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

Breast Screening Clinical Trial

Official title:

Tomosynthesis Mammographic Imaging Screening Trial (TMIST)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03233191
• Other study ID #: EA1151
• Secondary ID: NCI-2017-01111EA
• Status: Recruiting
• Phase: Phase 3
• Start date: September 28, 2017
• Est. completion date: December 31, 2030

Study information

• Verified date: June 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial studies digital tomosynthesis mammography and digital mammography in screening patients for breast cancer. Screening for breast cancer with tomosynthesis mammography may be superior to digital mammography for breast cancer screening and may help reduce the need for additional imaging or treatment.

Description:

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 3- 8 years after study entry.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 128905
• Est. completion date: December 31, 2030
• Est. primary completion date: December 31, 2030
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 45 Years to 74 Years

Eligibility

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.
• 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

Related Conditions & MeSH terms

• Breast Screening

Intervention

Procedure:
• Digital Mammography
Undergo DM
• Digital Tomosynthesis Mammography
Undergo TM

Other:
• Laboratory Biomarker Analysis
Correlative studies

Locations

Country	Name	City	State
Argentina	CERIM	Buenos Aires
Canada	Saint Joseph's Health Centre	London	Ontario
Canada	Hopital Du Sacre-Coeur de Montreal	Montreal	Quebec
Canada	Ottawa Hospital and Cancer Center-General Campus	Ottawa	Ontario
Canada	CHU de Quebec-Hopital du Saint-Sacrement (HSS)	Quebec City	Quebec
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Odette Cancer Centre- Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
Korea, Republic of	National Cancer Center-Korea	Goyang-si	Gyeonggi-do
Puerto Rico	San Juan City Hospital	San Juan
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	ThedaCare Regional Cancer Center	Appleton	Wisconsin
United States	Northside Hospital	Atlanta	Georgia
United States	University of Colorado Hospital	Aurora	Colorado
United States	Kern Radiology Medical Group Inc	Bakersfield	California
United States	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana
United States	Woman's Hospital	Baton Rouge	Louisiana
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Boston Medical Center	Boston	Massachusetts
United States	Northeast Georgia Medical Center Braselton	Braselton	Georgia
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Montefiore Medical Center-Weiler Hospital	Bronx	New York
United States	Aultman Health Foundation	Canton	Ohio
United States	Carson Tahoe Regional Medical Center	Carson City	Nevada
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle on Fairchild	Danville	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	The Women's Imaging Center	Denver	Colorado
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Duke University Medical Center	Durham	North Carolina
United States	Easton Hospital	Easton	Pennsylvania
United States	Arnot Ogden Medical Center/Falck Cancer Center	Elmira	New York
United States	Radiology Imaging Associates	Englewood	Colorado
United States	Southpointe-Sanford Medical Center Fargo	Fargo	North Dakota
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	Hunterdon Medical Center	Flemington	New Jersey
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	UCHealth Highlands Ranch Hospital	Highlands Ranch	Colorado
United States	University of North Carolina-Hillsborough Campus	Hillsborough	North Carolina
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Carle Hoopeston Regional Health Center	Hoopeston	Illinois
United States	M D Anderson Cancer Center	Houston	Texas
United States	Memorial Hermann Texas Medical Center	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Florida Health Science Center - Jacksonville	Jacksonville	Florida
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kaiser Permanente - Kensington Medical Center	Kensington	Maryland
United States	University of Tennessee - Knoxville	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	UCHealth Lone Tree Health Center	Lone Tree	Colorado
United States	Los Angeles County-USC Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	Baptist Memorial Hospital for Women	Memphis	Tennessee
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Mobile Infirmary Medical Center	Mobile	Alabama
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	MUSC Health East Cooper	Mount Pleasant	South Carolina
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	The Community Hospital	Munster	Indiana
United States	Women's Diagnostic Center - Munster	Munster	Indiana
United States	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Sentara Leigh Hospital	Norfolk	Virginia
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	Owensboro Health Mitchell Memorial Cancer Center	Owensboro	Kentucky
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Banner-University Medical Center Phoenix	Phoenix	Arizona
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	University of Arizona College of Medicine Phoenix	Phoenix	Arizona
United States	Valleywise Comprehensive Health Center - Phoenix	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Riverview Medical Center/Booker Cancer Center	Red Bank	New Jersey
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	University Hospital	San Antonio	Texas
