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Breast Neoplasms

Breast Diseases

Skin Diseases

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Vitamins

Vitamin D

Cholecalciferol

Trace Elements

Hormones

Calcium

Calcium, Dietary

Vitamin D3

Calciferol

Oral vitamin D3 (cholecalciferol) supplementation, 1000 IU daily, for 12 months

Oral vitamin D3 (cholecalciferol) supplementation, 2000 IU daily, for 12 months

Oral vitamin D3 (cholecalciferol) supplementation, 3000 IU daily, for 12 months

Placebo

Jacques Brisson, M.D., Sc.D.

There is some evidence that vitamin D could be used to reduce breast cancer risk. Randomized controlled trials would provide definitive evidence about this effect. However, trials with breast cancer as outcome are expensive and time-consuming. Use of surrogate outcomes has been advocated to accelerate progress in the identification of interventions that could prevent breast cancer. Mammographic breast density is one of the strongest breast cancer risk indicators and is already used as a surrogate outcome in several breast cancer prevention trials. The aim of this double-blind randomized controlled trial is to determine whether daily oral supplementation with vitamin D3 (1,000, 2,000 or 3,000 IU) over a period of 1 year reduces breast density in premenopausal women compared to placebo. A total of 376 women (94 per arm) who live in Quebec City will be recruited. Showing that vitamin D reduces breast density would provide strong support for the idea that vitamin D can be a safe and inexpensive approach for the prevention of breast cancer.

OBJECTIVES

Primary:

- to determine whether adding oral supplementation with vitamin D3 (cholecalciferol) at doses of 1,000, 2,000 and 3,000 IU/d to baseline total vitamin D intake over a period of 12 months reduces mammographic breast density among premenopausal women at moderate to high risk of breast cancer who reside in the Quebec City area, Canada.

Secondary:

* to assess the net increase in 25(OH)D levels resulting from this vitamin D3 supplementation;
* to document the compliance with, and safety of, supplementation with tested doses of vitamin D3 over one year.

OUTLINE This study is a double-blind, placebo-controlled, randomized trial among premenopausal women who live in the Quebec City area and have ≥ 20% breast density at baseline.

The intervention consists of the addition, over baseline total vitamin D intake from food and supplements, of three different doses of vitamin D3 (1000, 2000 or 3000 IU/day) for a period of 12 months. There are four arms in the trial:

* Arm 1: 1,000 IU vitamin D3/d (1 tablet vitamin D 1000 IU + 2 tablets placebo);
* Arm 2: 2,000 IU vitamin D3/d (2 tablets vitamin D 1000 IU + 1 tablet placebo);
* Arm 3: 3,000 IU vitamin D3/d (3 tablets vitamin D 1000 IU);
* Arm 4: placebo (3 tablets placebo/d).

Vitamin D tablets (1000 IU tablets) and the placebo tablets are undistinguishable in size, shape, color and taste, and are manufactured by the same company.

Vitamin D and Mammographic Breast Density

A Randomized Double-blind Placebo-controlled Trial of the Effect of Vitamin D Supplementation on Breast Density in Premenopausal Women

We will not share IPD. Results of the study are published in Cancer Epidemiology, Biomarkers and Prevention.

Difference in breast density between baseline and at 12 months

Quebec Breast Cancer Foundation

CHU de Quebec-Universite Laval

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.

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:

1. Women with non-dense breasts and low breast cancer risk are re-screened only with DBT every 2 years;
2. Women with dense breasts and low breast cancer risk are re-screened with DBT+US every 2 years;
3. Women with non-dense breasts and intermediate breast cancer risk are re-screened only with DBT every year;
4. Women with dense breasts and intermediate breast cancer risk are re-screened with DBT+US every year;
5. 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.

Personalized screening protocol

Francesca Caumo, MD

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.

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.

