Clinical trial NCT03233191: Digital Tomosynthesis Mammography and Digital Mammography in Screening Patients for Breast Cancer
Official title: Tomosynthesis Mammographic Imaging Screening Trial (TMIST)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Screening
Keywords: Digital Mammography
Breast Tomography
Screening Mammography
TMIST
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: Canadian Cancer Trials Group (CCTG)
First posted: 2017-07-28
Enrollment: 108508
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized to either Digital Breast Tomography (TM) or Full Field Digital Mammography (DM)
Primary purpose: SCREENING

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 4.5 years after last registration
Secondary outcomes:
measure: Agreement between local and expert study pathologists for all breast lesions (benign and malignant) biopsied during the five years of screening
timeFrame: Up to 8 years
measure: Breast Imaging-Reporting and Data System (BIRADS) imaging features
timeFrame: Up to 8 years
measure: Breast-cancer-specific mortality
timeFrame: Up to 8 years
measure: Centralized quality control (QC) monitoring program implementation
timeFrame: Up to 8 years
measure: Diagnostic and predictive performance of tomosynthesis mammography (TM) and digital mammography (DM) [AUC]
timeFrame: Up to 8 years
measure: Assess the predictive performance of tomosynthesis mammography (TM) and digital mammography (DM)
timeFrame: Up to 8 years
measure: 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)
timeFrame: Up to 8 years
measure: Health care utilization (including cancer care received) of an episode of breast cancer screening by tomosynthesis mammography (TM) versus digital mammography (DM)
timeFrame: Up to 8 years
measure: Histologically malignant (true positive cases) and benign lesions (false positive cases)
timeFrame: Up to 8 years
measure: Prevalence of breast cancer subtypes (luminal A, luminal B, HER2+, basal-like) and p53 signature in the two arms
timeFrame: Up to 8 years
measure: Proportion of women diagnosed with an ?advanced? breast cancer in the two arms
timeFrame: Up to 8 years
measure: Quality control (QC) tests useful for determination of image quality and those that are predictive of device failure
timeFrame: Up to 8 years
measure: Rate of interval cancers
timeFrame: Up to 8 years
measure: Recall rates
timeFrame: Up to 8 years
measure: Biopsy rates
timeFrame: Up to 8 years
measure: Task-based measure of image quality
timeFrame: Up to 8 years
measure: Variability of quality control parameters
timeFrame: Up to 8 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Mobile
country: United States
facility: Mobile Infirmary Medical Center
state: Alabama
city: Phoenix
country: United States
facility: Banner-University Medical Center Phoenix
state: Arizona
city: Phoenix
country: United States
facility: University of Arizona College of Medicine Phoenix
state: Arizona
city: Phoenix
country: United States
facility: Valleywise Comprehensive Health Center - Phoenix
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Hospital in Arizona
state: Arizona
city: Scottsdale
country: United States
facility: Scottsdale Medical Imaging Limited
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Bakersfield
country: United States
facility: Kern Radiology Medical Group Inc
state: California
city: Los Angeles
country: United States
facility: Los Angeles General Medical Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Modesto
country: United States
facility: Kaiser Permanente-Modesto
state: California
city: San Francisco
country: United States
facility: Zuckerberg San Francisco General Hospital
state: California
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Colorado Springs
country: United States
facility: Penrose-Saint Francis Healthcare
state: Colorado
city: Denver
country: United States
facility: The Women's Imaging Center
state: Colorado
city: Englewood
country: United States
facility: Radiology Imaging Associates
state: Colorado
city: Highlands Ranch
country: United States
facility: UCHealth Highlands Ranch Hospital
state: Colorado
city: Lone Tree
country: United States
facility: UCHealth Lone Tree Health Center
state: Colorado
city: Newark
country: United States
facility: Helen F Graham Cancer Center
state: Delaware
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Jacksonville
country: United States
facility: University of Florida Health Science Center - Jacksonville
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Braselton
country: United States
facility: Northeast Georgia Medical Center Braselton
state: Georgia
city: Savannah
country: United States
facility: Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
state: Georgia
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Boise
country: United States
facility: Saint Luke's Cancer Institute - Boise
state: Idaho
city: Bloomington
country: United States
facility: Bromenn Lifecare Center
state: Illinois
city: Chicago
country: United States
facility: John H Stroger Jr Hospital of Cook County
state: Illinois
city: Danville
country: United States
facility: Carle at The Riverfront
state: Illinois
city: Danville
country: United States
facility: Carle on Fairchild
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Hoopeston
country: United States
facility: Carle Hoopeston Regional Health Center
state: Illinois
city: Mattoon
country: United States
facility: Carle Physician Group-Mattoon/Charleston
state: Illinois
city: Normal
country: United States
facility: Bromenn Regional Medical Center
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Hobart
country: United States
facility: Saint Mary Medical Center
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Munster
country: United States
facility: The Community Hospital
state: Indiana
city: Munster
country: United States
facility: Women's Diagnostic Center - Munster
state: Indiana
city: Valparaiso
country: United States
facility: Northwest Cancer Center - Valparaiso
state: Indiana
city: Des Moines
country: United States
facility: Mercy Medical Center - Des Moines
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Owensboro
country: United States
facility: Owensboro Health Mitchell Memorial Cancer Center
state: Kentucky
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center
state: Louisiana
city: Baton Rouge
country: United States
facility: Woman's Hospital
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University School of Medicine
