Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs. METHODS: This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, which were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE. AUDIENCE AND PATIENT POPULATION: The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes. RECOMMENDATION 1: ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence). • Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure. • Use a GLP-1 agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. RECOMMENDATION 2: ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

Population Attributable Risk of Advanced-Stage Breast Cancer by Race and Ethnicity.

Importance: Advanced-stage breast cancer rates vary by race and ethnicity, with Black women having a 2-fold higher rate than White women among regular screeners. Clinical risk factors that explain a large proportion of advanced breast cancers by race and ethnicity are unknown. Objective: To evaluate the population attributable risk proportions (PARPs) for advanced-stage breast cancer (prognostic pathologic stage IIA or higher) associated with clinical risk factors among routinely screened premenopausal and postmenopausal women by race and ethnicity. Design, Setting, and Participants: This cohort study used data collected prospectively from Breast Cancer Surveillance Consortium community-based breast imaging facilities from January 2005 to June 2018. Participants were women aged 40 to 74 years undergoing 3 331 740 annual (prior screening within 11-18 months) or biennial (prior screening within 19-30 months) screening mammograms associated with 1815 advanced breast cancers diagnosed within 2 years of screening examinations. Data analysis was performed from September 2022 to August 2023. Exposures: Heterogeneously or extremely dense breasts, first-degree family history of breast cancer, overweight/obesity (body mass index >25.0), history of benign breast biopsy, and screening interval (biennial vs annual) stratified by menopausal status and race and ethnicity (Asian or Pacific Islander, Black, Hispanic/Latinx, White, other/multiracial). Main Outcomes and Measures: PARPs for advanced breast cancer. Results: Among 904 615 women, median (IQR) age was 57 (50-64) years. Of the 3 331 740 annual or biennial screening mammograms, 10.8% were for Asian or Pacific Islander women; 9.5% were for Black women; 5.3% were for Hispanic/Latinx women; 72.0% were for White women; and 2.0% were for women of other races and ethnicities, including those who were Alaska Native, American Indian, 2 or more reported races, or other. Body mass index PARPs were larger for postmenopausal vs premenopausal women (30% vs 22%) and highest for postmenopausal Black (38.6%; 95% CI, 32.0%-44.8%) and Hispanic/Latinx women (31.8%; 95% CI, 25.3%-38.0%) and premenopausal Black women (30.3%; 95% CI, 17.7%-42.0%), with overall prevalence of having overweight/obesity highest in premenopausal Black (84.4%) and postmenopausal Black (85.1%) and Hispanic/Latinx women (72.4%). Breast density PARPs were larger for premenopausal vs postmenopausal women (37% vs 24%, respectively) and highest among premenopausal Asian or Pacific Islander (46.6%; 95% CI, 37.9%-54.4%) and White women (39.8%; 95% CI, 31.7%-47.3%) whose prevalence of dense breasts was high (62%-79%). For premenopausal and postmenopausal women, PARPs were small for family history of breast cancer (5%-8%), history of breast biopsy (7%-12%), and screening interval (2.1%-2.3%). Conclusions and Relevance: In this cohort study among routinely screened women, the proportion of advanced breast cancers attributed to biennial vs annual screening was small. To reduce the number of advanced breast cancer diagnoses, primary prevention should focus on interventions that shift patients with overweight and obesity to normal weight.

Extending the Breast Cancer Surveillance Consortium Model of Invasive Breast Cancer.

PURPOSE: We extended the Breast Cancer Surveillance Consortium (BCSC) version 2 (v2) model of invasive breast cancer risk to include BMI, extended family history of breast cancer, and age at first live birth (version 3 [v3]) to better inform appropriate breast cancer prevention therapies and risk-based screening. METHODS: We used Cox proportional hazards regression to estimate the age- and race- and ethnicity-specific relative hazards for family history of breast cancer, breast density, history of benign breast biopsy, BMI, and age at first live birth for invasive breast cancer in the BCSC cohort. We evaluated calibration using the ratio of expected-to-observed (E/O) invasive breast cancers in the cohort and discrimination using the area under the receiver operating characteristic curve (AUROC). RESULTS: We analyzed data from 1,455,493 women age 35-79 years without a history of breast cancer. During a mean follow-up of 7.3 years, 30,266 women were diagnosed with invasive breast cancer. The BCSC v3 model had an E/O of 1.03 (95% CI, 1.01 to 1.04) and an AUROC of 0.646 for 5-year risk. Compared with the v2 model, discrimination of the v3 model improved most in Asian, White, and Black women. Among women with a BMI of 30.0-34.9 kg/m2, the true-positive rate in women with an estimated 5-year risk of 3% or higher increased from 10.0% (v2) to 19.8% (v3) and the improvement was greater among women with a BMI of ≥35 kg/m2 (7.6%-19.8%). CONCLUSION: The BCSC v3 model updates an already well-calibrated and validated breast cancer risk assessment tool to include additional important risk factors. The inclusion of BMI was associated with the largest improvement in estimated risk for individual women.

