Risk-Based Breast Screening in Young Women

Study Overview
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Brief Summary
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The RIBBS study is a single-arm single-center study that aims to evaluate the effectiveness of a risk-based breast screening model using digital breast tomosynthesis (DBT) as the baseline test, quantitative individual breast density to guide supplemental ultrasound (US) imaging for dense breasts, and individual risk (calculated taking into account breast density) to guide the screening interval (annual or biennial). Invited 45-year-old women are differentiated into five different screening protocols (based on breast density and risk), and screened according to a personalized model until they turn 50 and return to routine screening. The only primary endpoint in this study is the cumulative incidence of advanced breast cancers (stage II and above). This endpoint will be evaluated at the end of the five-year intervention period and at 10 years. The results of the personalized screening model will be compared with those obtained from an observational cohort from a neighboring region in which a one-size-fits-all approach involving annual mammography for women aged 45-49 years is used. The comparison will be conducted with the hypothesis of superiority of the personalized screening model.

Detailed Description
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The incidence of breast cancer in women aged 45 to 49 is not much lower than in women aged 50 to 54. However, while the Italian Health System offers mammography screening to all women aged 50 to 69 every two years, women aged 45 to 49 are invited for annual mammography screening in only a few regions. Breast density, i.e. the amount of fibroglandular tissue, more present in young women, decreases the performance of mammography by reducing the detectability of breast cancer; consequently, breast cancer in women with dense breasts can often be found only when it is larger and thus at a more advanced stage. In addition, breast density is an independent risk for breast cancer. The RIBBS study was designed to use the first round of screening to identify women with dense breasts and those at increased risk of breast cancer, and use this information to tailor the subsequent screening protocol, including supplemental US imaging for women with dense breasts, and establishing the frequency of screening cycles according to risk category. The reference imaging is digital breast tomosynthesis, which has already demonstrated greater sensitivity than digital mammography in the standard screening age (50-69). Volumetric breast density (VBD) is calculated from DBT, and lifetime risk (LTR) is obtained from the Tyrer-Cuzick risk model which also includes breast drnsity as a risk factor. After the first round of screening, women are divided into five groups: women with non-dense breasts and low breast cancer risk are screened every two years with DBT alone; women with dense breasts and low breast cancer risk are screened every two years with DBT plus additional ultrasound (DBT+US); women with non-dense breasts and intermediate risk of breast cancer are screened annually with DBT alone; women with dense breasts and intermediate risk of breast cancer are screened annually with DBT+US; finally, high-risk women with a family history of breast cancer (w/wo hereditary factors) are monitored with annual MRI and tomosynthesis. Our study hypothesizes that a screening model stratified by breast density and risk is more effective and sustainable in reducing the incidence of advanced breast cancer than standard annual mammography screening.

Official Title
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Risk-Based Breast Screening (RIBBS) in Young Women: Personalized Imaging Protocols

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Diagnostic Test: Personalized screening protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female Aged 45 years old Resident in the provinces of Padua and Rovigo (Italy) Willing and able to give written informed consent Willing and able to comply with scheduled visits, tests, and other procedures Exclusion Criteria: Recent mammography Personal history of breast carcinoma, either invasive or ductal carcinoma in situ (DCIS) Known BRCA carrier or PALB2 or ≥50% risk Psychiatric or other disorders that are not compatible with compliance to the protocol requirements and follow-up Pregnant or breastfeeding Unable to give informed consent Current participation in another interventional breast screening trial

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: RIBBS arm<br>This clinical trial is a single-arm study in which asymptomatic 45-year-old women undergo a triple screening test: (1) two-view tomosynthesis of both breasts; (2) calculation of volumetric breast density (VBD); (3) assessment of breast cancer risk using the Tyrer-Cuzick model. Mean VBD and lifetime risk (LTR) are used to determine the type of imaging and frequency of subsequent screening cycles. | Diagnostic Test: Personalized screening protocol<br>* At the first screening round (recruitment) all participating women had the same tests; Two-view tomosynthesis of both breasts Calculation of volumetric breast density (VBD) Calculation of lifetime risk (LTR) using the Tyrer-Cuzick model At subsequent rounds: Women with non-dense breasts and low breast cancer risk are re-screened only with DBT every 2 years; Women with dense breasts and low breast cancer risk are re-screened with DBT+US every 2 years; Women with non-dense breasts and intermediate breast cancer risk are re-screened only with DBT every year; Women with dense breasts and intermediate breast cancer risk are re-screened with DBT+US every year; Women at high risk of breast cancer associated with a family history of breast cancer (w/wo hereditary factors) undergo DBT and MRI every year.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Advanced Cancers | Percentage of breast cancer cases diagnosed at staged II or beyond, either during the entire screening period or thereafter. Advanced cancers occurring up to 10 years after the end of the screening intervention will be included | Up to 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recall rate (RR) | Number of women recalled for further diagnostic evaluation per thousand women screened, also known as the BI-RADS abnormal interpretation rate | Up to 6 years | 
| Cancer detection rate (CDR) | Number of cancers detected by screening test(s) per thousand women screened | Up to 6 years | 
| Proportional Incidence of Interval Cancer | Number of women diagnosed with interval cancer (detected after a negative screening episode) divided by the expected number of breast cancer cases in the absence of screening | Up to 8 years | 
| Total Assessment Rate | Number of women undergoing diagnostic evaluation per thousand women screened. Further breakdown into noninvasive and invasive assessment rates. | Up to 6 years | 
| Surgical Referral Rate | Number of women referred to excisional biopsy or definitive surgical treatment per thousand women screened | Up to 6 years | 
| Surgery Rate | Number of women undergoing excisional biopsy or definitive surgical treatment per thousand women screened | Up to 6 years | 
| Benign Lesion Detection Rate | Number of women with any histologically diagnosed benign lesion per thousand women screened | Up to 6 years | 
| Tumor-Stage Specific Detection Rate | Number of women with cancer detected by screening and classified by TNM tumor stage per thousand women screened | Up to 6 years | 
| Regular Re-Screening Rate | Number of women who regularly undergo the specific screening protocol (within ± 3 months) between ages 45 and 49 per thousand women screened | Up to 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Neoplasms, Cancer Screening, Personalized Medicine, Mammographic Breast Density, Risk Assessment