Pathogenic Variant Status of High-Risk Genes, Polygenic, Epidemiological Risk Factors, and Utilization of Risk Management Options in Breast Cancer

Thesis (Ph.D.)--University of Washington, 2023 ; Breast cancer is a heterogeneous disease with multiple established risk factors, which include high-penetrance germline variants in cancer predisposition genes such as ATM, BRCA1, BRCA2, CHEK2, and PALB2. Additionally, individual and behavioral factors such as age at menarche, parity, number of births, age at first full-term pregnancy, breastfeeding, age at natural menopause, height, pre- and post-menopausal body mass index (BMI), use of menopausal hormone treatment (PMH) and oral contraceptives (OC), history of benign breast disease (BBD), smoking and alcohol consumption have been consistently observed to be associated with breast cancer risk and may potentially modify the risk associated with pathogenic variants (PV). However, existing gene-environment interaction (GE) studies of rare PVs in breast cancer predisposition genes have been limited by sample size and the number of interactions assessed. GE studies have rarely been replicated1–5, due to issues related to statistical power, exposure measurement errors, and difficulties in harmonizing data across different studies. Further, breast cancer is often treated as one disease, without consideration of molecular subtypes, primarily defined by estrogen receptor (ER) status, ignoring well-known differences in etiologies. Further, women who have been identified to have an elevated lifetime risk of breast cancer through genetic testing for hereditary cancer syndromes can benefit from risk management options such as enhanced screening and preventive surgery. However, these recommended risk management strategies are underutilized in current clinical practice, and healthcare utilization patterns following genetic testing remain poorly understood, particularly in underserved populations facing access barriers to genetic services. In this dissertation, we explored how genetic, epidemiological, and behavioral factors collectively influence breast cancer risk. Specifically, we aimed to 1) examine GE interactions between ...