Breast Cancer
Conditions
Keywords
whole breast ultrasound, digital breast tomosynthesis, breast density, breast cancer screening
Brief summary
The purpose of this study is to evaluate the role of technologist-performed whole breast ultrasound for detecting breast cancer in the screening population of women with dense breasts.
Detailed description
This is a prospective study designed to evaluate the role of whole breast ultrasound (WBUS) in screening for breast cancer. In particular, there is interest in investigating the value of using WBUS as an adjunct (supplementary imaging) to Digital Breast Tomosynthesis (DBT) based screening of women with dense (heterogeneously or extremely dense) breasts or as a primary screening examination in this group of women. Women scheduled for their routine mammography that includes a DBT exam who agree to participate in the study and sign informed consent will undergo (at the same visit) DBT imaging as part of their clinical exam and whole breast ultrasound (WBUS) each year for three rounds of screening plus one year of follow-up. The DBT images and WBUS will be interpreted independently by two experienced radiologists under standard clinical screening procedures. One radiologist will interpret the DBT and the other radiologist will interpret the WBUS. Using a modified LOGICAL OR approach women/subjects may be recalled for further diagnostic work-up (examinations). If a subject is recalled, she will then follow the standard/routine clinical procedures for follow-up and the investigators will verify outcomes. If neither radiologist recalls the subject, then the subject will follow conventional management and the investigators will verify outcome. The findings from the DBT and WBUS examinations, as well as any resulting follow-up, will be collected, recorded and analyzed.
Interventions
DEVICEWhole breast ultrasound
Breast cancer screening with whole breast ultrasound
Sponsors
National Cancer Institute (NCI)
Wendie Berg
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SCREENING
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Women aged 40 to 75 years of age with heterogeneously dense or extremely dense parenchyma by prior digital mammography report (i.e., dense breasts), presenting for routine annual mammography with digital breast tomosynthesis.
Exclusion criteria
* Known to be at high risk for breast cancer due to known or suspected pathologic BRCA mutation (i.e. first-degree relative with known mutation) or prior chest radiation therapy before age 30; * No mammogram within the prior 3 years; * Signs or symptoms of breast disease including lump, bloody or spontaneous clear nipple discharge, eczema of the nipple; * Pregnancy or lactation within the prior 6 months; * Plan to become pregnant in the next two years, as mammography is not typically performed for screening pregnant women; * Breast implants, as assessment of breast density may be problematic; * Recent prior breast surgery or breast biopsy or cyst aspiration within the prior 12 months; * Prior or current malignancy other than the following: a) Breast cancer at least one year earlier (12 full months have elapsed since the last treatment surgery) with no known distant metastases and no known residual tumor; or b) Basal or squamous cell skin cancer or in situ cervical cancer or stage I thyroid cancer; or c) Other cancer for which the patient has been disease free for ≥ 5 years, with no recurrence of cancer in the last five years and no residual disease detected in the last five years. * Screening contrast-enhanced MRI or 99mTc-sestamibi based imaging of the breast(s) within the prior 12 months or planned within the next two years, to avoid contamination of results; * Unwilling or unable to provide consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cancer Yield Per 1,000 | 3 Years | Results from the first radiologist observer are presented |
| Sensitivity (True Positive Rate) | 3 years | DBT true positive findings for first observer (usual care) vs DBT and WBUS true positive findings for first observer |
| False-positive Recall Rate | 3 years | DBT false-positive findings for first observer (usual care) vs DBT and WBUS false positive findings for first observer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Types of Abnormalities Detected by Ultrasound and Tomosynthesis | 3 years | Counts and percentages of participants diagnosed with cancer and detected by first observer with DBT only, DBT and WBUS, and WBUS only |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Whole Breast Ultrasound All women will receive both 3D mammography and whole breast ultrasound for breast cancer screening; the order of interpretation will vary for each of two radiologists
Whole breast ultrasound: Breast cancer screening with whole breast ultrasound | 6,179 |
| Total | 6,179 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Between First and Second Screening | Lost to Follow-up | 65 |
| Between First and Second Screening | Withdrawal by Subject | 82 |
| Between First and Second Screening | women who skipped year 2 exam | 11 |
| Between Second and Third Screening | Death | 1 |
| Between Second and Third Screening | Lost to Follow-up | 75 |
| Between Second and Third Screening | Withdrawal by Subject | 181 |
| First Screening Round | Death | 1 |
| First Screening Round | excluded from analysis | 2 |
| First Screening Round | ineligible | 1 |
| First Screening Round | Lost to Follow-up | 56 |
| First Screening Round | Withdrawal by Subject | 28 |
| Second Screening Round | Death | 4 |
| Second Screening Round | Lost to Follow-up | 57 |
| Second Screening Round | Physician Decision | 2 |
| Second Screening Round | Withdrawal by Subject | 20 |
| Third Screening Round | Lost to Follow-up | 241 |
| Third Screening Round | PI excluded | 2 |
Baseline characteristics
| Characteristic | Whole Breast Ultrasound |
|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 8.8 |
| Breast Density extremely dense | 987 Participants |
| Breast Density heterogeneously dense | 4989 Participants |
| Breast Density scattered | 203 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6160 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 49 Participants |
| Race (NIH/OMB) Black or African American | 106 Participants |
