Digital breast tomosynthesis in mammographic screening: false negative cancer cases in the To-Be 1 trial.

OBJECTIVES: The randomized controlled trial comparing digital breast tomosynthesis and synthetic 2D mammograms (DBT + SM) versus digital mammography (DM) (the To-Be 1 trial), 2016-2017, did not result in higher cancer detection for DBT + SM. We aimed to determine if negative cases prior to interval and consecutive screen-detected cancers from DBT + SM were due to interpretive error. METHODS: Five external breast radiologists performed the individual blinded review of 239 screening examinations (90 true negative, 39 false positive, 19 prior to interval cancer, and 91 prior to consecutive screen-detected cancer) and the informed consensus review of examinations prior to interval and screen-detected cancers (n = 110). The reviewers marked suspicious findings with a score of 1-5 (probability of malignancy). A case was false negative if ≥ 2 radiologists assigned the cancer site with a score of ≥ 2 in the blinded review and if the case was assigned as false negative by a consensus in the informed review. RESULTS: In the informed review, 5.3% of examinations prior to interval cancer and 18.7% prior to consecutive round screen-detected cancer were considered false negative. In the blinded review, 10.6% of examinations prior to interval cancer and 42.9% prior to consecutive round screen-detected cancer were scored ≥ 2. A score of ≥ 2 was assigned to 47.8% of negative and 89.7% of false positive examinations. CONCLUSIONS: The false negative rates were consistent with those of prior DM reviews, indicating that the lack of higher cancer detection for DBT + SM versus DM in the To-Be 1 trial is complex and not due to interpretive error alone. CRITICAL RELEVANCE STATEMENT: The randomized controlled trial on digital breast tomosynthesis and synthetic 2D mammograms (DBT) and digital mammography (DM), 2016-2017, showed no difference in cancer detection for the two techniques. The rates of false negative screening examinations prior to interval and consecutive screen-detected cancer for DBT were consistent with the rates in prior DM reviews, indicating that the non-superior DBT performance in the trial might not be due to interpretive error alone. KEY POINTS: • Screening with digital breast tomosynthesis (DBT) did not result in a higher breast cancer detection rate compared to screening with digital mammography (DM) in the To-Be 1 trial. • The false negative rates for examinations prior to interval and consecutive screen-detected cancer for DBT were determined in the trial to test if the lack of differences was due to interpretive error. • The false negative rates were consistent with those of prior DM reviews, indicating that the lack of higher cancer detection for DBT versus DM was complex and not due to interpretive error alone.

European validation of an image-derived AI-based short-term risk model for individualized breast cancer screening-a nested case-control study.

Background: Image-derived artificial intelligence (AI)-based risk models for breast cancer have shown high discriminatory performances compared with clinical risk models based on family history and lifestyle factors. However, little is known about their generalizability across European screening settings. We therefore investigated the discriminatory performances of an AI-based risk model in European screening settings. Methods: Using four European screening populations in three countries (Italy, Spain, Germany) screened between 2009 and 2020 for women aged 45-69, we performed a nested case-control study to assess the predictive performance of an AI-based risk model. In total, 739 women with incident breast cancers were included together with 7812 controls matched on year of study-entry. Mammographic features (density, microcalcifications, masses, left-right breast asymmetries of these features) were extracted using AI from negative digital mammograms at study-entry. Two-year absolute risks of breast cancer were predicted and assessed after two years of follow-up. Adjusted risk stratification performance metrics were reported per clinical guidelines. Findings: The overall adjusted Area Under the receiver operating characteristic Curve (aAUC) of the AI risk model was 0.72 (95% CI 0.70-0.75) for breast cancers developed in four screening populations. In the 6.2% [529/8551] of women at high risk using the National Institute of Health and Care Excellence (NICE) guidelines thresholds, cancers were more likely diagnosed after 2 years follow-up, risk-ratio (RR) 6.7 (95% CI 5.6-8.0), compared with the 69% [5907/8551] of women classified at general risk by the model. Similar risk-ratios were observed across levels of mammographic density. Interpretation: The AI risk model showed generalizable discriminatory performances across European populations and, predicted ∼30% of clinically relevant stage 2 and higher breast cancers in ∼6% of high-risk women who were sent home with a negative mammogram. Similar results were seen in women with fatty and dense breasts. Funding: Swedish Research Council.

Benefits and harms of annual, biennial, or triennial breast cancer mammography screening for women at average risk of breast cancer: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC).

