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Epinephryl borate

Digital breast tomosynthesis plus synthesized 2D mammograms

DBT+s2D

2D-FFDM

Walter Heindel, MD, PhD

This study is a randomized, multicenter, multivendor, controlled, diagnostic superiority trial to compare digital breast tomosynthesis plus synthesized 2D mammograms (DBT+s2D) versus standard 2D full-field digital mammography (2D-FFDM) regarding the effectiveness as screening modality.

The primary objective of the study is to evaluate whether digital breast tomosynthesis plus synthesized 2D mammograms leads to a relevant increase in the detection rate of screening-detected invasive cancers compared to 2D full-field digital mammography in routine screening according to the European Guidelines. Furthermore, the incidence rate of interval cancers within a 24 months interval after screening will be compared between both study arms in order to investigate the potential for overdiagnosis.

According to the pre-defined order of both primary endpoints and the primary objective of the study in the planning phase, the initial sample size calculation was based solely on the first primary endpoint (invasive breast cancer detection rate). Given the increasing national and international attention of interval cancers to assess the impact of potential overdiagnosis caused by tomosynthesis, we have planned a sample size increase from 80,000 to 120,000 study participants to achieve a reasonable statistical power for the evaluation of both primary endpoints. The revised sample size calculation was carried out without knowledge of the data from the currently recruiting TOSYMA study, i.e. all planning assumptions were based on external data that do not belong to the ongoing study.

Participants will be randomized to either Digital Breast Tomosynthesis plus synthesized 2D mammograms (DBT+s2D) or 2D Full-Field Digital Mammography (2D-FFDM)

Breast Cancer Screening: Digital Breast Tomosynthesis Versus Digital 2D Mammography

Prospective Randomized Comparison of Digital Breast Tomosynthesis Plus Synthesized Images Versus Standard Full-field Digital Mammography in Population-based Screening (TOSYMA)

Number of women with screening-detected invasive breast cancer divided by the number of all women screened. A screening-detected breast cancer is classified as invasive carcinoma if the pT category (pathological tumor size) of the TNM classification falls into one of the following categories: pT1mic, pT1a, pT1b, pT1c, pT1, pT2, pT3, pT4a, pT4b, pT4c, pT4d, pT4, pTX (for evaluation purpose pTX defines histologically approved invasive breast cancer with missing tumor diameter) or the final pathological categorization has been done after neoadjuvant therapy (ypT), implying an invasive cancer prior to therapy.

The 24 months incidence of interval cancers is defined as the number of women that develop a ductal carcinoma in situ or an invasive breast cancer in the 24 months interval after a negative screening examination divided by the number of all women with a negative screening result.

Number of women with screening-detected ductal carcinoma in situ (if the pT category of the TNM classification falls into the category pTis) divided by the number of all women screened.

Number of women with screening-detected invasive breast cancers of the category pT1 divided by the number of all women screened. A screening-detected breast cancer is classified as breast cancer of tumor category pT1 if tumor size is ≤ 20 mm in greatest dimension and the respective pT subcategory of the pTNM classification is one of the following: pT1mic, pT1a, pT1b, pT1c, pT1.

Number of women with recalls for further assessment divided by the number of all women screened.

Number of women with screening-detected malignancies (ductal carcinoma in situ or invasive breast cancer) divided by the number of women with recalls for further assessment.

The 12 months incidence of interval cancers is defined as the number of women that develop a ductal carcinoma in situ or an invasive breast cancer in the 12 months interval after a negative screening examination divided by the number of all women with a negative screening result.

German Research Foundation

University Hospital Muenster

Digestive System Diseases

Immune System Diseases

Colorectal Neoplasms

Hypersensitivity

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

CRC diagnosed in the population excluded from screening

CRC diagnosed after a positive fecal immunochemical test (FIT)

CRCs diagnosed after a positive fecal immunochemical (FIT) test, but without colonoscopy or \> 2 years after a positive fecal immunochemical test

CRCs diagnosed 2 years after a negative FIT

CRCs diagnosed in the FIT non-responders population

CRCs diagnosed within 5 years after a colonoscopy performed following a positive test that did not find colorectal cancer

We evaluated CRCs screening campaign from January 1, 2016 to December 31, 2017, and interval cancers within two years after a negative test, and five years for post-colonoscopy interval cancers.