Impact of BMI on Prevalence of Dense Breasts by Race and Ethnicity.

BACKGROUND: Density notification laws require notifying women of dense breasts with dense breast prevalence varying by race/ethnicity. We evaluated whether differences in body mass index (BMI) account for differences in dense breasts prevalence by race/ethnicity. METHODS: Prevalence of dense breasts (heterogeneously or extremely dense) according to Breast Imaging Reporting and Data System and obesity (BMI > 30 kg/m2) were estimated from 2,667,207 mammography examinations among 866,033 women in the Breast Cancer Surveillance Consortium (BCSC) from January 2005 through April 2021. Prevalence ratios (PR) for dense breasts relative to overall prevalence by race/ethnicity were estimated by standardizing race/ethnicity prevalence in the BCSC to the 2020 U.S. population, and adjusting for age, menopausal status, and BMI using logistic regression. RESULTS: Dense breasts were most prevalent among Asian women (66.0%) followed by non-Hispanic/Latina (NH) White (45.5%), Hispanic/Latina (45.3%), and NH Black (37.0%) women. Obesity was most prevalent in Black women (58.4%) followed by Hispanic/Latina (39.3%), NH White (30.6%), and Asian (8.5%) women. The adjusted prevalence of dense breasts was 19% higher [PR = 1.19; 95% confidence interval (CI), 1.19-1.20] in Asian women, 8% higher (PR = 1.08; 95% CI, 1.07-1.08) in Black women, the same in Hispanic/Latina women (PR = 1.00; 95% CI, 0.99-1.01), and 4% lower (PR = 0.96; 95% CI, 0.96-0.97) in NH White women relative to the overall prevalence. CONCLUSIONS: Clinically important differences in breast density prevalence are present across racial/ethnic groups after accounting for age, menopausal status, and BMI. IMPACT: If breast density is the sole criterion used to notify women of dense breasts and discuss supplemental screening it may result in implementing inequitable screening strategies across racial/ethnic groups. See related In the Spotlight, p. 1479.

The effectiveness and value of gene therapy for hemophilia: A Summary from the Institute for Clinical and Economic Review's California Technology Assessment Forum.

DISCLOSURES: Dr Tice and Mr Sarker received ICER grants during the conduct of the study. Dr Moradi, Ms Herce-Hagiwara, Dr Faghim, Dr Agboola, Dr Rind, and Dr Pearson reports grants from Arnold Ventures, grants from Blue Cross Blue Shield of MA, grants from California Healthcare Foundation, grants from The Commonwealth Fund, grants from The Peterson Center on Healthcare, during the conduct of the study; other from Aetna, other from America's Health Insurance Plans, other from Anthem, other from AbbVie, other from Alnylam, other from AstraZeneca, other from Biogen, other from Blue Shield of CA, other from Cambia Health Services, other from CVS, other from Editas, other from Express Scripts, other from Genentech/Roche, other from GlaxoSmithKline, other from Harvard Pilgrim, other from Health Care Service Corporation, other from Health Partners, other from Johnson & Johnson (Janssen), other from Kaiser Permanente, other from LEO Pharma, other from Mallinckrodt, other from Merck, other from Novartis, other from National Pharmaceutical Council, other from Premera, other from Prime Therapeutics, other from Regeneron, other from Sanofi, other from Spark Therapeutics, other from United Healthcare, other from HealthFirst, other from Pfizer, other from Boehringer-Ingelheim, other from uniQure, other from Evolve Pharmacy Solutions, other from Humana, other from Sun Life, outside the submitted work.

Cumulative 6-Year Risk of Screen-Detected Ductal Carcinoma In Situ by Screening Frequency.

