The Importance of Outcomes Ascertainment for Accurate Assessment of the Mammography Screening Cancer Detection Rate: A Simulation Study.

PURPOSE: Cancer detection rate (CDR), an important metric in the mammography screening audit, is designed to ensure adequate sensitivity. Most practices use biopsy results as the reference standard; however, commonly ascertainment of biopsy results is incomplete. We used simulation to determine the relationship between the cancer ascertainment rate of biopsy (AR-biopsy), CDR estimation, and associated error rates in classifying whether practices and radiologists meet the established ACR benchmark of 2.5 per 1,000. MATERIALS AND METHODS: We simulated screening mammography volume, number of cancers detected, and CDR, using negative binomial and beta-binomial distributions, respectively. Simulations were performed at both the practice and radiologist level. Average CDR was based on linearly rescaling a published CDR by the AR-biopsy. CDR distributions were simulated for AR-biopsy between 5% and 100% in steps of five percentage points and were summarized with boxplots and smoothed histograms over the range of AR-biopsy, to quantify the proportion of practices and radiologists meeting the ACR benchmark at each level of AR-biopsy. RESULTS: Decreasing AR-biopsy led to an increasing probability of categorizing CDR performance as being below the ACR benchmark. Our simulation predicts that at the practice level, an AR-biopsy of 65% categorizes 17.6% below the benchmark (compared to 1.6% at an AR-biopsy of 100%), and at the radiologist level, an AR-biopsy of 65% categorizes 34.7% as being below the benchmark (compared to 11.6% at an AR-biopsy of 100%). CONCLUSIONS: Our simulation demonstrates that decreasing the AR-biopsy (in currently clinically relevant ranges) has the potential to artifactually lower the assessed CDR on both the practice and radiologist levels and may, in turn, increase the chance of erroneous categorization of underperformance per the ACR benchmark.

Management of Women at High Risk for Breast Cancer.

BACKGROUND: Primary care clinicians screen for breast cancer risk factors and assess the risk level of their patients. Women at high risk for breast cancer (eg, 5-year risk of at least 3% or lifetime risk of ≥20%) are eligible for enhanced screening and/or chemoprophylaxis. However, many clinicians do not identify women at high risk and offer appropriate referrals, screening, or chemoprophylaxis. METHODS: We reviewed a sample of 200 charts of women ages 35 to 50 years old with a family history of breast cancer. We identified factors that contribute to their risk for breast cancer and used the Tyrer-Cuzick Risk Assessment Calculator to determine their personal lifetime risk. We then assessed whether these patients received counseling for chemoprophylaxis, referrals, or screening. We also looked for correlations between combinations of risk factors and increased lifetime risk. RESULTS: Out of 200 charts reviewed, 71 women were identified as high risk for breast cancer (lifetime risk of ≥20%). Of those 71 women, just 17 were referred to a high-risk clinic for enhanced screening and/or chemoprophylaxis. Three risk factors, mammographic breast density of category C or D, first degree relatives with breast cancer, and age first given birth if after 30 years old had a significant impact on lifetime risk for breast cancer. DISCUSSION: Primary care clinicians can use these independent risk factors as cues to pursue a more formal calculation of a woman's lifetime risk for breast cancer and make appropriate referrals for enhanced screening and chemoprophylaxis counseling if indicated.

A leadership model supporting maturation of high-performance translational teams.

Despite understanding its impact on organizational effectiveness, practical guidance on how to train translational team (TT) leaders is lacking. Previously, we developed an evolutionary learning model of TT maturation consisting of three goal-directed phases: (1). team assembly (Formation); (2). conducting research (Knowledge Generation); and (3). dissemination and implementation (Translation). At each phase, the team acquires group-level knowledge, skills, and attitudes (KSAs) that enhance its performance. Noting that the majority of team-emergent KSAs are promoted by leadership behaviors, we examine the SciTS literature to identify the relevant behaviors for each phase. We propose that effective team leadership evolves from a hierarchical, transformational model early in team Formation to a shared, functional leadership model during Translation. We synthesized an integrated model of TT leadership, mapping a generic "functional leadership" taxonomy to relevant leadership behaviors linked to TT performance, creating an evidence-informed Leadership and Skills Enhancement for Research (LASER) training program. Empirical studies indicate that leadership behaviors are stable across time; to enhance leadership skills, ongoing reflection, evaluation, and practice are needed. We provide a comprehensive multi-level evaluation framework for tracking the growth of TT leadership skills. This work provides a framework for assessing and training relevant leadership behaviors for high-performance TTs.

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. RESULTS: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results. CONCLUSIONS: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

Temporal development of high-performance translational teams.

