Patients must be women age 45 or older and under age 75 at the time of study entry

Women of childbearing potential must not be known to be pregnant or lactating

Patients must be scheduled for, or have intent to schedule, a screening mammogram

Patients must be able to tolerate digital breast tomosynthesis and full-field digital mammographic imaging required by protocol

Patients must be willing and able to provide a written informed consent

Patients must not have new symptoms or signs of benign or malignant breast disease (e.g., bloody or clear nipple discharge, breast lump) based on physician physical exam or self breast exam that have not been previously worked up with imaging; patients with physiologic nipple discharge or breast pain are eligible as long as other criteria are met

Patients must not have had a screening mammogram within the last 11 months prior to date of randomization

Patients must not have previous personal history of breast cancer including ductal carcinoma in situ

Patients must not currently have breast enhancements (e.g., implants or radiopaque injections)

ANNUAL SCREENING REGIMEN ELIGIBILITY CHECK

To be eligible for inclusion in the annual screening regimen one of the following three conditions must be met in addition to the eligibility criteria above:
* Patients are pre-menopausal; OR
* Post-menopausal aged 45-69 with any of the following four risk factors:
** Dense breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
** At least one benign breast biopsy with a diagnosis of lobular carcinoma in situ (LCIS) or atypia of any kind (atypical ductal hyperplasia, atypical lobular hyperplasia, atypical hyperplasia not otherwise specified [NOS], or intraductal papilloma with atypia), or
** Family history of breast cancer (first degree relative with breast cancer) or family history of breast cancer is not known, or, participant positive genetic testing for any deleterious genes that indicate an increased risk for breast cancer, or
** Currently on hormone therapy; OR
* Post-menopausal ages 70-74 with either of the following three risk factors:
** Dense breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
** At least one benign breast biopsy with a diagnosis of LCIS or atypia of any kind (atypical ductal hyperplasia, atypical lobular hyperplasia, atypical hyperplasia NOS, or intraductal papilloma with atypia), or
** Currently on hormone therapy
*** For this study we define hormone therapies as those that increase breast cancer risk, including: estrogen, progesterone, estrogen/progesterone analogs, or hormonal birth control prescribed by a doctor, and include hormones in oral contraceptives, patch, gel, etc. BUT, for this study; soy use is not considered hormone therapy

Postmenopausal women are defined as those with their last menstrual period more than 12 months prior to study entry; for the purpose of defining menopausal status for women who have had surgical cessation of their periods, women who no longer have menses due to bilateral oophorectomy with either hysterectomy or endometrial ablation will be considered postmenopausal; women who no longer have menses due to either hysterectomy or endometrial ablation, and who have at least one ovary will be considered premenopausal until age 52 and postmenopausal thereafter

All other postmenopausal women are eligible for inclusion in the biennial screening regimen

For those women who cannot be assigned to annual or biennial screening at the time of study entry and randomization because they are postmenopausal, have no family history or known deleterious breast cancer mutation, are not on hormone therapy AND for whom a prior mammogram interpretation is not available, breast density will be determined by the radiologist’s recording of it at the time of interpretation of the first study screening examination, either DM or TM; for those who are randomized to TM, radiologists will assign BI-RADS density through review of the DM or synthetic 2D portion of the TM examination; such women cannot be part of the planned stratification by screening frequency and are expected to represent far less than 1% of the Tomosynthesis Mammographic Imaging Screening Trial (TMIST) population

Breast density will be determined by prior mammography reports, when available, or by radiologist review of prior imaging; 
* NOTE: If the latter method is used, a signed, dated attestation by the radiologist indicating the resulting determination must be kept as a record and made available for monitoring/auditing
* All other risk factors used to determine patient eligibility for annual or biennial screening will be determined by subject self-report

PRIMARY OBJECTIVE:
I. To compare the cumulative proportions of participants reaching the primary endpoint in the two study arms, using time-to-advanced cancer measured from randomization.