United States	Zuckerberg San Francisco General Hospital	San Francisco	California
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Scottsdale Medical Imaging Limited	Scottsdale	Arizona
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Sidney Kimmel Cancer Center Washington Township	Sewell	New Jersey
United States	LSU Health Sciences Center at Shreveport	Shreveport	Louisiana
United States	Ochsner LSU Health Saint Mary's Medical Center	Shreveport	Louisiana
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Spartanburg Medical Center - Mary Black Campus	Spartanburg	South Carolina
United States	Sanford Thief River Falls Medical Center	Thief River Falls	Minnesota
United States	Carle Cancer Center	Urbana	Illinois
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	Sentara Princess Anne Hospital	Virginia Beach	Virginia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
ECOG-ACRIN Cancer Research Group	Canadian Cancer Trials Group (CCTG), National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  Korea, Republic of,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of women diagnosed with 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 follow up after the last screen	The cumulative proportions of participants experiencing the primary endpoint in the two study arms will be compared. The primary comparison of the two study arms will be approached from an Intent-to-Treat perspective and will be based on a two-sided test for comparing binomial proportions.	4.5 years after last registration
Secondary	Agreement between local and expert study pathologists for all breast lesions (benign and malignant) biopsied during the five years of screening	Measures of agreement such as kappa statistics and concordance coefficients to assess the agreement of local and central pathology readings. In addition, the variability among local pathologists will be examined with respect to the degree of agreement with the central study interpretation. This analysis will utilize mixed models with random effects for local pathologists. There will be up to two central study independent pathologist interpretations for each representative diagnostic slide set.	Up to 8 years
Secondary	Breast Imaging-Reporting and Data System (BIRADS) imaging features	The correlation between 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 will be examined. Using data on patients with cancer, estimates of the correlation between the two sets of features (BIRADS imaging features and histologic/genetic features) will be derived. Cluster analysis will be used to identify clusters of patients based on imaging features and will examine the association of these clusters with histology and genetic features. Using data from the fu	Up to 8 years
Secondary	Breast-cancer-specific mortality	Breast-cancer-specific mortality between the two study arms will be estimated and compared. Information on cancer recurrence and mortality will be obtained for a period of at least 4.5-8 years on all study participants. Mortality rates will be estimated as the ratio of the number of breast cancer deaths during a time period to the number of person-years at risk. Person-years will be measured as time from randomization to breast cancer death or censoring. Cumulative mortality rates from breast cancer at the end of the study period in each arm will be compared via the relative risk (rate ratio).	Up to 8 years
Secondary	Centralized quality control (QC) monitoring program implementation	Centralized QC monitoring program for both DM and TM, which provides rapid feedback on image quality, using quantitative tools, taking advantage of the automated analysis of digital images. The QC program will provide an auditable trail of QC activities and image quality parameters, while at the same time reducing QC effort required by the technologist at the site.; Constant monitoring of data from all sites will occur, and Root Cause Analysis will be performed for non-compliant items. The remote monitoring system will be evaluated in terms of its percent ?up-time?, technologist compliance (vi	Up to 8 years
Secondary	Diagnostic and predictive performance of tomosynthesis mammography (TM) and digital mammography (DM) [AUC]	ROC analysis will be performed to compare the performance characteristics of DM vs TM at each screening visit	Up to 8 years
Secondary	Assess the predictive performance of tomosynthesis mammography (TM) and digital mammography (DM)	Compare the predictive characteristics (PPV,NPV,Sens, and Spec) of DM vs TM at each screening visit	Up to 8 years
Secondary	Health care costs (including diagnostic procedures and cancer care received) as the result of an episode of breast cancer screening by tomosynthesis mammography (TM) versus digital mammography (DM)	Rates of utilization of key diagnostic procedures (e.g. extra TM or DM views, Ultrasound, Short-term interval follow-up, surgical consultation, percutaneous biopsy with, needle-localized open surgical biopsy, breast MRI) will be estimated; Medicare reimbursement costs will be used to derive a standardized measure of cost per participant; and these costs will be compared across the two study arms. These measures of cost will be compared across study arms using non-parametric methods.	Up to 8 years
