Impact of Lifestyle, Hormones, and Genes on Breast Cancer

Sammanfattning: Approximately 7000 women are diagnosed and 1500 women die from breast cancer in Sweden every year. The aim of this thesis was to study the interplay of polymorphisms, hormone levels, lifestyle, and the use of concomitant medication in relation to risk and prognosis in two cohorts: one composed of young healthy women from high-risk breast cancer families and the other of breast cancer patients from the general population. In paper I and II, testosterone levels were lower in current oral contraceptive (OC) users than in non-users in most women. However, the AR GGC (S/S) genotype and rare AR variant diplotypes were associated with higher testosterone levels during OC use. The GGC (S/S) genotype, but not rare variant AR diplotypes was associated with incident breast cancer, irrespective of the BRCA1/2 mutation status. Since higher testosterone levels may be a risk factor for breast cancer, OC use may increase breast cancer risk among women with the GGC (S/S) genotype or the rare variant AR diplotypes. In paper III, post-lactational prolactin levels were determined by breast-feeding duration of the ?rst child and not simply by the ?rst full-term pregnancy. Since prolactin modi?es the risk for breast cancer, adequate counseling in favor of breast-feeding is essential. In paper IV, 21.3 % of patients used biologically based complementary and alternative medicine (CAM) preoperatively, and 38.8 % reported the use of CAM during at least one visit. CAM use was associated with certain patient characteristics, such as antidepressant and alcohol use, and with tamoxifen treatment, but not with tumor characteristics or early breast cancer events. CAM use may cause clinically significant drug interactions and it is therefore of clinical interest to identify potential CAM users. In paper V, antidepressant use was associated with an over three-fold increased risk and potent CYP2D6 inhibitors with a five-fold increased risk of early breast cancer events among tamoxifen-treated patients with invasive ER positive tumors. Antidepressant use, but not CYP2D6 genotype, was associated with premature tamoxifen cessation. Antidepressant and CYP2D6 inhibitor use, but not CYP2D6 genotype alone or in combination with CYP2D6 inhibitors, predicted five-year disease-free survival in a large prospective cohort of tamoxifen-treated patients. In conclusion, lifestyle and genetic polymorphisms that modify hormone levels and treatment response may play an important role in breast cancer.