Routine mammographic screening for breast cancer reduces breast cancer mortality. On a mammogram, radiologists assess mammographic density (MD), or the amount of fibroglandular tissue (FGT) in the breast, which is a strong risk factor for breast cancer. Women with dense breasts are more likely to be diagnosed in the “interval” between screening exams, contributing to increased breast cancer mortality. However, current screening guidelines for average-risk women do not take imaging risk markers into account. Women with very high risk of breast cancer, regardless of MD, receive an intensified screening schedule with supplemental contrast-enhanced magnetic resonance imaging (MRI). On MRI, radiologists assess FGT as well as background parenchymal enhancement (BPE). BPE is the degree to which healthy FGT brightens due to the presence of contrast, reflecting the metabolic activity within the FGT. We recently demonstrated that BPE on MRI was associated with breast cancer risk independently of the amount of FGT. Other studies corroborate our findings, supporting our premise that BPE is a new marker of breast cancer risk. However, due to the select population receiving MRI, alternative measurement approaches are needed to increase the impact of BPE for women who are not able to receive screening MRI. Contrast-enhanced mammography (CEM) is an increasingly-used breast screening modality that substantially improves breast cancer detection, comparable in sensitivity to MRI. After injection of a contrast agent, two mammograms at high and low energies are taken in quick succession. MD is assessed on the low-energy image and BPE is assessed subjectively by radiologists as “minimal”, “mild”, “moderate”, or “marked” on a processed (“recombined”) image per the Breast Imaging – Reporting and Data System (BI-RADS). BI-RADS BPE measured on CEM has good agreement with BI-RADS BPE measured on MRI. However, subjective measurement of BPE varies between readers, preventing reproducible risk assessment research. An objective, quantitative measure of BPE on CEM is needed to rigorously evaluate the relationship between increased BPE and breast cancer risk. To address this research gap, we propose to assess the association between cancer and a fully automated measure of BPE on CEM. Aim 1. Evaluate BPE as a reproducible marker of breast cancer risk: we will implement a fully automated measure of quantitative BPE on 462 CEMs, evaluate the agreement with the gold standard BI-RADS measure, and compare with BPE on MRI. Aim 2. Determine whether quantitative BPE improves breast cancer risk assessment: in a matched case-control study of 154 newly diagnosed breast cases matched to 308 cancer- free controls, we will determine the association of breast cancer with BPE, accounting for FGT, race/ethnicity, reproductive factors, and other risk factors for breast cancer. Our long-term goal is to use quantitative BPE on CEM to improve breast cancer risk assessment, thereby enabling personalization of breast cancer screening to improve screening outcomes and reduce mortality due to breast cancer.

PROJECT NARRATIVE Background parenchymal enhancement (BPE) is a promising new marker of breast cancer risk that has been studied almost exclusively using magnetic resonance imaging, an expensive screening modality that is indicated primarily for women with high risk of breast cancer. We propose here to measure BPE quantitatively using contrast-enhanced mammogram (CEM), a rapidly emerging screening modality that is more affordable and generalizable than MRI, and assess the potential of BPE measured on CEM as a marker of breast cancer risk. Our long-term goal is to use our new, objective measure of BPE on CEM to improve assessment of breast cancer risk, enabling personalization of breast cancer screening to detect breast cancer earlier and ultimately reduce breast cancer mortality.