Tomosynthesis as Primary Test for Breast Cancer Screening

Study Overview
=================
Brief Summary
-----------------
Randomized trial comparing tomosynthesis plus synthetic 2D Mammography vs Digital Mammography in respect to incidence of advanced cancers (interval and following round) and interval cancers.

Detailed Description
-----------------
This is a companion study of the other Italian studies on tomosyntesis as primary screening test for breast cancer: RETomo (NCT02698202), PROTEUS (NCT02590315), IMPETO (NCT03587259). The investigators conduct a randomized trial in three centres with a protocol that is similar to that of the other three studies. As for IMPETO and differently from the RETomo and PROTEUS studies, the intervention will be tomosynthesis + synthetic 2D. In the three centres about 8000 women will be recruited (4000 in the experimental arm and 4000 in the control arm). The study will compare the performance of tomosynthesis plus synthetic 2D vs digital mammography in respect to incidence of advanced cancers (interval and following round) and interval cancers. Women 50 to 65 years old will be screened once according to randomization arm for one round, then all will be screened with digital mammography after two years. The investigators also will measure detection rates, specificity, interval cancers, advanced cancers occurring as interval cancers or at subsequent screens and allowing to estimate excess overdiagnosis comparing overall cumulative incidence after two or three rounds of screening. Women will be asked for informed consent when they attend the mammography. If they accept they will be randomised to one of the two arms. All examinations will be read by two independent radiologists, in case of discordance a third reading is asked.

Official Title
-----------------
Tomosynthesis as Primary Test for Breast Cancer Screening: A Multicenter Randomized Controlled Trial

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Diagnostic Test: tomosynthesis + synthetic 2D
* Diagnostic Test: digital mammography


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women scheduled for a new round of mammographic screening resident in the province Exclusion Criteria: previous breast cancer diagnosis pregnancy or suspicion of pregnancy presence of BRCA1/2 gene mutation Previous Digital Breast Tomosynthesis performed unable to understand informed consent chemotherapy in progress presence of breast implant

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Women 45-65 participating in the mammographic screening program will be randomized to one round of screening with tomosynthesis + synthetic 2D or with digital mammography. Then all women will be re-screened after 2 years (1 year for women 45-49) for at least one round with digital mammography.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tomosynthesis + synthetic 2D<br>Women will be screened for one round with tomosynthesis + synthetic 2D, two projections, double reading with consensus or arbitration, according to local protocols, for discordant readings. After two years (one years for women 45-49 yo) women will be re-screened with digital mammography. | Diagnostic Test: tomosynthesis + synthetic 2D<br>* Women will be screened for one round with tomosynthesis + synthetic 2D, two projections, double reading with consensus or arbitration, according to local protocols, for discordant readings. After two years (one years for women 45-49 yo) women will be re-screened with digital mammography.<br>|
| Active Comparator: Digital Mammography<br>Women will be screened for digital mammography, two projections, double reading with consensus or arbitration, according to local protocols, for discordant readings. After two years (one years for women 45-49 yo) women will be re-screened with digital mammography. | Diagnostic Test: digital mammography<br>* Women will be screened for one round digital mammography, two projections, double reading with consensus or arbitration, according to local protocols, for discordant readings. After two years (one years for women 45-49 yo) women will be re-screened with digital mammography.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| advanced cancer incidence | cumulative incidence of T2+ cancers after first screening round | 2 years (+9 months to complete second round assessment) | 
| advanced cancer incidence | cumulative incidence of T2+ cancers after first screening round | 4 years (+9 months to complete third round assessment) | 
| interval cancer incidence | incidence of cancers occurring after a negative screening test and before the next scheduled screening round. Outcome 3 and 4 will are combined in one single outcome. | 2 years for 50-65 years old women | 
| interval cancer incidence | incidence of cancers occurring after a negative screening test and before the next scheduled screening round. Outcome 3 and 4 will are combined in one single outcome. | 1 year for 45-49 years old women | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall cumulative incidence | overall cumulative incidence of breast cancer, including ductal carcinoma in situ. This outcome is a proxy of the excess over-diagnosis eventually induced by tomosynthesis compared with digital mammography. | 2 years (+9 months to complete second round assessment) | 
| overall cumulative incidence | overall cumulative incidence of breast cancer, including ductal carcinoma in situ. This outcome is a proxy of the excess over-diagnosis eventually induced by tomosynthesis compared with digital mammography. | 4 years (+9 months to complete second round assessment) | 
| detection rate | cancer detected by the screening round on total screened women | This outcome is measured at the baseline screening. cancer diagnosed within 9 months will be considered | 
| recall rate | number of women referred to assessment after the first leve screening test on total screened women | This outcome is measured at the baseline screening. | 
| positive predictive value | proportion of cancer among women recalled for assessment | This outcome is measured at the baseline screening. cancer diagnosed within 9 months will be considered | 
| Detection rate of ductal carcinoma in situ | ductal carcinoma in situ detected by the screening round on total screened women | This outcome is measured at the baseline screening. cancer diagnosed within 9 months will be considered | 
| biopsy rate | number of women undergoing biopsy after the first leve screening test on total screened women | This outcome is measured at the baseline screening. | 
| x-ray dose | average glandular dose receive by women during first level test | This outcome is measured at the baseline screening. | 
| reading time | time needed to read an imaging first level examination | This outcome is measured at the baseline screening. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
breast cancer screening, tomosynthesis