Positive fecal immunochemical test (FIT)

Negative fecal immunochemical test (FIT)

Fecal immunochemical test (FIT) not performed

Michel ROBASZKIEWICZ

Fecal immunochemical test (FIT) was introduced in France late 2015, FIT has better diagnostic accuracy for colorectal cancers (CRCs) than previous screening tests. Our primary objective was to evaluate the sensitivity of FIT and the proportion of interval cancer.

Fecal immunochemical test (FIT) aims to detect pre-symptomatic lesions, i.e., early stage colorectal cancers (CRCs) or pre-cancerous lesions such as colonic adenomas in order to reduce CRC mortality. FIT was introduced in France late 2015, FIT has better diagnostic accuracy for CRCs than previous screening tests. Determining the incidence of post-test interval CRCs, diagnosed after a negative FIT and before the recommended date of the next test (2-year interval), allows assessment of the sensitivity of the test. The primary objective of this study was to evaluate the performance of FIT during the CRC screening campaign in the Finistère department (France) from January 1, 2016 to December 31, 2017. Its secondary objectives were the evaluation of diagnostic circumstances and their impact on treatment and survival, and risk factors for interval cancer (IC).

Sensitivity of Fecal Immunochemical Test (FIT) for Colorectal Cancer (CRC) Screening

Sensitivity of Fecal Immunochemical Test (FIT) for Colorectal Cancer (CRC) Screening and Interval Cancer Risk : a Population Based Study

Sensitivity = True positive / True positive + False negative = SD CRCs / SD CRCs + FIT IC

Age, sex, stages, localizations, comparison by Chi2 or Fisher's test for categorical data and Student's test for quantitative data. Multivariate analysis using logistic regression.

FIT value, comprised between 10 and 200 µg haemoglobin/g faeces (analytical limits of quantification),

Analysis of survival according to diagnostic circumstances

Analysis of treatment according to diagnostic circumstances

Registre des Tumeurs Digestives du Finistère

Centre Régional de Coordination des Dépistages des Cancers Bretagne (CRCDC Bretagne)

University Hospital, Brest

Digital Breast Tomosynthesis+synthetic mammography (DBT+SM) All women are screened with DBT+SM. All examinations are independently double read. Consensus used to decide whether or not to recall.

Two-view tomosynthesis performed with GE Senographe Pristina.

Digital Breast Tomosynthesis+synthetic mammography

Solveig Hofvind, Professor

The aim of the study is to compare early performance measures and economic aspects of organized breast cancer screening for women screened using digital breast tomosynthesis+synthetic mammography (DBT+SM) to women with a prior DBT+SM or digital mammography (DM) from To-Be 1 (NCT02835625).

Digital breast tomosynthesis (DBT) is a new "three-dimensional" screening tool for breast cancer, claimed to be superior to standard two-dimensional (2D) digital mammography (DM) based on results of lower or similar recall rate, and a 30-50% higher rate of screen-detected breast cancer for DBT compared to DM.

The Bergen Tomosynthesis Trial (To-Be) is a randomized controlled trial investigating whether DBT, including synthetic mammography (SM), is superior for breast cancer screening to DM (ClinicalTrials.gov Identifier: NCT02835625) - hereafter referred to as To-Be 1. The study is run as part of BreastScreen Norway (inviting women aged 50-69 to screening every two years). It started in October 2015 and finished recruitment in December 2017, after two years - one screening round - of data collection.

Results from To-Be 1 will fill some of the knowledge gaps regarding DBT+SM in screening. However, running To-Be 1 and recent publications on the topic have identified additional challenges and new evidence gaps that are important to address before DBT can be considered for use in organized screening. Thus, the To-Be trail will be extended with five more year (To-Be 2), consisting of one additional screening round (two years) where all women in the study population are screened with DBT+SM with a three year follow-up.