Successful translation involves the coupled application of knowledge-generating research with product development to advance a device, drug, diagnostic, or evidence-based intervention for clinical adoption to improve human health. Critical to the success of the CTSA consortium, translation can be more effectively accomplished by training approaches that focus on improving team-emergent knowledge skills and attitudes (KSAs) linked to performance. We earlier identified 15 specific evidence-informed, team-emergent competencies that facilitate translational team (TT) performance. Here, we examine the SciTS literature describing developmental, temporal dynamics, and adaptive learning stages of interdisciplinary teams and integrate these with real-world observations on TT maturation pathways. We propose that TTs undergo ordered developmental phases, each representing a learning cycle that we call Formation, Knowledge Generation, and Translation. We identify major activities of each phase linked to development goals. Transition to subsequent phases is associated with a team learning cycle, resulting in adaptations that enabling progression towards clinical translation. We present known antecedents of stage-dependent competencies and rubrics for their assessment. Application of this model will ease assessment, facilitate goal identification and align relevant training interventions to improve performance of TTs in the CTSA context.

Competencies supporting high-performance translational teams: A review of the SciTS evidence base.

A translational team (TT) is a specific type of interdisciplinary team that seeks to improve human health. Because high-performing TTs are critical to accomplishing CTSA goals, a greater understanding of how to promote TT performance is needed. Previous work by a CTSA Workgroup formulated a taxonomy of 5 interrelated team-emergent competency "domains" for successful translation: 1). affect, 2). communication, 3). management, 4). collaborative problem-solving, and 5). leadership. These Knowledge Skills and Attitudes (KSAs) develop within teams from the team's interactions. However, understanding how practice in these domains enhance team performance was unaddressed. To fill this gap, we conducted a scoping literature review of empirical team studies from the broader Science of Team Science literature domains. We identified specific team-emergent KSAs that enhance TT performance, mapped these to the earlier "domain" taxonomy, and developed a rubric for their assessment. This work identifies important areas of intersection of practices in specific competencies across other competency domains. We find that inclusive environment, openness to transdisciplinary knowledge sharing, and situational leadership are a core triad of team-emergent competencies that reinforce each other and are highly linked to team performance. Finally, we identify strategies for enhancing these competencies. This work provides a grounded approach for training interventions in the CTSA context.

Deployment of Real-time Natural Language Processing and Deep Learning Clinical Decision Support in the Electronic Health Record: Pipeline Implementation for an Opioid Misuse Screener in Hospitalized Adults.

BACKGROUND: The clinical narrative in electronic health records (EHRs) carries valuable information for predictive analytics; however, its free-text form is difficult to mine and analyze for clinical decision support (CDS). Large-scale clinical natural language processing (NLP) pipelines have focused on data warehouse applications for retrospective research efforts. There remains a paucity of evidence for implementing NLP pipelines at the bedside for health care delivery. OBJECTIVE: We aimed to detail a hospital-wide, operational pipeline to implement a real-time NLP-driven CDS tool and describe a protocol for an implementation framework with a user-centered design of the CDS tool. METHODS: The pipeline integrated a previously trained open-source convolutional neural network model for screening opioid misuse that leveraged EHR notes mapped to standardized medical vocabularies in the Unified Medical Language System. A sample of 100 adult encounters were reviewed by a physician informaticist for silent testing of the deep learning algorithm before deployment. An end user interview survey was developed to examine the user acceptability of a best practice alert (BPA) to provide the screening results with recommendations. The planned implementation also included a human-centered design with user feedback on the BPA, an implementation framework with cost-effectiveness, and a noninferiority patient outcome analysis plan. RESULTS: The pipeline was a reproducible workflow with a shared pseudocode for a cloud service to ingest, process, and store clinical notes as Health Level 7 messages from a major EHR vendor in an elastic cloud computing environment. Feature engineering of the notes used an open-source NLP engine, and the features were fed into the deep learning algorithm, with the results returned as a BPA in the EHR. On-site silent testing of the deep learning algorithm demonstrated a sensitivity of 93% (95% CI 66%-99%) and specificity of 92% (95% CI 84%-96%), similar to published validation studies. Before deployment, approvals were received across hospital committees for inpatient operations. Five interviews were conducted; they informed the development of an educational flyer and further modified the BPA to exclude certain patients and allow the refusal of recommendations. The longest delay in pipeline development was because of cybersecurity approvals, especially because of the exchange of protected health information between the Microsoft (Microsoft Corp) and Epic (Epic Systems Corp) cloud vendors. In silent testing, the resultant pipeline provided a BPA to the bedside within minutes of a provider entering a note in the EHR. CONCLUSIONS: The components of the real-time NLP pipeline were detailed with open-source tools and pseudocode for other health systems to benchmark. The deployment of medical artificial intelligence systems in routine clinical care presents an important yet unfulfilled opportunity, and our protocol aimed to close the gap in the implementation of artificial intelligence-driven CDS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05745480; https://www.clinicaltrials.gov/ct2/show/NCT05745480.