Importance: Detection of ductal carcinoma in situ (DCIS) by mammography screening is a controversial outcome with potential benefits and harms. The association of mammography screening interval and woman's risk factors with the likelihood of DCIS detection after multiple screening rounds is poorly understood. Objective: To develop a 6-year risk prediction model for screen-detected DCIS according to mammography screening interval and women's risk factors. Design, Setting, and Participants: This Breast Cancer Surveillance Consortium cohort study assessed women aged 40 to 74 years undergoing mammography screening (digital mammography or digital breast tomosynthesis) from January 1, 2005, to December 31, 2020, at breast imaging facilities within 6 geographically diverse registries of the consortium. Data were analyzed between February and June 2022. Exposures: Screening interval (annual, biennial, or triennial), age, menopausal status, race and ethnicity, family history of breast cancer, benign breast biopsy history, breast density, body mass index, age at first birth, and false-positive mammography history. Main Outcomes and Measures: Screen-detected DCIS defined as a DCIS diagnosis within 12 months after a positive screening mammography result, with no concurrent invasive disease. Results: A total of 916 931 women (median [IQR] age at baseline, 54 [46-62] years; 12% Asian, 9% Black, 5% Hispanic/Latina, 69% White, 2% other or multiple races, and 4% missing) met the eligibility criteria, with 3757 screen-detected DCIS diagnoses. Screening round-specific risk estimates from multivariable logistic regression were well calibrated (expected-observed ratio, 1.00; 95% CI, 0.97-1.03) with a cross-validated area under the receiver operating characteristic curve of 0.639 (95% CI, 0.630-0.648). Cumulative 6-year risk of screen-detected DCIS estimated from screening round-specific risk estimates, accounting for competing risks of death and invasive cancer, varied widely by all included risk factors. Cumulative 6-year screen-detected DCIS risk increased with age and shorter screening interval. Among women aged 40 to 49 years, the mean 6-year screen-detected DCIS risk was 0.30% (IQR, 0.21%-0.37%) for annual screening, 0.21% (IQR, 0.14%-0.26%) for biennial screening, and 0.17% (IQR, 0.12%-0.22%) for triennial screening. Among women aged 70 to 74 years, the mean cumulative risks were 0.58% (IQR, 0.41%-0.69%) after 6 annual screens, 0.40% (IQR, 0.28%-0.48%) for 3 biennial screens, and 0.33% (IQR, 0.23%-0.39%) after 2 triennial screens. Conclusions and Relevance: In this cohort study, 6-year screen-detected DCIS risk was higher with annual screening compared with biennial or triennial screening intervals. Estimates from the prediction model, along with risk estimates of other screening benefits and harms, could help inform policy makers' discussions of screening strategies.

Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians.

DESCRIPTION: The purpose of this guideline from the American College of Physicians (ACP) is to present updated clinical recommendations on nonpharmacologic and pharmacologic interventions as initial and second-line treatments during the acute phase of a major depressive disorder (MDD) episode, based on the best available evidence on the comparative benefits and harms, consideration of patient values and preferences, and cost. METHODS: The ACP Clinical Guidelines Committee based these recommendations on an updated systematic review of the evidence. AUDIENCE AND PATIENT POPULATION: The audience for this guideline includes clinicians caring for adult patients in the acute phase of MDD in ambulatory care. The patient population includes adults in the acute phase of MDD. RECOMMENDATION 1A: ACP recommends monotherapy with either cognitive behavioral therapy or a second-generation antidepressant as initial treatment in patients in the acute phase of moderate to severe major depressive disorder (strong recommendation; moderate-certainty evidence). RECOMMENDATION 1B: ACP suggests combination therapy with cognitive behavioral therapy and a second-generation antidepressant as initial treatment in patients in the acute phase of moderate to severe major depressive disorder (conditional recommendation; low-certainty evidence). The informed decision on the options of monotherapy with cognitive behavioral therapy versus second-generation antidepressants or combination therapy should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients' specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences. RECOMMENDATION 2: ACP suggests monotherapy with cognitive behavioral therapy as initial treatment in patients in the acute phase of mild major depressive disorder (conditional recommendation; low-certainty evidence). RECOMMENDATION 3: ACP suggests one of the following options for patients in the acute phase of moderate to severe major depressive disorder who did not respond to initial treatment with an adequate dose of a second-generation antidepressant: • Switching to or augmenting with cognitive behavioral therapy (conditional recommendation; low-certainty evidence) • Switching to a different second-generation antidepressant or augmenting with a second pharmacologic treatment (see Clinical Considerations) (conditional recommendation; low-certainty evidence) The informed decision on the options should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients' specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences.

Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians.

DESCRIPTION: This guideline updates the 2017 American College of Physicians (ACP) recommendations on pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults. METHODS: The ACP Clinical Guidelines Committee based these recommendations on an updated systematic review of evidence and graded them using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. AUDIENCE AND PATIENT POPULATION: The audience for this guideline includes all clinicians. The patient population includes adults with primary osteoporosis or low bone mass. RECOMMENDATION 1A: ACP recommends that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis (strong recommendation; high-certainty evidence). RECOMMENDATION 1B: ACP suggests that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis (conditional recommendation; low-certainty evidence). RECOMMENDATION 2A: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; moderate-certainty evidence). RECOMMENDATION 2B: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; low-certainty evidence). RECOMMENDATION 3: ACP suggests that clinicians use the sclerostin inhibitor (romosozumab, moderate-certainty evidence) or recombinant PTH (teriparatide, low-certainty evidence), followed by a bisphosphonate, to reduce the risk of fractures only in females with primary osteoporosis with very high risk of fracture (conditional recommendation). RECOMMENDATION 4: ACP suggests that clinicians take an individualized approach regarding whether to start pharmacologic treatment with a bisphosphonate in females over the age of 65 with low bone mass (osteopenia) to reduce the risk of fractures (conditional recommendation; low-certainty evidence).

Cumulative Probability of False-Positive Results After 10 Years of Screening With Digital Breast Tomosynthesis vs Digital Mammography.

Importance: Breast cancer screening with digital breast tomosynthesis may decrease false-positive results compared with digital mammography. Objective: To estimate the probability of receiving at least 1 false-positive result after 10 years of screening with digital breast tomosynthesis vs digital mammography in the US. Design, Setting, and Participants: An observational comparative effectiveness study with data collected prospectively for screening examinations was performed between January 1, 2005, and December 31, 2018, at 126 radiology facilities in the Breast Cancer Surveillance Consortium. Analysis included 903 495 individuals aged 40 to 79 years. Data analysis was conducted from February 9 to September 7, 2021. Exposures: Screening modality, screening interval, age, and Breast Imaging Reporting and Data System breast density. Main Outcomes and Measures: Cumulative risk of at least 1 false-positive recall for further imaging, short-interval follow-up recommendation, and biopsy recommendation after 10 years of annual or biennial screening with digital breast tomosynthesis vs digital mammography, accounting for competing risks of breast cancer diagnosis and death. Results: In this study of 903 495 women, 2 969 055 nonbaseline screening examinations were performed with interpretation by 699 radiologists. Mean (SD) age of the women at the time of the screening examinations was 57.6 (9.9) years, and 58% of the examinations were in individuals younger than 60 years and 46% were performed in women with dense breasts. A total of 15% of examinations used tomosynthesis. For annual screening, the 10-year cumulative probability of at least 1 false-positive result was significantly lower with tomosynthesis vs digital mammography for all outcomes: 49.6% vs 56.3% (difference, -6.7; 95% CI, -7.4 to -6.1) for recall, 16.6% vs 17.8% (difference, -1.1; 95% CI, -1.7 to -0.6) for short-interval follow-up recommendation, and 11.2% vs 11.7% (difference, -0.5; 95% CI, -1.0 to -0.1) for biopsy recommendation. For biennial screening, the cumulative probability of a false-positive recall was significantly lower for tomosynthesis vs digital mammography (35.7% vs 38.1%; difference, -2.4; 95% CI, -3.4 to -1.5), but cumulative probabilities did not differ significantly by modality for short-interval follow-up recommendation (10.3% vs 10.5%; difference, -0.1; 95% CI, -0.7 to 0.5) or biopsy recommendation (6.6% vs 6.7%; difference, -0.1; 95% CI, -0.5 to 0.4). Decreases in cumulative probabilities of false-positive results with tomosynthesis vs digital mammography were largest for annual screening in women with nondense breasts (differences for recall, -6.5 to -12.8; short-interval follow-up, 0.1 to -5.2; and biopsy recommendation, -0.5 to -3.1). Regardless of modality, cumulative probabilities of false-positive results were substantially lower for biennial vs annual screening (overall recall, 35.7 to 38.1 vs 49.6 to 56.3; short-interval follow-up, 10.3 to 10.5 vs 16.6 to 17.8; and biopsy recommendation, 6.6 to 6.7 vs 11.2 to 11.7); older vs younger age groups (eg, among annual screening in women ages 70-79 vs 40-49, recall, 39.8 to 47.0 vs 60.8 to 68.0; short-interval follow-up, 13.3 to 14.2 vs 20.7 to 20.9; and biopsy recommendation, 9.1 to 9.3 vs 13.2 to 13.4); and women with entirely fatty vs extremely dense breasts (eg, among annual screening in women aged 50-59 years, recall, 29.1 to 36.3 vs 58.8 to 60.4; short-interval follow-up, 8.9 to 11.6 vs 19.5 to 19.8; and biopsy recommendation, 4.9 to 8.0 vs 15.1 to 15.3). Conclusions and Relevance: In this comparative effectiveness study, 10-year cumulative probabilities of false-positive results were lower on digital breast tomosynthesis vs digital mammography. Biennial screening interval, older age, and nondense breasts were associated with larger reductions in false-positive probabilities than screening modality.