Risk-Based Breast Screening in Young Women

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

This analysis examines both the direct costs associated with implementing and operating the stratified screening program, as well as the economic feasibility and financial implications of adopting the personalized approach

This analysis compares the proportions of women categorized as low, intermediate, and high risk for breast cancer using different risk models (Tyrer-Cuzick, Gail, Boadicea) to assess risk stratification implications within personalized screening

This analysis compares the proportions of women with dense and non-dense breasts using various breast density metrics (Volumetric Breast Density, Area-Based Breast Density, BI-RADS category) to evaluate breast density stratification implications in personalized screening

This analysis compares proportions of women classified as low, intermediate, and high risk using the Tyrer-Cuzick risk model when different breast density metrics are utilized. Examines implications of diverse density measures for risk stratification within personalized screening

This analysis studies distribution of breast cancer subtypes (luminal A, luminal B, HER2-positive, basal-like) across the overall study population and when stratified by breast density and risk category. Analyzes subtype prevalence variations based on breast density and individual risk profilesand stratified by density and risk category.

Explores AI integration into personalized screening protocols. Assesses potential reduction in required readers for personalized protocols with double reading and workload reduction from AI's accurate classification of clearly negative exams. Evaluates benefits like cost savings, efficiency, resource utilization, radiologist productivity, and job satisfaction. Measures AI effectiveness in different subgroups based on breast density and risk categories

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

Number of women recalled for further diagnostic evaluation per thousand women screened, also known as the BI-RADS abnormal interpretation rate

Number of cancers detected by screening test(s) per thousand women screened

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

Number of women undergoing diagnostic evaluation per thousand women screened. Further breakdown into noninvasive and invasive assessment rates.

Number of women referred to excisional biopsy or definitive surgical treatment per thousand women screened

Number of women undergoing excisional biopsy or definitive surgical treatment per thousand women screened

Number of women with any histologically diagnosed benign lesion per thousand women screened

Number of women with cancer detected by screening and classified by TNM tumor stage per thousand women screened

Number of women who regularly undergo the specific screening protocol (within ± 3 months) between ages 45 and 49 per thousand women screened

Regione del Veneto (Italy)

Istituto Oncologico Veneto IRCCS

Anti-Infective Agents

Iodine

Cadexomer iodine

Subject will be asked to complete a questionnaire that will ask you about your general attitude toward Contrast-Enhanced Spectral Mammography (CESM). Questions will include:

* Thoughts regarding risk of breast cancer
* Concerns regarding contrast procedures such as the CESM
* Past mammogram/breast imaging experience

CESM is a mammogram performed after the injection of IV contrast. CESM is used most often when additional information is needed after a standard mammogram. CESM has also been used to determine the extent of a known breast cancer, to screen patients at high risk for developing breast cancer due to a family history or positive cancer genes, and for women with dense breast tissue. Two images are taken almost at the same time during the exam, after the iodine based contrast injection is administered. The first image is comparable to a regular mammogram. The second image shows areas that take up the contrast (enhance) showing increased blood flow. Breast cancers often enhance with contrast due to a greater amount of blood vessels. Non-cancerous lesions can also have greater blood flow.

Contrast-enhanced spectral mammography (CESM)

Kathy L Repich, RN

Matthew M Miller, MD

Kathy Repich

The purpose of this study is to evaluate how well women may adopt a Contrast-enhanced Spectral Mammography (CESM) as their yearly breast screening test compared to the standard 2-D or 3-D mammogram.

Contrast-enhanced spectral mammography (CESM) is an FDA approved tool for breast cancer detection. However, adoption into clinical practice has been slow. In this study, we will explore patient issues related to the use of CESM for breast cancer screening. For this study, 210 women with heterogeneous or dense breast tissue reported on a previous mammogram, will be recruited to undergo a screening Contrast-enhanced Spectral Mammography (CESM). The CESM will serve as the subject's annual screening breast exam for clinical care. A survey will be administered before and after the examination that evaluates the patient experience. Women will not be at high risk for breast cancer (\<20% lifetime risk). All abnormal findings will be acted upon independently. Results of the general screening population survey will be compared with those of women who choose to undergo the CESM examination in order to evaluate the influence of age, education, and lifetime risk on decision making about advanced screening.

