Assessing Breast Density's Value in Imaging - A Comparative Effectiveness Study

Study Overview
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Brief Summary
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This Breast Cancer Surveillance Consortium (BCSC) ADVANCE study is a large, observational pragmatic comparative effectiveness research study using high-quality, prospectively collected data from BCSC registries to generate evidence on how breast density should be integrated into decision making around breast cancer screening and preoperative diagnostic work-up. We will augment existing BCSC registry infrastructure with additional prospective data collection and collection of patient reported outcomes (PROs), CISNET modeling of long-term screening outcomes, and qualitative data from focus groups with women represented in two aims.

Detailed Description
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Aim 1: Compare the effectiveness of breast cancer screening using digital mammography alone versus digital mammography plus supplemental screening (digital breast tomosynthesis or MRI) by extent of breast density. Sub aim 1: Evaluate whether the performance of tomosynthesis improves with years of experience, and whether any learning curve depends on radiologist specialty (i.e., breast imaging specialist vs. general radiologist). Aim 2: Compare the effectiveness of preoperative MRI versus no MRI by extent of breast density among women with an initial, pathologically confirmed diagnosis of DCIS or invasive breast cancer. Covid-19 Enhancement Aim and Hypotheses: Develop patient-focused messaging content through focus groups that radiology facilities can use when scheduling appointments to inform women of the safety to schedule or postpone breast screening or diagnostic services.

Official Title
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Comparative Effectiveness of Breast Cancer Screening and Diagnostic Evaluation by Extent of Breast Density

Conditions
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Breast Cancer

Intervention / Treatment
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* Other: Screening digital mammography
* Other: Screening digital breast tomosynthesis
* Other: Screening breast magnetic resonance imaging
* Other: Diagnostic mammography
* Other: Pre-operative breast magnetic resonance imaging


