Sex, hormonal factors and pancreatic cancer

Sammanfattning: 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 risk among postmenopausal women with a history of ever using hormonal replacement therapy.Paper III provides evidence of a prognostic interaction between stromal PR expression and KRAS mutation status in periampullary cancer, being particularly evident in women. More specifically, stromal PR positivity signified a prolonged survival in patients with KRAS-mutated tumours, and shorter survival in patients with KRAS wild-type tumours.Paper IV is a protocol for a single-centre, randomized, double-blind, placebo-controlled, two-arm, phase II clinical trial, investigating the effects of tamoxifen treatment on survival and quality of life in women with advanced pancreatic cancer.In summary, the thesis provides further evidence of tobacco smoking as one of the strongest risk factors for pancreatic cancer, with women being potentially more susceptible to these hazardous effects. Moreover, exogenous female hormones appear to have a protective effect, which is also in line with findings from some previous studies. The presence of ER and PR in the tumour-associated stroma in pancreatic and other periampullary adenocarcinoma, and the prognostic interaction between PR expression and KRAS status further supports that hormonal factors drive the pathogenesis and progression of these cancers. Based on the observations in Paper III, we will launch a randomized trial with tamoxifen treatment and control in women with advanced pancreatic cancer, that will also include relevant biomarker analyses.