state: Louisiana
city: New Orleans
country: United States
facility: University Medical Center New Orleans
state: Louisiana
city: Shreveport
country: United States
facility: Ochsner LSU Health Saint Mary's Medical Center
state: Louisiana
city: Shreveport
country: United States
facility: LSU Health Sciences Center at Shreveport
state: Louisiana
city: Kensington
country: United States
facility: Kaiser Permanente - Kensington Medical Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial Medical Center - University Campus
state: Massachusetts
city: Ann Arbor
country: United States
facility: Trinity Health Saint Joseph Mercy Hospital Ann Arbor
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Farmington Hills
country: United States
facility: Weisberg Cancer Treatment Center
state: Michigan
city: Grand Rapids
country: United States
facility: Corewell Health Grand Rapids Hospitals - Butterworth Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: West Bloomfield
country: United States
facility: Henry Ford West Bloomfield Hospital
state: Michigan
city: Duluth
country: United States
facility: Essentia Health Cancer Center
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Thief River Falls
country: United States
facility: Sanford Thief River Falls Medical Center
state: Minnesota
city: Virginia
country: United States
facility: Essentia Health Virginia Clinic
state: Minnesota
city: Southhaven
country: United States
facility: Baptist Memorial Hospital and Cancer Center-Desoto
state: Mississippi
city: Carson City
country: United States
facility: Carson Tahoe Regional Medical Center
state: Nevada
city: Flemington
country: United States
facility: Hunterdon Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Saint Peter's University Hospital
state: New Jersey
city: Red Bank
country: United States
facility: Riverview Medical Center/Booker Cancer Center
state: New Jersey
city: Sewell
country: United States
facility: Sidney Kimmel Cancer Center Washington Township
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center-Weiler Hospital
state: New York
city: Elmira
country: United States
facility: Arnot Ogden Medical Center/Falck Cancer Center
state: New York
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Hillsborough
country: United States
facility: University of North Carolina-Hillsborough Campus
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Southpointe-Sanford Medical Center Fargo
state: North Dakota
city: Beachwood
country: United States
facility: Cleveland Clinic Cancer Center Beachwood
state: Ohio
city: Canton
country: United States
facility: Aultman Health Foundation
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center-UC Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Easton
country: United States
facility: Easton Hospital
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Wexford
country: United States
facility: Wexford Health and Wellness Pavilion
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Columbia
country: United States
facility: Prisma Health Richland Hospital
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Greenville Memorial Hospital
state: South Carolina
city: Mount Pleasant
country: United States
facility: MUSC Health East Cooper
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Medical Center
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Medical Center - Mary Black Campus
state: South Carolina
city: Knoxville
country: United States
facility: University of Tennessee - Knoxville
state: Tennessee
city: Memphis
country: United States
facility: Baptist Memorial Hospital and Cancer Center-Memphis
state: Tennessee
city: Memphis
country: United States
facility: Baptist Memorial Hospital for Women
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Breast Center at One Hundred Oaks
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Texas Medical Center
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Imaging Center - Upper Kirby
state: Texas
city: San Antonio
country: United States
facility: University Hospital
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Midlothian
country: United States
facility: Bon Secours Westchester Emergency Center
state: Virginia
city: Norfolk
country: United States
facility: Sentara Leigh Hospital
state: Virginia
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
city: Virginia Beach
country: United States
facility: Sentara Princess Anne Hospital
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Healthcare
state: West Virginia
city: Appleton
country: United States
facility: ThedaCare Regional Cancer Center
state: Wisconsin
city: La Crosse
country: United States
facility: Gundersen Lutheran Medical Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center-Marshfield
state: Wisconsin
city: Mukwonago
country: United States
facility: ProHealth D N Greenwald Center
state: Wisconsin
city: Oconomowoc
country: United States
facility: ProHealth Oconomowoc Memorial Hospital
state: Wisconsin
city: Superior
country: United States
facility: Essentia Health Saint Mary's Hospital - Superior
state: Wisconsin
city: Waukesha
country: United States
facility: UW Cancer Center at ProHealth Care
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: CERIM
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
city: London
country: Canada
facility: Saint Joseph's Health Care London
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital and Cancer Center-General Campus
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre- Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hopital Du Sacre-Coeur de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Quebec-Hopital du Saint-Sacrement (HSS)
state: Quebec
city: Puente Alto
country: Chile
facility: Hospital Sotero Del Rio
state: Santiago
city: Treviso
country: Italy
facility: Ospedale Ca Foncello di Treviso - ULSS 2 Marca Trevigiana
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center-Korea
state: Gyeonggi-do
city: Lima
country: Peru
facility: Oncosalud S.A.C.
city: San Juan
country: Puerto Rico
facility: San Juan City Hospital
city: Sabadell
country: Spain
facility: Parc Tauli Sabadell Hospital Universitari
state: Barcelona
city: Taipai
country: Taiwan
facility: Taipei Veterans General Hospital
city: Chiang Mai
country: Thailand
facility: Chiang Mai University
state: Muang
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: Etta Pisano
role: PRINCIPAL_INVESTIGATOR
References: