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Pancreatic cancer represents three percent of all incident cancer cases in developed countries, but stands the 7th most common cause of cancer related death. Worldwide, pancreatic cancer is more common among men, however in Sweden, the incidence ratio between sexes is levelling. Despite extensive research to map underlying risk factors, results are still largely inconclusive. Furthermore, there is a lack of knowledge regarding the influence of hormonal factors on risk and clinical outcome. A few studies have investigated the expression of female hormone receptors in pancreatic cancer, and others have reported beneficial effects of tamoxifen treatment in advanced pancreatic cancer, particularly in elderly women. The primary aim of this thesis was to investigate potential risk factors for pancreatic cancer, with particular reference to sex differences, and furthermore, to evaluate the presence and prognostic significance of hormone receptors in pancreatic and other periampullary cancers. Finally, based on the third paper, we composed a protocol for a clinical trial investigating the impact of tamoxifen treatment in women with advanced pancreatic cancer.The thesis is based on the Malmö Diet and Cancer Study (MDCS), a prospective population-based cohort with 28 098 participants, as well as a retrospective cohort with 175 consecutive cases of resected pancreatic and other periampullary adenocarcinoma. Cox proportional hazards regression models were applied to study the potential associations between investigative baseline factors and risk of pancreatic cancer in the MDCS. Immunohistochemical expression of estrogen and progesterone receptors (ER, PR) was analysed on tumour tissue microarrays from the retrospective cohort.Paper I confirms smoking as one of the most significant risk factors for pancreatic cancer, also proposing a greater risk increase among women.Paper II demonstrates an increased risk of pancreatic cancer among women with high age at menarche and a lower r

Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor-1 alpha (HIF-1 alpha), and HIF-1 alpha has been associated with an impaired prognosis in breast cancer and down-regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF-1 alpha regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF-1 alpha using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF-1 alpha was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki-67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF-1 alpha expressing tumours. In lymph node-positive patients as well as NHG 1/2 tumours, high HIF-1 alpha protein expression was significantly associated with an impaired recurrence-free survival (p = 0.014, 0.0.18). When analyzing the subgroup of NHG 1/2 tumours, a high HIF-1 alpha expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF-1a might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis. (c) 2005 Wiley-Liss, Inc.