Secondary	Health care utilization (including cancer care received) of an episode of breast cancer screening by tomosynthesis mammography (TM) versus digital mammography (DM)	Rates of utilization of key diagnostic procedures (e.g. extra TM or DM views, Ultrasound, Short-term interval follow-up, surgical consultation, percutaneous biopsy with, needle-localized open surgical biopsy, breast MRI) will be estimated and compared across the two study arms. The comparisons will be made using regression modeling	Up to 8 years
Secondary	Histologically malignant (true positive cases) and benign lesions (false positive cases)	Classification of histologically benign-appearing lesions (false positive cases) will be explored as normal-like or tumor-like using the PAM50 gene expression assay subtype and low, medium, or high proliferation according to a PAM50 proliferation signature, and p53 mutant-like or wild-type-like according to a validated p53-dependent signature, and according to histological features. The benign-appearing (false positive) biopsies will be characterized using digital histologic analysis tools that capture percent of area represented by stroma, epithelium, and fat as well as the density of nuclei	Up to 8 years
Secondary	Prevalence of breast cancer subtypes (luminal A, luminal B, HER2+, basal-like) and p53 signature in the two arms	Prevalence of breast cancer subtypes (luminal A, luminal B, HER2+, basal-like) and p53 signature in the two arms will be estimated and compared, overall and stratified on whether cancers were detected through screening or as interval cancers. subtypes in each arm and to compare them across arms. The analysis will be performed overall, and stratified by screen detected or interval detected. Estimates of the prevalence of subtypes and confidence intervals will be developed for each screening round and for the full period of screening. The comparison of rates across arms will be based on multinom	Up to 8 years
Secondary	Proportion of women diagnosed with an ?advanced? breast cancer in the two arms	The potential effect of age, menopausal and hormonal status, breast density, and family cancer history will be assessed on the primary endpoint difference between the two arms. Regression modeling will be used to assess the effect of age, menopausal and hormonal status, breast density, and family cancer history. Multiple imputation will be used to handle missing data in the response and the covariates, and a sensitivity analysis to assumptions about the missing data will be performed. An exploratory analysis using alternative definitions of the primary endpoint will also be conducted in order	Up to 8 years
Secondary	Quality control (QC) tests useful for determination of image quality and those that are predictive of device failure	QC tests that are useful for determination of image quality and those that are predictive of device failure will be evaluated, in order to recommend an optimal QC program for TM. Tests that are most sensitive to changes in system performance will be established and tests that are inferior and/or redundant and can be eliminated. Changes will be tracked against site records of alterations or repairs to the system, recalibration and changes in imaging parameters. Changes in test results will be observed and if they are suggestive that remedial action is required, we will determine after such acti	Up to 8 years
Secondary	Rate of interval cancers	The rate of interval cancers for TM and DM will be compared and the mechanism of diagnosis for these interval cancers will be assessed with categorization by symptomatic vs asymptomatic, and how detected: diagnosed via physical examination, mammography, ultrasound (US), magnetic resonance imaging (MRI) or other technologies. Interval cancers are those that occur between screening examinations. Interval cancer rates for each screening occasion and over the full set of screens will be estimated using Wilson intervals and compared across arms using two-sided tests for binomial proportions. The di	Up to 8 years
Secondary	Recall rates	The recall rates for TM versus (vs) DM will be compared. Recall rates are defined as the number of screening examinations that are interpreted as BIRADS 0, 3, 4 and 5 divided by the total number of screening examinations. Recall rates for each screening occasion and over the full set of screens will be estimated using Wilson intervals and compared across arms using two-sided tests for binomial proportions. Logistic regression will be used to analyze potential differences across patient subsets.	Up to 8 years
Secondary	Biopsy rates	The biopsy rates for TM versus (vs) DM will be compared. biopsy rates are defined as the number of biopsies divided by the total number of screening examinations. rates for each screening occasion and over the full set of screens will be estimated using Wilson intervals and compared across arms using two-sided tests for binomial proportions. Logistic regression will be used to analyze potential differences across patient subsets	Up to 8 years
Secondary	Task-based measure of image quality	Task-based measures of image quality will be refined and implemented to assess the effects of technical parameters, including machine type, and detector spatial and contrast resolution on diagnostic accuracy for TM. the diagnostic accuracy of the resulting Task-based analysis, using mathematical observers, will be assessed from image information using techniques based on signal and noise transfer.	Up to 8 years
Secondary	Variability of quality control parameters	The variability of standard quality control parameters will be assessed and compared temporally, within, and across sites for both DM and TM.	Up to 8 years