Team Science Principles Enhance Cancer Care Delivery Quality Improvement: Interdisciplinary Implementation of Breast Cancer Screening Shared Decision Making.

PURPOSE: Implementing shared decision making (SDM), recommended in screening mammography by national guidelines for women age 40-49 years, faces challenges that innovations in quality improvement and team science (TS) are poised to address. We aimed to improve the effectiveness, patient-centeredness, and efficiency of SDM in primary care for breast cancer screening. METHODS: Our interdisciplinary team included primary and specialty care, psychology, epidemiology, communication science, engineering, and stakeholders (patients and clinicians). Over a 6-year period, we executed two iterative cycles of plan-do-study-act (PDSA) to develop, revise, and implement a SDM tool using TS principles. Patient and physician surveys and retrospective analysis of tool performance informed our first PDSA cycle. Patient and physician surveys, toolkit use, and clinical outcomes in the second PDSA cycle supported SDM implementation. We gathered team member assessments on the importance of individual TS activities. RESULTS: Our first PDSA cycle successfully generated a SDM tool called Breast Cancer Risk Estimator, deemed valuable by 87% of patients surveyed. Our second PDSA cycle increased Breast Cancer Risk Estimator utilization, from 2,000 sessions in 2017 to 4,097 sessions in 2019 while maintaining early-stage breast cancer diagnoses. Although TS activities such as culture, trust, and communication needed to be sustained throughout the project, shared goals, research/data infrastructure support, and leadership were more important earlier in the project and persisted in the later stages of the project. CONCLUSION: Combining rigorous quality improvement and TS principles can support the complex, interdependent, and interdisciplinary activities necessary to improve cancer care delivery exemplified by our implementation of a breast cancer screening SDM tool.

Patient-provider communication while using a clinical decision support tool: explaining satisfaction with shared decision making for mammography screening.

BACKGROUND: Clinical decision aids may support shared decision-making for screening mammography. To inform shared decision-making between patients and their providers, this study examines how patterns of using an EHR-integrated decision aid and accompanying verbal patient-provider communication predict decision-making satisfaction. METHODS: For 51 patient visits during which a mammography decision aid was used, linguistic characteristics of patient-provider verbal communication were extracted from transcribed audio recordings and system logs automatically captured uses of the decision aid. Surveys assessed patients' post-visit decisional satisfaction and its subcomponents. Linear mixed effects models assessed how patients' satisfaction with decision making was related to patterns of verbal communication and navigation of the decision aid. RESULTS: The results indicate that providers' use of quantitative language during the encounter was positively associated with patients' overall satisfaction, feeling informed, and values clarity. Patients' question-asking was negatively associated with overall satisfaction, values clarity, and certainty perception. Where system use data indicated the dyad had cycled through the decision-making process more than once ("looping" back through pages of the decision aid), patients reported improved satisfaction with shared decision making and all subcomponents. Overall satisfaction, perceived support, certainty, and perceived effectiveness of decision-making were lowest when a high number of navigating clicks occurred absent "looping." CONCLUSIONS: Linguistic features of patient-provider communication and system use data of a decision aid predict patients' satisfaction with shared decision making. Our findings have implications for the design of decision aid tools and clinician training to support more effective shared decision-making for screening mammography.

A new perspective on breast cancer diagnostic guidelines to reduce overdiagnosis.

Overdiagnosis of breast cancer, defined as diagnosing a cancer that would otherwise not cause symptoms or death in a patient's lifetime, costs U.S. health care system over $1.2 billion annually. Overdiagnosis rates, estimated to be around 10%-40%, may be reduced if indolent breast findings can be identified and followed with noninvasive imaging rather than biopsy. However, there are no validated guidelines for radiologists to decide when to choose imaging options recognizing cancer grades and types. The aim of this study is to optimize breast cancer diagnostic decisions based on cancer types using a large-scale finite-horizon Markov decision process (MDP) model with 4.6 million states to help reduce overdiagnosis. We prove the optimality of a divide-and-search algorithm that relies on tight upper bounds on the optimal decision thresholds to find an exact optimal solution. We project the high-dimensional MDP onto two lower dimensional MDPs and obtain feasible upper bounds on the optimal decision thresholds. We use real data from two private mammography databases and demonstrate our model performance through a previously validated simulation model that has been used by the policy makers to set the national screening guidelines in the United States. We find that a decision-analytical framework optimizing diagnostic decisions while accounting for breast cancer types has a strong potential to improve the quality of life and alleviate the immense costs of overdiagnosis. Our model leads to a 20 % reduction in overdiagnosis on the screening population, which translates into an annual savings of approximately $300 million for the U.S. health care system.