BACKGROUND: Although mammography screening is recommended in most European countries, the balance between the benefits and harms of different screening intervals is still a matter of debate. This review informed the European Commission Initiative on Breast Cancer (BC) recommendations. METHODS: We searched PubMed, EMBASE, and the Cochrane Library to identify RCTs, observational or modelling studies, comparing desirable (BC deaths averted, QALYs, BC stage, interval cancer) and undesirable (overdiagnosis, false positive related, radiation related) effects from annual, biennial, or triennial mammography screening in women of average risk for BC. We assessed the certainty of the evidence using the GRADE approach. RESULTS: We included one RCT, 13 observational, and 11 modelling studies. In women 50-69, annual compared to biennial screening may have small additional benefits but an important increase in false positive results; triennial compared to biennial screening may have smaller benefits while avoiding some harms. In younger women (aged 45-49), annual compared to biennial screening had a smaller gain in benefits and larger harms, showing a less favourable balance in this age group than in women 50-69. In women 70-74, there were fewer additional harms and similar benefits with shorter screening intervals. The overall certainty of the evidence for each of these comparisons was very low. CONCLUSIONS: In women of average BC risk, screening intervals have different trade-offs for each age group. The balance probably favours biennial screening in women 50-69. In younger women, annual screening may have a less favourable balance, while in women aged 70-74 years longer screening intervals may be more favourable.

Digital breast tomosynthesis compared to diagnostic mammographic projections (including magnification) among women recalled at screening mammography: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC).

BACKGROUND: Diagnostic mammography projections (DxMM) have been traditionally used in the assessment of women recalled after a suspicious screening mammogram. Digital breast tomosynthesis (DBT) reduces the tissue overlap effect, thus improving image assessment. Some studies have suggested DBT might replace DxMM with at least equivalent performance. OBJECTIVE: To evaluate the replacement of DxMM with DBT in women recalled at screening. METHODS: We searched PubMed, EMBASE, and the Cochrane Library databases to identify diagnostic paired cohort studies or RCTs comparing DBT vs DxMM, published in English that: reported accuracy outcomes, recruited women recalled for assessment at mammography screening, and included a reference standard. Subgroup analysis was performed over lesion characteristics. We provided pooled accuracy estimates and differences between tests using a quadrivariate model. We assessed the certainty of the evidence using the GRADE approach. RESULTS: We included ten studies that reported specificity and sensitivity. One study included 7060 women while the remaining included between 52 and 738 women. DBT compared with DxMM showed a pooled difference for the sensitivity of 2% (95% CI 1%-3%) and a pooled difference for the specificity of 6% (95%CI 2%-11%). Restricting the analysis to the six studies that included women with microcalcification lesions gave similar results. In the context of a prevalence of 21% of breast cancer (BC) in recalled women, DBT probably detects 4 (95% CI 2-6) more BC cases and has 47 (95%CI 16-87) fewer false-positive results per 1000 assessments. The certainty of the evidence was moderate due to risk of bias. CONCLUSION: The evidence in the assessment of screen-recalled findings with DBT is sparse and of moderate certainty. DBT probably has higher sensitivity and specificity than DxMM. Women, health care providers and policymakers might value as relevant the reduction of false-positive results and related fewer invasive diagnostic procedures with DBT, without missing BC cases.

Benefits and harms of breast cancer mammography screening for women at average risk of breast cancer: A systematic review for the European Commission Initiative on Breast Cancer.

OBJECTIVES: Mammography screening is generally accepted in women aged 50-69, but the balance between benefits and harms remains controversial in other age groups. This study systematically reviews these effects to inform the European Breast Cancer Guidelines. METHODS: We searched PubMed, EMBASE and Cochrane Library for randomised clinical trials (RCTs) or systematic reviews of observational studies in the absence of RCTs comparing invitation to mammography screening to no invitation in women at average breast cancer (BC) risk. We extracted data for mortality, BC stage, mastectomy rate, chemotherapy provision, overdiagnosis and false-positive-related adverse effects. We performed a pooled analysis of relative risks, applying an inverse-variance random-effects model for three age groups (<50, 50-69 and 70-74). GRADE (Grading of Recommendations Assessment, Development and Evaluation) was used to assess the certainty of evidence. RESULTS: We identified 10 RCTs including 616,641 women aged 38-75. Mammography reduced BC mortality in women aged 50-69 (relative risk (RR) 0.77, 95%CI (confidence interval) 0.66-0.90, high certainty) and 70-74 (RR 0.77, 95%CI 0.54-1.09, high certainty), with smaller reductions in under 50s (RR 0.88, 95%CI 0.76-1.02, moderate certainty). Mammography reduced stage IIA+ in women 50-69 (RR 0.80, 95%CI 0.64-1.00, very low certainty) but resulted in an overdiagnosis probability of 23% (95%CI 18-27%) and 17% (95%CI 15-20%) in under 50s and 50-69, respectively (moderate certainty). Mammography was associated with 2.9% increased risk of invasive procedures with benign outcomes (low certainty). CONCLUSIONS: For women 50-69, high certainty evidence that mammography screening reduces BC mortality risk would support policymakers formulating strong recommendations. In other age groups, where the net balance of effects is less clear, conditional recommendations will be more likely, together with shared decision-making.

