Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Breast Ultrasound and Mammography in Screening Women at High Risk for Breast Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs No phase specified Screening Closed 25 and over NCI ACRIN-6666 NCT00072501, ACRIN-6666

Objectives

Primary

1. Determine the diagnostic yield of whole breast bilateral screening ultrasound and mammography for the detection of breast cancer in women at high risk for breast cancer.
2. Determine the cancer detection yield of a single contrast-enhanced magnetic resonance imaging (MRI) examination after 3 rounds of annual screening with ultrasound and mammography in these participants. (MRI component of the study)

Secondary

1. Determine the independent sensitivity and specificity of these screening methods in these participants.
2. Correlate performance of these screening methods with selected participant characteristics (e.g., breast density and heterogeneity of the parenchyma).
3. Validate the sonographic classification of lesions as "probably benign" and estimate the rate of malignancy in participants screened with these methods.
4. Determine the cost effectiveness associated with screening breast ultrasound, in terms of radiologist and resource time performing the exam and the induced cost of screening ultrasound (e.g., follow-up and biopsy).
5. Determine the reproducibility of lesion identification, measurement of lesion diameters, and volume and recording of lesion location on ultrasound in these participants.
6. Determine the size, type, grade, and nodal status of cancers seen only on MRI in these participants. (MRI component of the study)
7. Estimate the rate of benign biopsies and short interval follow-up induced only by MRI in these participants. (MRI component of the study)
8. Determine the cost effectiveness of MRI, including induced costs of unnecessary biopsies and follow-up. (MRI component of the study)
9. Compare the agreement among multiple examiners in sonographic, mammographic, and MRI feature analysis (using terms from the BI-RADS® lexicon) and final assessment (e.g., estimated probability of malignancy and/or recommendation for biopsy) in the enriched set of diagnostic training cases with consensus and histopathologic reference standards.

Entry Criteria

Disease Characteristics:

• At high risk for breast cancer, as defined by at least 1 of the following:
  • Known BRCA1 or BRCA2 mutation
  • Personal history of breast cancer with conserved breast analyzed separately
  • Prior biopsy showing atypical ductal hyperplasia, atypical lobular hyperplasia, or atypical papilloma and not receiving chemoprevention (i.e., not on tamoxifen, raloxifene, anastrazole, or any other aromatase inhibitor) OR any of these atypical lesions (including phyllodes tumors) AND first-degree relative diagnosed with breast cancer under age 50
  • Prior biopsy showing lobular carcinoma in situ
  • Age 30 and under and received prior chest and/or mediastinal and/or axillary irradiation ≥ 8 years ago
  • Risk of breast cancer meeting one of the following criteria:
    • Gail or Claus lifetime cancer risk ≥ 25%
    • Gail 5-year cancer risk ≥ 2.5%
    • Gail 5-year cancer risk ≥ 1.7% AND known to have extremely dense breasts (≥ 75% dense) by most recent mammogram



• Heterogeneously dense (≥ 50% dense) or extremely dense (≥ 75% dense throughout the entire breast) breast parenchyma in at least 1 breast by mammogram* OR unknown breast density due to no prior mammogram

   [Note: *No fatty breasts or minimal scattered fibroglandular density]




• Most recent mammogram* (if any) was interpreted as negative, benign, and/or remarkable only for post-treatment changes

   [Note: *At least 11 full months since prior mammogram]




• No current signs or symptoms of breast cancer (e.g., palpable breast masses, bloody or spontaneous clear nipple discharge, axillary mass, or abnormal skin changes in the breast[s] or nipple[s])
  • History of breast cancer allowed provided ≥ 1 year has elapsed since the last treatment with surgery and there is no known distant metastases and no known residual tumor



• No bilateral breast implants
  • Participants with a unilateral breast implant who would otherwise be eligible for study participation allowed (only breast without implant is evaluated)



• Hormone receptor status:
  • Not specified

Prior/Concurrent Therapy:

Biologic therapy

• Not specified

Chemotherapy

• No concurrent chemotherapy (MRI component of the study)

Endocrine therapy

• See Disease Characteristics
• Concurrent chemoprevention with tamoxifen, raloxifene, anastrozole, exemestane or other aromatase inhibitor for participants with a personal history of cancer allowed (MRI component of the study)