To investigate the effect of subsequent screening with DBT+SM all women attending mammography screening in Bergen in 2018 and 2019 will be screened with DBT+SM. To-Be 2 is a prospective cohort study targeting 32 000 women, and all women attending screening will be asked if they are willing to take part in the study after receiving written and oral information about the study. Women willing to participate in the study will sign an informed consent form. We expect a participation rate of 90%. The participating women will be screened with DBT+SM. Women not willing to participate in the study will be screened with DM, and not included in our study.

Continuing To-Be 1 with To-Be 2 is the only opportunity to get information on women subsequently screened with DBT+SM, that have a prior DBT+SM or DM based on random allocation. This will also allow the investigators to analyze data on interval breast cancer among women screened with DBT+SM after DBT+SM and with DBT+SM after DM in To-Be 1 in 2020.

The investigators aim to address the following topics and research questions:

Part I: Early performance measures for screening with DBT+SM after DBT+SM, and DBT+SM after DM.

Part II: Interval breast cancer following screening with DBT+SM versus DM, focusing on interval breast cancers identified among women screened in To-Be 1.

Part III: Missed and true screen-detected and interval breast cancer in mammographic screening with DBT+SM versus DM.

Part IV: Expected and experienced discomfort and pain in DBT+SM by compression force and pressure.

Part V: Economic evaluation of continuous use of DBT.

Only women are invited to breast cancer screening in BreastScreenn Norway.

The Tomosynthesis Trial in Bergen - Part 2

Digital Breast Tomosynthesis - The Future Screening Tool for Breast Cancer?

We will not share the data outside the project group

Rate of screening detected breast cancer, among those screened

Rate of recalled women due to mammographic findings, among those screened

Rate of breast cancer cases among those recalled

Distribution of characteristics among the women diagnosed with breast cancer

Rates and prognostic and predictive tumor characteristics of interval cancer among women screened in To-Be 1, stratified by mammographic density.

Retrospective review of prior and actual mammograms from women with interval and screen-detected breast cancers detected in To-Be 1 and 2, respectively.

Estimation of the financial impact of running a screening program with DBT+SM in an everyday setting.

Evaluation of difference in interpretation time for subsequent versus prevalent DBT+SM screens

Explore whether individualized, standardized compression pressure influences women's screening experiences using a numeric rating scale (0 "No discomfort/pain" to 10 "Very much discomfort/pain"). Drafting of the questionnaire is in progress.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Breast Cancer Screening: Digital Breast Tomosynthesis Versus Digital 2D Mammography	NCT03377036	Breast Cancer S...	DBT+s2D 2D-FFDM	50 Years - 69 Years	University Hospital Muenster
Sensitivity of Fecal Immunochemical Test (FIT) for Colorectal Cancer (CRC) Screening	NCT05163236	Colorectal Neop... Colonoscopy Early Detection... Female Mass Screening Middle Aged Occult Blood	Positive fecal ... Negative fecal ... Fecal immunoche...	50 Years - 77 Years	University Hospital, Brest
Sensitivity of Fecal Immunochemical Test (FIT) for Colorectal Cancer (CRC) Screening	NCT05163236	Colorectal Neop... Colonoscopy Early Detection... Female Mass Screening Middle Aged Occult Blood	Positive fecal ... Negative fecal ... Fecal immunoche...	50 Years - 77 Years	University Hospital, Brest
The Tomosynthesis Trial in Bergen - Part 2	NCT03669926	Breast Neoplasm...	Digital Breast ...	48 Years - 71 Years	Cancer Registry of Norway
Breast Cancer Screening: Digital Breast Tomosynthesis Versus Digital 2D Mammography	NCT03377036	Breast Cancer S...	DBT+s2D 2D-FFDM	50 Years - 69 Years	University Hospital Muenster

Spots Global Cancer Trial Database for interval cancer