| Race (NIH/OMB) More than one race | 29 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5991 Participants |
| Region of Enrollment United States | 6179 Participants |
| Sex: Female, Male Female | 6179 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 6,266 |
| other Total, other adverse events | 0 / 6,266 |
| serious Total, serious adverse events | 0 / 6,266 |
Outcome results
Primary
Cancer Yield Per 1,000
Results from the first radiologist observer are presented
Time frame: 3 Years
Population: Screens 2 \& 3 include women who were analyzable after the end of Screening Round 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Digital Breast Tomosynthesis (DBT) | Cancer Yield Per 1,000 | Screen 1 | 5.0 Cancer yield per 1,000 |
| Digital Breast Tomosynthesis (DBT) | Cancer Yield Per 1,000 | Screens 2 & 3 | 4.9 Cancer yield per 1,000 |
| DBT and WBUS | Cancer Yield Per 1,000 | Screen 1 | 6.3 Cancer yield per 1,000 |
| DBT and WBUS | Cancer Yield Per 1,000 | Screens 2 & 3 | 5.9 Cancer yield per 1,000 |
Comparison: The primary unit of analysis was the screening examination. A sample size of 16,700 screens (6,200 women, estimating 8%-10% loss to follow-up each year) was expected to provide 82% power to identify an added cancer detection rate (CDR) from US of 1.1/1,000. Screens were included for analysis if the patient was diagnosed with breast cancer or at least 10.5-month imaging or clinical follow-up (ie, at end of study participation) showed no evidence of breast cancer.p-value: 0.00595% CI: [0.3, 2.1]nonparametric bootstrap approach
Comparison: The primary unit of analysis was the screening examination. A sample size of 16,700 screens (6,200 women, estimating 8%-10% loss to follow-up each year) was expected to provide 82% power to identify an added cancer detection rate (CDR) from US of 1.1/1,000. Screens were included for analysis if the patient was diagnosed with breast cancer or at least 10.5-month imaging or clinical follow-up (ie, at end of study participation) showed no evidence of breast cancer.p-value: <0.00195% CI: [0.4, 1.5]nonparametric bootstrap approach
Primary
False-positive Recall Rate
DBT false-positive findings for first observer (usual care) vs DBT and WBUS false positive findings for first observer
Time frame: 3 years
Population: Women who did not have a cancer diagnosis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Digital Breast Tomosynthesis (DBT) | False-positive Recall Rate | Year/Screen 1 | 7.0 percent of participants without cancer |
| Digital Breast Tomosynthesis (DBT) | False-positive Recall Rate | Years/Screens 2 & 3 | 5.9 percent of participants without cancer |
| DBT and WBUS | False-positive Recall Rate | Year/Screen 1 | 11.5 percent of participants without cancer |
| DBT and WBUS | False-positive Recall Rate | Years/Screens 2 & 3 | 9.7 percent of participants without cancer |
p-value: <0.00195% CI: [3.8, 5.1]nonparametric bootstrap approach
p-value: <0.00195% CI: [3.3, 4.1]nonparametric bootstrap approach
Primary
Sensitivity (True Positive Rate)
DBT true positive findings for first observer (usual care) vs DBT and WBUS true positive findings for first observer
Time frame: 3 years
Population: Women diagnosed with cancer
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Digital Breast Tomosynthesis (DBT) | Sensitivity (True Positive Rate) | Year/Screen 1 | 68.9 percentage of participants with cancer |
| Digital Breast Tomosynthesis (DBT) | Sensitivity (True Positive Rate) | Years/Screens 2 & 3 | 69.1 percentage of participants with cancer |
| DBT and WBUS | Sensitivity (True Positive Rate) | Year/Screen 1 | 86.7 percentage of participants with cancer |
| DBT and WBUS | Sensitivity (True Positive Rate) | Years/Screens 2 & 3 | 82.7 percentage of participants with cancer |
Comparison: The primary unit of analysis was the screening examination. A sample size of 16,700 screens (6,200 women, estimating 8%-10% loss to follow-up each year) was expected to provide 82% power to identify an added cancer detection rate (CDR) from US of 1.1/1,000. Screens were included for analysis if the patient was diagnosed with breast cancer or at least 10.5-month imaging or clinical follow-up (ie, at end of study participation) showed no evidence of breast cancer.p-value: 0.00595% CI: [4.4, 31.1]nonparametric bootstrap approach
Comparison: The primary unit of analysis was the screening examination. A sample size of 16,700 screens (6,200 women, estimating 8%-10% loss to follow-up each year) was expected to provide 82% power to identify an added CDR from US of 1.1/1,000.Screens were included for analysis if the patient was diagnosed with breast cancer or at least 10.5-month imaging or clinical follow-up (ie, at end of study participation) showed no evidence of breast cancer.p-value: <0.00195% CI: [4.9, 22.3]nonparametric bootstrap approach
Secondary
Types of Abnormalities Detected by Ultrasound and Tomosynthesis
Counts and percentages of participants diagnosed with cancer and detected by first observer with DBT only, DBT and WBUS, and WBUS only
Time frame: 3 years
Population: Cancers detected by first observer for all 3 Screenings/Years combined
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Digital Breast Tomosynthesis (DBT) | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of invasive cancers | 32 Participants |
| Digital Breast Tomosynthesis (DBT) | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of Cancers | 55 Participants |
| Digital Breast Tomosynthesis (DBT) | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of Node-positive among available staging | 3 Participants |
| DBT and WBUS | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of invasive cancers | 31 Participants |
| DBT and WBUS | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of Cancers | 32 Participants |
| DBT and WBUS | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of Node-positive among available staging | 5 Participants |
| WBUS Only | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of Cancers | 19 Participants |
| WBUS Only | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of Node-positive among available staging | 3 Participants |
| WBUS Only | Types of Abnormalities Detected by Ultrasound and Tomosynthesis | No. of invasive cancers | 16 Participants |