PROJECT SUMMARY/ABSTRACT While great strides have been made in reducing breast cancer mortality over the last two decades, most of this reduction is attributed to advances in treatment. Screening?s contribution to breast cancer mortality reduction has been stagnant as screening continues to rely on mammography?s x-ray technology that preferentially detects less aggressive cancers and can mask tumors in dense breasts, due to the similar x-ray attenuation characteristics of breast tumors and dense tissue. Over half of women who undergo screening in the US have mammographically dense breasts (MDB), and mammography fails to detect 75% of cancers in women with MDB when it is compared to a functional screening tool such as MRI. However, the cost and complexity of MRI as well as concerns about safety and tolerability have been barriers to screening women with MDB, and there remains no consensus on whether or how supplemental screening should be performed in women with MDB, which underscores the need for a functional modality with a more favorable cost, tolerability, and safety profile. Molecular Breast Imaging (MBI) is a functional screening tool that utilizes gamma detectors to image the preferential uptake of a radiotracer in breast cancers. Like MRI, MBI detects invasive breast cancers that are not visible on mammography due to breast density and preferentially detects aggressive cancers, but is less costly and complex to interpret compared to MRI. MBI has shown promise when evaluated in single-center studies, but has yet to be evaluated across diverse breast imaging practices and patient populations, and has yet to be compared to 3D mammography (also known as digital breast tomosynthesis [DBT]), which is becoming the new standard screening mammography test. This need for multicenter validation, coupled with additional concerns about cost and radiation dose have limited MBI adoption to date. We propose the Density MATTERS (Molecular Breast Imaging and Tomosynthesis to Eliminate the Reservoir of Undetected Cancers) clinical trial in which 3000 women will undergo concurrent MBI and DBT at study entry and one year later. We hypothesize that MBI, whether in combination with DBT or alone, will detect at least twice as many invasive cancers as DBT and will lead to fewer advanced cancers in the second year of screening, which are associated with higher breast cancer mortality. We will also compare the costs of these two screening approaches and validate a new image processing tool so MBI can be acquired at a radiation effective dose as low as DBT. This project is timely as a February 2019 federal law now mandates that women with MDB are informed of the risk of tumor masking on mammography. Thus, up to half of women nationwide will be seeking a solution for improved screening. Project outcomes could change clinical practice for women with MDB by validating MBI as an immediately available, safe and well-tolerated screening solution to detect invasive cancers missed on mammography and DBT, without increasing costs or radiation exposure.