Surveillance Imaging vs Symptomatic Recurrence Detection and Survival in Stage II-III Breast Cancer (AFT-01).

BACKGROUND: Guidelines for follow-up after locoregional breast cancer treatment recommend imaging for distant metastases only in the presence of patient signs and/or symptoms. However, guidelines have not been updated to reflect advances in imaging, systemic therapy, or the understanding of biological subtype. We assessed the association between mode of distant recurrence detection and survival. METHODS: In this observational study, a stage-stratified random sample of women with stage II-III breast cancer in 2006-2007 and followed through 2016 was selected, including up to 10 women from each of 1217 Commission on Cancer facilities (n = 10 076). The explanatory variable was mode of recurrence detection (asymptomatic imaging vs signs and/or symptoms). The outcome was time from initial cancer diagnosis to death. Registrars abstracted scan type, intent (cancer-related vs not, asymptomatic surveillance vs not), and recurrence. Data were merged with each patient's National Cancer Database record. RESULTS: Surveillance imaging detected 23.3% (284 of 1220) of distant recurrences (76.7%, 936 of 1220 by signs and/or symptoms). Based on propensity-weighted multivariable Cox proportional hazards models, patients with asymptomatic imaging compared with sign and/or symptom detected recurrences had a lower risk of death if estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative (triple negative; hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.54 to 0.99), or HER2 positive (HR = 0.51, 95% CI = 0.33 to 0.80). No association was observed for ER- or PR-positive, HER2-negative (HR = 1.14, 95% CI = 0.91 to 1.44) cancers. CONCLUSIONS: Recurrence detection by asymptomatic imaging compared with signs and/or symptoms was associated with lower risk of death for triple-negative and HER2-positive, but not ER- or PR-positive, HER2-negative cancers. A randomized trial is warranted to evaluate imaging surveillance for metastases results in these subgroups.

How to better identify and manage women with elevated breast cancer risk.

This case-based review details screening and management strategies that can maximize the care you provide to women at heightened risk.

Utilization and Cancer Yield of Probably Benign Assessment Category in the National Mammography Database: 2009 to 2018.

PURPOSE: Data on utilization rate and cancer yield of BI-RADS® category 3 in routine clinical practice in diagnostic mammography are sparse. The aim of this study was to determine utilization rate and cancer yield of BI-RADS 3 in diagnostic mammography in the ACR National Mammography Database (NMD). METHODS: Retrospective analysis of NMD mammograms from January 1, 2009, to June 30, 2018, was performed. BI-RADS 3 utilization rate in diagnostic setting was calculated and stratified by patient, facility, and examination-level variables. Patient-level cancer yield was calculated among women with BI-RADS 3 assessment and adequate follow-up (imaging follow-up ≥24 months or biopsy). Logistic regression was performed to assess the odds of utilization of BI-RADS 3, with respect to facility, examination, and patient variables, and the odds of malignancy among patients with probably benign findings. Chi-square and t tests were used to determine significance (P < .05). RESULTS: Data from 19,443,866 mammograms from 500 NMD facilities across 31 states were analyzed, of which 3,039,952 were diagnostic mammograms. Utilization rate of BI-RADS 3 was 15.5% (470,155 of 3,039,952) in the diagnostic setting. There was a statistically significant difference in BI-RADS 3 utilization rate across all collected variables (P < .001). Patient-level cancer yield at 2-year follow-up was 0.91% (2,009 of 220,672; 95% confidence interval [CI], 0.87%-0.95%) in the diagnostic setting. Patient and examination variables associated with significantly higher likelihood of malignancy included calcifications (odds ratio, 4.27; 95% CI, 2.43-7.51), patient age > 70 years (odds ratio, 3.77; 95% CI, 2.49-5.7), and presence of prior comparisons (odds ratio, 1.23; 95% CI, 1.07-1.42). CONCLUSIONS: In the NMD, BI-RADS 3 assessment was common in diagnostic mammography (15.5%), with an overall cancer yield of 0.91%, less than the benchmark of 2%. Utilization trends in diagnostic mammography warrant further research for optimization of use.

Patient and Clinician Characteristics That Predict Breast Cancer Screening Behavior in 40-49-Year-Old Women.

Guidelines recommend that clinicians practice shared decision-making (SDM) with women in their 40s to discuss breast cancer screening. Traditionally, SDM includes discussion of values and preferences to help determine a decision that is congruent with what the patient desires. We analyzed 54 women's breast cancer screening decisions after a SDM conversation with their clinician. We looked at both patient and clinician characteristics that predicted whether or not a woman would get a screening mammogram. Women with a family history of breast cancer or who had a previous abnormal mammogram had higher rates of screening. Screening rates also varied widely between clinicians, raising the question of whether clinician attitudes impacted the SDM conversation.

Preliminary Evaluation of a Breast Cancer Screening Shared Decision-Making Aid Utilized Within the Primary Care Clinical Encounter.

INTRODUCTION: The US Preventative Services Task Force recommends shared decision-making (SDM) between women aged 40 and 49 years and their physician regarding timing of mammography screening. This preliminary study evaluates women's and physician's satisfaction using Breast Cancer Risk Estimator & Decision Aid (BCARE-DA), a shared decision aid utilized during the clinical encounter, and examines SDM quality for these encounters. METHODS: Fifty-three women and their physician utilized BCARE-DA and completed surveys measuring satisfaction with Likert-type and open-ended items and women completed the Decision Conflict Scale. Clinic visit transcripts were evaluated for SDM quality using Observer OPTION-5 and Breast Cancer Screening Decision Core Components Checklist. RESULTS: Women and physicians positively evaluated BCARE-DA. Women had low decision conflict. Physicians demonstrated moderate effort toward SDM, greatest in offering options, and lowest for team talk. Physicians demonstrated 2/3 of core SDM elements in 80% to 100% of encounters. CONCLUSION: Preliminary findings suggest specific promise for such Decision Aids to facilitate SDM through understanding of personal risks for breast cancer formulated within each screening option, while some SDM elements likely require additional facilitating.

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women.

PURPOSE: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score.

PURPOSE: This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS: A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS: The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION: PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

Quantitative breast density analysis to predict interval and node-positive cancers in pursuit of improved screening protocols: a case-control study.

BACKGROUND: This study investigates whether quantitative breast density (BD) serves as an imaging biomarker for more intensive breast cancer screening by predicting interval, and node-positive cancers. METHODS: This case-control study of 1204 women aged 47-73 includes 599 cancer cases (302 screen-detected, 297 interval; 239 node-positive, 360 node-negative) and 605 controls. Automated BD software calculated fibroglandular volume (FGV), volumetric breast density (VBD) and density grade (DG). A radiologist assessed BD using a visual analogue scale (VAS) from 0 to 100. Logistic regression and area under the receiver operating characteristic curves (AUC) determined whether BD could predict mode of detection (screen-detected or interval); node-negative cancers; node-positive cancers, and all cancers vs. controls. RESULTS: FGV, VBD, VAS, and DG all discriminated interval cancers (all p < 0.01) from controls. Only FGV-quartile discriminated screen-detected cancers (p < 0.01). Based on AUC, FGV discriminated all cancer types better than VBD or VAS. FGV showed a significantly greater discrimination of interval cancers, AUC = 0.65, than of screen-detected cancers, AUC = 0.61 (p < 0.01) as did VBD (0.63 and 0.53, respectively, p < 0.001). CONCLUSION: FGV, VBD, VAS and DG discriminate interval cancers from controls, reflecting some masking risk. Only FGV discriminates screen-detected cancers perhaps adding a unique component of breast cancer risk.

A Population-Based Study of Genes Previously Implicated in Breast Cancer.

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).

Framing the Clinical Encounter: Shared Decision-Making, Mammography Screening, and Decision Satisfaction.

The study examines whether physicians' framing of clinical interactions is related to patient shared decision-making (SDM) satisfaction when using a clinical decision support tool (CDST) concerning mammographic screening. To answer this question, we combined (a) system log data from a CDST, (b) content coding of the physicians' message framing while using the CDST, and (c) a post-visit patient survey to assess SDM satisfaction concerning screening mammography. Results suggest that two types of message frames - consequence frames and numerical frames - moderated the relationship of the CDST on SDM satisfaction. When the CDST displayed low risk of breast cancer for a patient, physicians were able to improve the cognitive aspects of SDM satisfaction by framing the consequences of mammography screening in positive terms. However, when the physician delivered the numerical information in relative, rather than absolute terms, the patient's SDM satisfaction was reduced. Our study advances previous message framing effect research in health communication from experimental settings to clinical encounters. It also discusses the importance of delivering risk-congruent frames in clinical settings.