Impact of pregnancies on ovarian cancer : Risk, prognosis and tumor biology

Abstract: Ovarian cancer is the most lethal gynecological malignancy. The etiology is complex and not fully understood, partly since ovarian cancer is not one distinct disease, but rather several histologically and clinically different subtypes. The two main groups are epithelial (90%) and non-epithelial (10%) cancers, further divided into five epithelial and two main non-epithelial subtypes. Women who have given birth have a lower risk of developing epithelial ovarian cancer, and the risk is further reduced with each additional childbirth. However, the association between several pregnancy-related factors, such as pregnancy length, maternal age at birth, offspring size, and subsequent risk of ovarian cancer has been unclear. In addition, the impact of pregnancy-related risk factors on non-epithelial ovarian cancer is unknown. Further, the underlying mechanism behind the protection of childbirth has not been revealed and the prognostic impact of pregnancies is not established.In my first two studies, I evaluated associations between pregnancy-related factors and risk of epithelial ovarian cancer and its different subtypes [Study I] and non-epithelial ovarian cancer [Study II]. These case-control studies were based on linked data from the population-based medical birth registers and cancer registers in Denmark, Finland, Norway and Sweden. In Study I, preterm birth was associated with an increased risk of epithelial ovarian cancer among parous women, whereas increased number of births and pregnancies at older age were associated with decreased risk. In Study II, increasing age at last birth was associated with lower risk of sex cord-stroma cell tumors (SCSTs), as was shorter time since last birth.In Study III, the prognostic impact of parity on both epithelial and non-epithelial ovarian cancer by subtype was investigated by linkage of data from the Swedish medical birth register, the cancer register and the cause of death register. Parity was associated with reduced cancer-specific mortality in ovarian germ cell tumors. We found no prognostic impact of parity in patients with SCSTs or epithelial ovarian cancer.In Study IV, we investigated whether hormones and proteins involved in pregnancy and tumor development differed according to the woman’s parity status in patients with high-grade serous ovarian cancer. Parous women more often had progesterone receptor (PR) positive tumors, in comparison with nulliparous women, and increased number of children was associated with PR positive tumors.In summary, a woman’s reproductive history will not only impact on the risk of developing ovarian cancer, but also have a long-lasting influence on the tumor biology.