Prognostic factors in periampullary adenocarcinoma. A retrospective study over an 11 year period

Abstract: Periampullary adenocarcinoma, including pancreatic cancer, has a poor prognosis that has not improved in the last decades. Therefore, in order to find more effective treatment regimens, it is necessary to gain more insight into the biology and clinical behaviour of these tumours. This thesis entails a thorough histopathological characterization of retrospectively collected tumours from a consecutive cohort of patients with resected periampullary adenocarcinoma, followed by tissue microarray-based immunohistochemical studies of eight candidate protein biomarkers. Tumours were classified as being of pancreatobiliary type (PB-type) or intestinal type (I-type), using histological criteria, and all biomarker analyses were performed in strata according to morphological type. In Paper I, histopathological studies showed that a standardized and meticulous protocol for assessment of the surgical specimens, as well as blind revisions of slides, had impact on the decision on tumour origin, the number of involved lymph nodes and involved margins. The biomarker studies in Paper II revealed that expression of the global gene regulator special AT-rich sequencebinding protein 1 (SATB1) was an independent factor of poor prognosis in PB-type tumours. SATB1 expression, however, also indicated a better response to adjuvant chemotherapy, in particular in I-type tumours. A closely related protein, SATB2, was found to be expressed in a few tumours only, making it difficult to draw any firm conclusions on its prognostic value. In Paper III, biomarker studies on proteins related togemcitabine metabolism revealed that a high ratio between cytoplasmic and nuclear expression of human protein R (HuR) indicated resistance to chemotherapy in PB-type tumours. In I-type tumours, high expression of human equilibrative nucleoside transporter 1 (hENT1) was a favourable prognostic factor and high expression of deoxycytidine kinase (dCK) indicated sensitivity to chemotherapy. In Paper IV, biomarker studies on the human epidermal growth factor receptors 1-3 (HER1-3) revealed a potential negative predictive effect of high EGFR (HER1) expression in relation to adjuvant chemotherapy in PB-type tumours. Six percent of I-type tumours had high expression of HER2, and gene amplification was confirmed in assessable cases. In I-type tumours, high expression of HER3 was a favourable prognostic factor, but not independent of other prognostic factors. Several of the potentially treatment predictive associations described in this thesis are novel, and may be of clinical interest if the results can be repeated in other cohorts and if the mechanistic basis is understood. The results presented here must be however be interpreted with caution, since the cohort is retrospective and many tests have been made.