapy in patients with PB-type tumors. Speculatively, some of these patients may instead benefit from immunotherapy. Moreover, high expression of both PODXL and EGFR signifies a particularly poor prognosis for patients with periampullary adenocarcinoma and the in vitro support of a functional link between these proteins might be of clinical importance. Given the retrospective design and that many tests have been made on a small patient group, results must be interpreted with caution, but may nevertheless be of clinical significance and therefore merit further validation in the prospective setting