Breast Ultrasound and Mammography in Screening Women at High Risk for Breast Cancer
Breast Ultrasound and Mammography in Screening Women at High Risk for Breast Cancer
RATIONALE: Screening tests such as ultrasound and mammography may help doctors detect cancer
 cells early and plan more effective treatment for breast cancer. It is not yet known whether
 ultrasound is more effective than mammography in detecting breast cancer.

 PURPOSE: This clinical trial is studying breast ultrasound to see how well it works compared
 to mammography in detecting cancer in women who are at high risk for breast cancer.
OBJECTIVES:

 Primary

 -  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.

 -  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

 -  Determine the independent sensitivity and specificity of these screening methods in
 these participants.

 -  Correlate performance of these screening methods with selected participant
 characteristics (e.g., breast density and heterogeneity of the parenchyma).

 -  Validate the sonographic classification of lesions as "probably benign" and estimate the
 rate of malignancy in participants screened with these methods.

 -  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).

 -  Determine the reproducibility of lesion identification, measurement of lesion diameters,
 and volume and recording of lesion location on ultrasound in these participants.

 -  Determine the size, type, grade, and nodal status of cancers seen only on MRI in these
 participants. (MRI component of the study)

 -  Estimate the rate of benign biopsies and short interval follow-up induced only by MRI in
 these participants. (MRI component of the study)

 -  Determine the cost effectiveness of MRI, including induced costs of unnecessary biopsies
 and follow-up. (MRI component of the study)

 -  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.

 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.

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

 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

 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