The Cost-Effectiveness of Belimumab and Voclosporin for Patients with Lupus Nephritis in the United States.

BACKGROUND AND OBJECTIVES: Despite existing therapies, people with lupus nephritis progress to kidney failure and have reduced life expectancy. Belimumab and voclosporin are two new disease-modifying therapies recently approved for the treatment of lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A de novo economic model was developed to estimate the cost-effectiveness of these therapies, including the following health states: "complete response," "partial response," and "active disease" defined by eGFR and proteinuria changes, kidney failure, and death. Short-term data and mean cohort characteristics were sourced from pivotal clinical trials of belimumab (the Belimumab International Study in Lupus Nephritis) and voclosporin (the Aurinia Urinary Protection Reduction Active-Lupus with Voclosporin trial and Aurinia Renal Response in Active Lupus With Voclosporin). Risk of mortality and kidney failure were on the basis of survival modeling using published Kaplan-Meier data. Each drug was compared with the standard of care as represented by the comparator arm in its respective pivotal trial(s) using US health care sector perspective, with a societal perspective also explored. RESULTS: In the health care perspective probabilistic analysis, the incremental cost-effectiveness ratio for belimumab compared with its control arm was estimated to be approximately $95,000 per quality-adjusted life year. The corresponding incremental ratio for voclosporin compared with its control arm was approximately $150,000 per quality-adjusted life year. Compared with their respective standard care arms, the probabilities of belimumab and voclosporin being cost effective at a threshold of $150,000 per quality-adjusted life year were 69% and 49%, respectively. Cost-effectiveness was dependent on assumptions made regarding survival in response states, costs and utilities in active disease, and the utilities in response states. In the analysis from a societal perspective, the incremental ratio for belimumab was estimated to be approximately $66,000 per quality-adjusted life year, and the incremental ratio for voclosporin was estimated to be approximately $133,000 per quality-adjusted life year. CONCLUSIONS: Compared with their respective standard care arms, belimumab but not voclosporin met willingness-to-pay thresholds of $100,000 per quality-adjusted life year. Despite potential clinical superiority in the informing trials, there remains high uncertainty around the cost-effectiveness of voclosporin.

Cumulative Advanced Breast Cancer Risk Prediction Model Developed in a Screening Mammography Population.

BACKGROUND: Estimating advanced breast cancer risk in women undergoing annual or biennial mammography could identify women who may benefit from less or more intensive screening. We developed an actionable model to predict cumulative 6-year advanced cancer (prognostic pathologic stage II or higher) risk according to screening interval. METHODS: We included 931 186 women aged 40-74 years in the Breast Cancer Surveillance Consortium undergoing 2 542 382 annual (prior mammogram within 11-18 months) or 752 049 biennial (prior within 19-30 months) screening mammograms. The prediction model includes age, race and ethnicity, body mass index, breast density, family history of breast cancer, and prior breast biopsy subdivided by menopausal status and screening interval. We used fivefold cross-validation to internally validate model performance. We defined higher than 95th percentile as high risk (>0.658%), higher than 75th percentile to 95th or less percentile as intermediate risk (0.380%-0.658%), and 75th or less percentile as low to average risk (<0.380%). RESULTS: Obesity, high breast density, and proliferative disease with atypia were strongly associated with advanced cancer. The model is well calibrated and has an area under the receiver operating characteristics curve of 0.682 (95% confidence interval = 0.670 to 0.694). Based on women's predicted advanced cancer risk under annual and biennial screening, 69.1% had low or average risk regardless of screening interval, 12.4% intermediate risk with biennial screening and average risk with annual screening, and 17.4% intermediate or high risk regardless of screening interval. CONCLUSION: Most women have low or average advanced cancer risk and can undergo biennial screening. Intermediate-risk women may consider annual screening, and high-risk women may consider supplemental imaging in addition to annual screening.

