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

PRIMARY OBJECTIVES:

I. To compare the proportions of participants in the tomosynthesis mammography (TM) and
digital mammography (DM) study arms experiencing the occurrence of an ?advanced? breast
cancer at any time during a period of 4.5 years from randomization, including the period of
active screening and a period of clinical follow-up after the last screen (T4).

SECONDARY OBJECTIVES:

I. To assess the potential effect of age, menopausal and hormonal status, breast density, and
family cancer history on the primary endpoint difference between the two arms.

II. To compare the diagnostic performance of TM and 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, and
p53 mutant-like or wild-type-like according to a validated p53 dependent signature in the two
arms, overall and stratified on whether cancers were detected through screening or as
interval cancers, and 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, and p53 mutant-like or wild-type-like according to a
validated p53-dependent signature.

X. To assess the agreement between local and expert study pathologists for all breast lesions
(benign and malignant) biopsied during the 4.5 years of screening with TM or DM.

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.

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.

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.

After completion of study, patients are followed up for at least 4.5-8 years after study
entry.

Inclusion Criteria:

- 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, to be performed at an American College of
Radiology Imaging Network (ACRIN)-qualified facility

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

- Patients must not have symptoms or signs of benign or malignant breast disease (eg,
nipple discharge, breast lump) warranting a diagnostic rather than a screening
mammogram, and/or other imaging studies (eg, sonogram); patients with 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 have breast enhancements (e.g., implants or 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 three risks factors:

- Dense breasts (BIRADS density categories c-heterogeneously dense or
d-extremely dense), or

- Family history of breast cancer (first degree relative with breast cancer),
or, 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 two risk factors:

- Dense breasts (BIRADS density categories c-heterogeneously dense or
d-extremely dense), or

- Currently on 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 hysterectomy and oophorectomy will be considered postmenopausal; women
who no longer have menses due to hysterectomy without oophorectomy 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 have not
had a prior mammogram, 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 DM 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; all
other risk factors used to determine patient eligibility for annual or biennial
screening will be determined by subject self-report