Contrast-enhanced Spectral Mammography (CESM) Breast Cancer Screening

Willingness of Women to Undergo a Contrast-enhanced Spectral Mammography (CESM) for Breast Cancer Screening and Their Experience Before and After CESM

Plan for primary variable analysis: To evaluate the patient experience during a screening CESM to better understand if women find the experience of contrast injection to be too invasive or unpleasant to repeat or recommend to a friend.

Data summarization: Pre and post CESM survey responses that are binary or Likert scaled responses will be summarized by frequencies and percentages. Pre and post CESM survey responses that are continuous scaled responses will be summarized by the mean and standard deviation, the median and interquartile range, and the range of distribution.

We will evaluate differences by age, education, and risk factors as to whether these drive willingness to undergo CESM.

Data summarization: Binary risk factors will be summarized by frequencies and percentages. Continuous scaled risk factors will be summarized by the mean and standard deviation, the median and interquartile range, and the range of distribution.

University of Virginia

Radiology-Breast Imaging Faculty, Clinical Assistant Professor, Principal Investigator

This tool represents a physics-based model which extract pixel-wise information from the FFDM or DBT images, and combine it with metadata information from the DICOM header and appropriate linear attenuation coefficients of both adipose and glandular tissue.

Volpara

Oliver Diaz, PhD

Javier del Riego, MD

Amaya Martín, MD

Lidia Tortajada, MD

M Teresa Villajos, MD

Clara Codina, MD

Fernanda Escribano, MD

Laura Navarro

Joan C Oliva

M Magdalena Villa

Rosa Ariza

Cecilia Aynes

Estefania Martín

Eva Doncel

Robert Martí, PhD

Eloy García, PhD

Anissa Lingtang, MSc

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide. The cause of developing BC is currently unknown. However, there are several risk factors, such as volumetric breast density (VBD), which have been proved to have a relationship with BC. The assessment of breast density is typically performed subjectively using the 4-classes density classification described by American College of Radiology. However, in the last years, automated breast density software tools have been developed (e.g. Volpara, Quantra). In this work, VBD measurements from VolparaTM (v. 1.5.4.0) will be compared between Full-Field Digital Mammography (FFDM) and Digital Breast Tomosynthesis (DBT) of the same pacient ('combo mode'). Images will be acquired in a Hologic Selenia Dimensions, the most common FFDM/DTB system, where image resolution is different for FFDM (70 um) and DBT (140 um).

This study (1) evaluates the consistency between Volpara's breast density measurements and spatial distribution for the two imaging techniques (FFDM and DBT) in a Hologic Selenia Dimensions, and (2) compares VDB measurements with other similar tool (Quantra) and radiologists breast density manual classification.

Monocentric, prospective and observational study which will analyse a series of 300 cases (FFDM + DBT) from consecutive women. Image acquisitions will take place within the Área de radiología Mamaria y Ginecológica located at Parc Taulí Hospital Universitari, Sabadell. The purposes of this study will be explained to each potential candidate and if agreed to participate, a consent form will be signed.

Inclusion criteria:

* Subjects over 18 years old.
* Acceptance of participation through a signed consent form.
* Asymptomatic subjects

Exclusion criteria:

* Subjects refusing to participate or sign the consent form.
* Subjects with prior history of breast surgery or biopsy with markers.
* Subjects with breast prostheses.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Vitamin D and Mammographic Breast Density	NCT01747720	Breast Cancer	Vitamin D3 Placebo	18 Years - 55 Years	CHU de Quebec-Universite Laval
Risk-Based Breast Screening in Young Women	NCT05675085	Breast Neoplasm...	Personalized sc...	45 Years - 45 Years	Istituto Oncologico Veneto IRCCS
Contrast-enhanced Spectral Mammography (CESM) Breast Cancer Screening	NCT04904757	Mammographic Br... Mammography	Contrast-enhanc...	40 Years - 69 Years	University of Virginia
Vitamin D and Mammographic Breast Density	NCT01747720	Breast Cancer	Vitamin D3 Placebo	18 Years - 55 Years	CHU de Quebec-Universite Laval
Breast Density Measurements in Digital Mammography and Breast Tomosynthesis Systems of Different Pixel Size	NCT04127175	Mammographic Br...	Volpara	40 Years - 99 Years	Corporacion Parc Tauli

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