Participation Criteria
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Eligibility Criteria
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Aim 1 Clinical Outcomes Inclusion criteria: Women aged 40-79 undergoing screening mammography from 2010-2017 for comparisons with tomosynthesis and 2005-2017 for comparison with breast MRI at a facility that participates in one of six BCSC breast imaging registries Digital mammography exams performed for screening and performed with or without supplemental screening with digital breast tomosynthesis from 2010-2017 or breast MRI from 2005-2017, at a facility that participates in one of seven BCSC breast imaging registries, and in women who meet inclusion criteria. Exclusion criteria: Exams performed on women with a history of breast cancer, mastectomy, or breast augmentation. Unilateral mammograms and mammograms performed within 9 months of a prior mammogram to avoid classifying diagnostic exams as screening Exams without complete cancer capture during the follow-up period Aim 1 Patient Reported Outcomes Inclusion criteria: Women aged 40-74 years undergoing screening mammography, with or without supplemental screening with digital breast tomosynthesis or breast MRI, at selected BCSC facilities Women within 12 months of a digital screening mammogram with known breast density and no known breast cancer diagnosis For MRI subgroup, we will include women with a screening MRI within the prior 24 months Within strata defined by BCSC registry, breast density subgroup (dense vs. not dense), and race/ethnicity, women with supplemental screening with digital breast tomosynthesis or breast MRI will be matched to women without supplemental screening Aim 1 Focus Groups Inclusion criteria: Women age 40-74 years undergoing screening mammography, with or without supplemental screening (defined as digital breast tomosynthesis or breast MRI) Women within 12 months post-most recent screening examination with known dense breasts from most recent screening mammogram and no known breast cancer diagnosis Women who are able to speak English and can travel to a nearby location for a discussion Subaim 1 Inclusion criteria: Radiologists interpreting digital mammography and/or tomosynthesis for at least one year from 2010-2017 at a facility that participates in the BCSC Digital mammography exams and digital breast tomosynthesis performed for screening and evaluated by a radiologist meeting inclusion criteria from 2010-2017 Exclusion criteria: Exams performed on women with a history of breast cancer, mastectomy, or breast augmentation Unilateral mammograms and mammograms performed within 9 months of a prior mammogram to avoid classifying diagnostic exams as screening Exams without complete cancer capture during one year following the screening mammogram Aim 2 Clinical Outcomes Inclusion criteria: Women at least 18 years of age with a first breast cancer diagnosis (DCIS or invasive) from 2005-2017 for whom there was a mammogram performed within the year prior to breast cancer diagnosis at one of the participating BCSC registry facilities Women for whom we have pathologically-confirmed breast cancer (DCIS or invasive) with a pathology or biopsy record related to the incident cancer diagnosis in the BCSC data MRI and mammography examinations performed for pre-operative work-up from 2005-2017 at one of the participating BCSC registry facilities in women meeting eligibility criteria Aim 2 Patient Reported Outcomes Inclusion criteria: Women at least 18 years of age with a first pathology-confirmed breast cancer diagnosis (DCIS or stage I-III invasive) within 6-18 months Known breast density at the time of breast cancer diagnosis Aim 2 Focus Groups Inclusion criteria: Women age ≥18 with a first breast cancer diagnosis (DCIS or stage I-III invasive cancer) within 1-5 years and after completion of active breast cancer treatment who have undergone mammography or MRI pre-operatively. Women who are able to speak English and can travel to a nearby location for a discussion COVID-19 Enhancement Focus Groups Inclusion criteria: Women age 18-74 who were due for breast imaging services during the COVID pandemic and have either canceled their appointment, delayed their appointment, or kept their appointment Women who are able to speak English and can attend calls virtually through Zoom or over the phone In addition, for focus groups with women who have prior breast cancer: First breast cancer diagnosis (DCIS or stage I-III invasive cancer) within 1-3 years prior to March, 2020. Completed active cancer treatment (ongoing endocrine and Herceptin therapy acceptable) No evidence of a second breast cancer event in cancer registry or pathology data before recruitment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Screening group<br>Women without a history of breast cancer undergoing screening digital mammography, screening digital breast tomosynthesis, or screening breast magnetic resonance imaging. | Other: Screening digital mammography<br>* Screening with digital mammography alone<br>Other: Screening digital breast tomosynthesis<br>* Screening with digital mammography plus digital breast tomosynthesis<br>Other: Screening breast magnetic resonance imaging<br>* Screening with digital mammography plus breast magnetic resonance imaging<br>|
| Women with breast cancer<br>Women diagnosed with stage 0-III breast cancer undergoing pre-operative work-up with diagnostic mammography alone or diagnostic mammography plus pre-operative breast magnetic resonance imaging. | Other: Diagnostic mammography<br>* Pre-operative diagnostic work-up with mammography alone<br>Other: Pre-operative breast magnetic resonance imaging<br>* Pre-operative diagnostic work-up with mammography plus breast magnetic resonance imaging<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Screening Benefits: Rate of early stage invasive cancer detection (Aim 1) | Number of stage I or IIA cancers diagnosed within 1 year of a positive screen divided by total number of screens | Within one year after screen | 
| Screening Failures: Interval or advanced breast cancer rate (Aim 1) | Number of invasive cancer cases within 1 year of a negative screen divided by total number of screens Number of advanced cancers (stage IIB or higher) within 1 year of a screen divided by total number of screens | Within one year after screen | 
| Screening Harms: Recall rate (Aim 1) | Number of positive screens divided by total number of screens | Within one year after screen | 
| Screening Harms: False-positive (FP) recall rate (Aim 1) | Number of positive screens without a cancer diagnosed within 1 year divided by total number of screens | Within one year after screen | 
| Screening Harms: FP biopsy recommendation rate (Aim 1) | Number of screens with a biopsy recommendation and no cancer diagnosed within 1 year divided by total number of screens | Within one year after screen | 
| Screening Harms: Other consequences (Aim 1) | Number of DCIS diagnoses within 1 year of a positive screen divided by total number of screens, reported overall and by grade | Within one year after screen | 
| Patient Reported Outcomes (Aim 1) | Patient surveys targeted to determining outcomes of interest to patients | Measured within one year post-screening | 
| Rates of additional breast cancers detected (Aim 2) | Number of women with contralateral breast cancer diagnosed within 6 months of initial diagnosis over total number of women | 6 months after initial diagnosis | 
| 3-year rate of 2nd breast cancer events (Aim 2) | Rate of 2nd breast cancers diagnosed within 3 years of follow-up (starting 6 months after initial diagnosis) calculated separately for ipsilateral and contralateral cancers | 3 years after initial diagnosis | 
| Patient Reported Outcomes (Aim 2) | Patient surveys targeted to determining outcomes of interest to patients | Measured 6-18 months post-diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Performance Measures: Sensitivity (Aim 1) | Number of cancer cases within 1 year of positive screen divided by number of breast cancer cases | Within one year after screen | 
| Performance Measures: Specificity (Aim 1) | Number of negative screens without cancer diagnosed within 1 year of screen divided by number of screens without breast cancer | Within one year after screen | 
| Performance Measures: Positive predictive value (Aim 1) | Number of cancer cases within 1 year of positive screen divided by number of positive screens | Within one year after screen | 
| Definitive surgery type (Aim 2) | Rates of unilateral mastectomy, or bilateral mastectomy, lumpectomy with reconstruction, lumpectomy without reconstruction | 6 months after initial diagnosis | 
| Negative predictive value of work-up with MRI (Aim 2) | Number of women with a negative pre-operative MRI and no additional cancers diagnosed within 6 months after initial diagnosis over the total number of women with a negative pre-operative MRI | 6 months after initial diagnosis | 
| Negative predictive value of work-up without MRI (Aim 2) | Number of women without a pre-operative MRI with no additional cancers diagnosed within 6 months after initial diagnosis over the total number of women without a pre-operative MRI | 6 months after initial diagnosis | 
| Core biopsy rates (Aim 2) | Number of core biopsies within 6 months of initial diagnosis over number of breast biopsies | 6 months after initial diagnosis | 
| Surgical biopsy rate (Aim 2) | Number of surgical biopsies within 6 months of initial diagnosis over number of breast biopsies | 6 months after initial diagnosis | 
| Benign biopsy rate (Aim 2) | Number of initial benign biopsies over number of breast biopsies | 6 months after initial diagnosis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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digital mammography, digital breast tomosynthesis, breast magnetic resonance imaging, screening, breast density, breast imaging, pre-operative magnetic resonance imaging