Radiotherapy

• See Disease Characteristics

Surgery

• See Disease Characteristics
• More than 1 year since prior fine needle aspiration, core needle biopsy, or surgical procedure
• No prior bilateral mastectomy (MRI component of the study)
• More than 1 year since prior breast surgery on the study breast(s) (MRI component of the study)
• More than 5 months since prior core biopsy of the study breast(s) (MRI component of the study)

Other

• More than 1 year since prior contrast-enhanced MRI of the breast
• More than 1 year (≥ 11 full months) since prior whole breast bilateral ultrasound
• More than 1 year since prior sonographic or mammographic contrast agent injection or tomosynthesis
• More than 2 years since prior screening contrast-enhanced MRI of the study breast(s) (MRI component of the study)
• More than 1 year since prior diagnostic contrast-enhanced MRI of the study breast(s) (MRI component of the study)
• No concurrent participation in any other breast cancer screening trial
• No concurrent participation in any other study involving breast MRI, sonographic or mammographic contrast agents, or tomosynthesis
• No concurrent dialysis

Patient Characteristics:

Age

• 25 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Glomerular filtration rate ≥ 30 mL/min

Other

• Not pregnant or nursing
• Fertile participants must use effective contraception
• Able to undergo adequate mammography and cooperate with breast ultrasound
• No concurrent medical or psychiatric condition that would preclude biopsy
• No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No contraindications to MRI (e.g., pacemaker, aneurysm clip, or other implanted magnetic device)*
• No claustrophobia that cannot be controlled by medication with valium, ativan, or other sedative*
• Must have intravenous access*
• Weight < 300 pounds*
• Physically able to tolerate positioning in the MRI scanner*
• Able to undergo contrast-enhanced MRI within 4 weeks after completing both study ultrasound and mammogram at 24-month time point*
• Agrees to undergo follow-up MRI at 6 months and/or MRI-guided vacuum-assisted biopsy or ultrasound-guided core biopsy (if needed)*

 [Note: *MRI component of the study]

Expected Enrollment

A total of 2,808 participants will be accrued for this study within 2 years.

Outline

This is a randomized, multicenter study. Participants are randomized to 1 of 2 screening arms.

• Arm I: Participants undergo physician-performed bilateral whole breast ultrasound (US) followed by mammogram within 2 weeks.



• Arm II: Participants undergo mammogram followed by physician-performed bilateral whole breast US within 2 weeks.

In both arms, participants with negative or benign findings are rescreened according to their screening arm at 1 and 2 years. Participants with "probably benign" findings are rescreened at the 6-month follow-up visit. Participants with findings that are suspicious or highly suggestive of malignancy are recommended for biopsy.

A subset of participants* in both arms undergo contrast-enhanced breast MRI within 4 weeks after completion of the 2-year screening US and mammogram. Participants with "probably benign" findings seen only on MRI may undergo an additional breast MRI at the 6-month follow-up visit. Participants with additional suspicious lesions seen only on MRI undergo second-look targeted US for biopsy guidance or MRI-guided vacuum-assisted biopsy after completion of any biopsies or additional views prompted by the 2-year screening US and mammogram visit.

 [Note: *No diagnosis of metastatic cancer of any type since entering this clinical trial.]

Participants are followed annually for 3 years.

Berg WA, Blume JD, Cormack JB, et al.: Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA 299 (18): 2151-63, 2008.[PUBMED Abstract]

Berg WA, Blume JD, Cormack JB, et al.: Lesion detection and characterization in a breast US phantom: results of the ACRIN 6666 Investigators. Radiology 239 (3): 693-702, 2006.[PUBMED Abstract]

Madsen EL, Berg WA, Mendelson EB, et al.: Anthropomorphic breast phantoms for qualification of Investigators for ACRIN Protocol 6666. Radiology 239 (3): 869-74, 2006.[PUBMED Abstract]

Berg WA: Supplemental screening sonography in dense breasts. Radiol Clin North Am 42 (5): 845-51, vi, 2004.[PUBMED Abstract]

Berg WA: Rationale for a trial of screening breast ultrasound: American College of Radiology Imaging Network (ACRIN) 6666. AJR Am J Roentgenol 180 (5): 1225-8, 2003.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

American College of Radiology Imaging Network

Wendie Berg, MD, PhD, Protocol chair		Ph: 410-616-2811

Registry Information
Official Title		Screening Breast Ultrasound in High-Risk Women
Trial Start Date		2004-04-20
Registered in ClinicalTrials.gov		NCT00072501
Date Submitted to PDQ		2003-10-01
Information Last Verified		2006-02-06
NCI Grant/Contract Number		CA080098