A prospective study of circulating autoantibodies and breast cancer risk in the NYU Women’s Health Study - SUMMARY Breast cancer is the most commonly diagnosed cancer among US women, accounting for ~30% of all new cancer cases in women. Identifying biomarkers associated with breast cancer risk may reveal new pathophysiological mechanisms and potentially lead to improvements in risk stratification. The immune system is known to play a critical role in cancer control, and experimental studies suggest that common autoantibodies (AAbs) are involved in the earliest phase of immunosurveillance, i.e. elimination of transforming cells. Common AAbs, which include both natural and acquired AAbs, are abundant in healthy individuals and have been implicated in maintaining immune homeostasis and clearing apoptotic and cancerous cells. Therefore, varying levels of certain common AAbs could indicate active immunosurveillance mechanisms that prevent cancer development through antibody-mediated mechanisms. Levels of AAbs are now measurable at the omics-scale in small volumes of serum. However, no prospective studies have searched for common AAbs associated with risk of breast cancer. The New York University Women's Health Study (NYUWHS) is a prospective cohort study that enrolled 14,274 women aged 35–65 years between 1985 and 1991. All women donated blood at the time of enrollment. The cohort is well suited to discover new biomarkers of breast cancer risk because of its biorepository, long follow-up, excellent cancer case ascertainment, and detailed data on breast cancer risk factors. In a study involving NYUWHS healthy participants and two serum samples collected 1 year apart from each woman, we tested for common AAbs using the HuProt human proteome microarray with >20,000 AAb probes. We found that common AAbs are abundant in healthy women and that levels of most of the AAbs are stable over time. Our goal is to identify a panel of circulating common AAbs that are protective against breast cancer development. We will continue cancer case ascertainment through linkages to the Virtual Pooled Registry Cancer Linkage System and electronic health records (EHRs), medical records review and data harmonization to expand our data on tumor subtype and increase the representation of non-white cases in the proposed study (Aim 1). We will conduct a prospective case–control study nested in the NYUWHS including 800 cases of invasive breast cancer and 1-to-1 matched controls, with 300 case–control pairs in a discovery phase and 500 pairs in a validation phase (Aim 2). We will use cases of invasive breast cancer who had serum samples collected >2 years before diagnosis. We will also identify correlates of AAbs (Aim 3). This study has the potential to advance our understanding of the pathophysiological processes of breast cancer.