A case-case analysis of women with breast cancer: predictors of interval vs screen-detected cancer.

PURPOSE: The Breast Cancer Surveillance Consortium (BCSC) model is a widely used risk model that predicts 5- and 10-year risk of developing invasive breast cancer for healthy women aged 35-74 years. Women with high BCSC risk may also be at elevated risk to develop interval cancers, which present symptomatically in the year following a normal screening mammogram. We examined the association between high BCSC risk (defined as the top 2.5% by age) and breast cancers presenting as interval cancers. METHODS: We conducted a case-case analysis among women with breast cancer in which we compared the mode of detection and tumor characteristics of patients in the top 2.5% BCSC risk by age with age-matched (1:2) patients in the lower 97.5% risk. We constructed logistic regression models to estimate the odds ratio (OR) of presenting with interval cancers, and poor prognosis tumor features, between women from the top 2.5% and bottom 97.5% of BCSC risk. RESULTS: Our analysis included 113 breast cancer patients in the top 2.5% of risk for their age and 226 breast cancer patients in the lower 97.5% of risk. High-risk patients were more likely to have presented with an interval cancer within one year of a normal screening, OR 6.62 (95% CI 3.28-13.4, p < 0.001). These interval cancers were also more likely to be larger, node positive, and higher stage than the screen-detected cancers. CONCLUSION: Breast cancer patients in the top 2.5% of BCSC risk for their age were more likely to present with interval cancers. The BCSC model could be used to identify healthy women who may benefit from intensified screening.

Comparing Mammographic Density Assessed by Digital Breast Tomosynthesis or Digital Mammography: The Breast Cancer Surveillance Consortium.

Background Consistency in reporting Breast Imaging Reporting and Data System (BI-RADS) breast density on mammograms is important because breast density is used for breast cancer risk assessment and is reported directly to women and clinicians to inform decisions about supplemental screening. Purpose To assess the consistency of BI-RADS density reporting between digital breast tomosynthesis (DBT) and digital mammography (DM) and evaluate density as a breast cancer risk factor when assessed using DM versus DBT. Materials and Methods The Breast Cancer Surveillance Consortium is a prospective cohort study of women undergoing mammography with DM or DBT. This secondary analysis included women aged 40-79 years who underwent at least two screening mammography examinations less than 36 months apart. Percentage agreement and κ statistic were estimated for pairs of BI-RADS density assessments. Cox proportional hazards regression was used to calculate hazard ratios (HRs) of breast density as a risk factor for invasive breast cancer. Results A total of 403 326 pairs of mammograms from 342 149 women were evaluated. There were no significant differences in breast density assessment in pairs consisting of one DM and one DBT examination (57 516 of 74 729 [77%]; κ = 0.64), two DM examinations (238 678 of 301 743 [79%]; κ = 0.67), and two DBT examinations (20 763 of 26 854 [77%]; κ = 0.65). Results were similar when restricting the analyses to pairs read by the same radiologist. The breast cancer HRs for breast density were similar for DM and DBT (P = .45 for interaction). The HRs for density acquired using DM and DBT, respectively, were 0.55 (95% CI: 0.49, 0.63) and 0.37 (95% CI: 0.21, 0.66) for almost entirely fat, 1.47 (95% CI: 1.37, 1.58) and 1.36 (95% CI: 1.02, 1.82) for heterogeneously dense, and 1.72 (95% CI: 1.54, 1.93) and 2.05 (95% CI: 1.25, 3.36) for extremely dense breasts. Conclusion Radiologist reporting of Breast Imaging Reporting and Data System density obtained with digital breast tomosynthesis did not differ from that obtained with digital mammography. © RSNA, 2021 Online supplemental material is available for this article.