Development and use of health outcome descriptors: a guideline development case study.

BACKGROUND: During healthcare guideline development, panel members often have implicit, different definitions of health outcomes that can lead to misunderstandings about how important these outcomes are and how to balance benefits and harms. McMaster GRADE Centre researchers developed 'health outcome descriptors' for standardizing descriptions of health outcomes and overcoming these problems to support the European Commission Initiative on Breast Cancer (ECIBC) Guideline Development Group (GDG). We aimed to determine which aspects of the development, content, and use of health outcome descriptors were valuable to guideline developers. METHODS: We developed 24 health outcome descriptors related to breast cancer screening and diagnosis for the European Commission Breast Guideline Development Group (GDG). Eighteen GDG members provided feedback in written format or in interviews. We then evaluated the process and conducted two health utility rating surveys. RESULTS: Feedback from GDG members revealed that health outcome descriptors are probably useful for developing recommendations and improving transparency of guideline methods. Time commitment, methodology training, and need for multidisciplinary expertise throughout development were considered important determinants of the process. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. CONCLUSIONS: Health outcome descriptors are feasible and should be developed prior to the outcome prioritization step in the guideline development process. Guideline developers should involve a subgroup of multidisciplinary experts in all stages of development and ensure all guideline panel members are trained in guideline methodology that includes understanding the importance of defining and understanding the outcomes of interest.

Breast Cancer Screening and Diagnosis: A Synopsis of the European Breast Guidelines.

Description: The European Commission Initiative for Breast Cancer Screening and Diagnosis guidelines (European Breast Guidelines) are coordinated by the European Commission's Joint Research Centre. The target audience for the guidelines includes women, health professionals, and policymakers. Methods: An international guideline panel of 28 multidisciplinary members, including patients, developed questions and corresponding recommendations that were informed by systematic reviews of the evidence conducted between March 2016 and December 2018. GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision frameworks were used to structure the process and minimize the influence of competing interests by enhancing transparency. Questions and recommendations, expressed as strong or conditional, focused on outcomes that matter to women and provided a rating of the certainty of evidence. Recommendations: This synopsis of the European Breast Guidelines provides recommendations regarding organized screening programs for women aged 40 to 75 years who are at average risk. The recommendations address digital mammography screening and the addition of hand-held ultrasonography, automated breast ultrasonography, or magnetic resonance imaging compared with mammography alone. The recommendations also discuss the frequency of screening and inform decision making for women at average risk who are recalled for suspicious lesions or who have high breast density.

Methods for Development of the European Commission Initiative on Breast Cancer Guidelines: Recommendations in the Era of Guideline Transparency.

Neither breast cancer prevention and early-detection programs, nor their outcomes, are uniform across Europe. This article describes the rationale, methods, and process for development of the European Commission (EC) Initiative on Breast Cancer Screening and Diagnosis Guidelines. To be consistent with standards set by the Institute of Medicine and others, the EC followed 6 general principles. First, the EC selected, via an open call, a panel with broad representation of areas of expertise. Second, it ensured that all recommendations were supported by systematic reviews. Third, the EC separately considered important subgroups of women, included patient advocates in the guidelines development group, and focused on good communication to inform women's decisions. Fourth, EC rules on conflicts of interest were followed and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision frameworks were used to structure the process and minimize the influence of competing interests. Fifth, it focused its recommendations on outcomes that matter to women, and certainty of the evidence is rated for each. Sixth, the EC elicited stakeholder feedback to ensure that the recommendations remain up to date and relevant to practice. This article describes the approach and highlights ways of disseminating and adapting the recommendations both within and outside Europe, using innovative information technology tools.