Digital Tomosynthesis Mammography and Digital Mammography in Screening Patients for Breast Cancer

Summary

Objectives

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.