SECONDARY OBJECTIVES:
I. To assess the potential effect of age, menopausal and hormonal status, breast density, race, ethnicity and family cancer history on the primary endpoint difference between the two arms.
II. To compare the diagnostic performance of tomosynthesis (TM) and digital mammography (DM), as measured by the area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).
III. To compare the recall rates and biopsy rates for TM versus DM, with subset analyses by the same variables as listed in aim II.
IV. To compare the rate of interval cancers for TM and DM and to assess the mechanism of diagnosis for these interval cancers with categorization by symptomatic versus (vs) asymptomatic, and how detected: diagnosed via physical examination, mammography, ultrasound (US), magnetic resonance imaging (MRI) or other technologies.
V. To examine the correlation between Breast Imaging Reporting and Data System (BIRADS) imaging features and histologic and genetic features, such as invasive ductal and invasive lobular histology, high grade, high stage at diagnosis, and aggressive genetic subtypes.
VI. To assess different combinations of TM and synthesized 2 dimensional (2D) or DM in reader studies to assist in determining the optimum balance between diagnostic performance, radiation exposure and technique.
VII. To estimate and compare breast-cancer-specific mortality between the two study arms.
VIII. To estimate and compare the prevalence of breast cancer subtypes (luminal A, luminal B, HER2+, basal-like) low, medium or high proliferation via PAM50 proliferation signatures: p53 mutant-like or wild-type-like according to a validated p53 dependent signature; immune subtypes using a multigene signature of immune markers; deoxyribonucleic acid (DNA) repair phenotypes using a multigene signature of DNA repair genes; and a research version the 21-gene recurrence score in the two arms, overall and stratified on (a) whether cancers were detected through screening or as interval cancers, and (b) whether cancers were invasive or in situ.
IX. To classify histologically malignant (true positive cases) and benign lesions (false positive cases) as normal-like or tumor-like using the PAM50 gene expression assay subtype (luminal A, luminal B, HER2, basal-like,), and low, medium, or high proliferation according to PAM50 proliferation signatures, p53 mutant-like or wild-type like according to a validated p53-dependent signature, immune active or inactive using a multi-gene immune signature, DNA repair high or low a DNA repair signature, and high or low/medium (med) risk based on the 21- gene recurrence assay.
X. To assess the agreement between local and expert study pathologists for all breast lesions (benign and malignant) biopsied during the study.
XI. To create a blood and buccal cell biobank for future biomarker and genetic testing.
XII. To compare health care utilization (including cancer care received) and cost of an episode of breast cancer screening by TM versus DM, overall and within subsets as described in Aim II.
XIII. To implement a centralized quality control (QC) monitoring program for both 2D digital mammography (DM) and tomosynthesis (TM), which provides rapid feedback on image quality, using quantitative tools, taking advantage of the automated analysis of digital images.
XIV. To assess temporal and site-to site variations in image quality, breast radiation dose, and other quality control parameters in TM vs. DM.
XV. To refine and implement task-based measures of image quality to assess the effects of technical parameters, including machine type, and detector spatial and contrast resolution on measures of diagnostic accuracy for TM.
XVI. To evaluate which QC tests are useful for determination of image quality and those that are predictive of device failure, in order to recommend an optimal QC program for TM.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo bilateral screening DM with standard craniocaudal (CC) and mediolateral oblique (MLO) views at baseline, 12, 24, 36, and 48 months if pre-menopausal or at baseline, 24, and 48 months if post-menopausal. Patients may optional blood and buccal sample collection at baseline. 

ARM B: Patients undergo manufacturer-defined screening TM at baseline, 12, 24, 36, and 48 months if pre-menopausal or at baseline, 24, and 48 months if post-menopausal. Patients may optional blood and buccal sample collection at baseline. 

After completion of study, patients are followed up for 3-8 years after study entry, dependent on when patients enroll.