The effectiveness and value of eculizumab and efgartigimod for generalized myasthenia gravis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Agboola, Nikitin, and Pearson are employed by ICER. Through their affiliated institutions, Tice, Touchette, and Lien received funding from ICER for the work described in this summary.

Acceptability of an mHealth breast cancer risk-reduction intervention promoting risk assessment, education, and discussion of risk in the primary care setting.

BACKGROUND: Breast cancer risk assessment tools and risk reduction strategies have advanced significantly over the past few decades but are underutilized in practice, due in part to limited acceptability by patients and physicians. We implemented a tablet-based Breast Cancer Risk Education Intervention (BreastCARE) tailored towards increasing patients' knowledge about their individual risk of developing breast cancer, increasing patient-physician discussion of breast cancer risk reduction practices, and increasing participation in recommended screening. METHODS: We surveyed patients and physicians who received the BreastCARE intervention and analyzed their satisfaction and acceptability of the intervention. We compared patient satisfaction measures by race/ethnicity and used multivariable logistic regression models to examine the effect of race/ethnicity on measures of patient satisfaction with the tablet-based risk assessment and with the breast cancer risk report. We also compared measures of physician satisfaction by resident vs. attending/NP status. Finally, we identified patients' and physicians' suggestions for implementation. RESULTS: Overall, both patients and physicians were highly satisfied with BreastCARE, with some variation by patient race/ethnicity and breast cancer risk status. The risk assessment tool and accompanying risk report helped transmit complex information in an efficient way. CONCLUSIONS: Patient self-administered risk assessment with a health education component at the point of care is acceptable for both patients and physicians, and represents a novel approach to facilitating health promotion. This risk assessment tool should be made routine in primary care accompanied by results that are easy for the patient to understand and actionable for the clinician.

The effectiveness and value of belimumab and voclosporin for lupus nephritis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Pearson is employed by ICER. Through their affiliated institutions, Tice, Mandrik, Thokala, and Fotheringham received funding from ICER for the work described in this summary.

Association of Endogenous Pregnenolone, Progesterone, and Related Metabolites with Risk of Endometrial and Ovarian Cancers in Postmenopausal Women: The B∼FIT Cohort.

BACKGROUND: Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism. METHODS: Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992-1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk. RESULTS: Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85-4.11); P trend = 0.17] or ovarian cancer risk [1.16 (0.58-2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09-0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18-0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39-6.93); 0.01]. CONCLUSIONS: Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer. IMPACT: While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

Elevated risk thresholds predict endocrine risk-reducing medication use in the Athena screening registry.

Risk-reducing endocrine therapy use, though the benefit is validated, is extremely low. The FDA has approved tamoxifen and raloxifene for a 5-year Breast Cancer Risk Assessment Tool (BCRAT) risk ≥ 1.67%. We examined the threshold at which high-risk women are likely to be using endocrine risk-reducing therapies among Athena Breast Health Network participants from 2011-2018. We identified high-risk women by a 5-year BCRAT risk ≥ 1.67% and those in the top 10% and 2.5% risk thresholds by age. We estimated the odds ratio (OR) of current medication use based on these thresholds using logistic regression. One thousand two hundred and one (1.2%) of 104,223 total participants used medication. Of the 33,082 participants with 5-year BCRAT risk ≥ 1.67%, 772 (2.3%) used medication. Of 2445 in the top 2.5% threshold, 209 (8.6%) used medication. Participants whose 5-year risk exceeded 1.67% were more likely to use medication than those whose risk was below this threshold, OR 3.94 (95% CI = 3.50-4.43). The top 2.5% was most strongly associated with medication usage, OR 9.50 (8.13-11.09) compared to the bottom 97.5%. Women exceeding a 5-year BCRAT ≥ 1.67% had modest medication use. We demonstrate that women in the top 2.5% have higher odds of medication use than those in the bottom 97.5% and compared to a risk of 1.67%. The top 2.5% threshold would more effectively target medication use and is being tested prospectively in a randomized control clinical trial.

Development and pilot of an online, personalized risk assessment tool for a breast cancer precision medicine trial.

Breast cancer risk reduction has been validated by large-scale clinical trials, but uptake remains low. A risk communication tool could provide personalized risk-reduction information for high-risk women. A low-literacy-friendly, visual, and personalized tool was designed as part of the Women Informed to Screen Depending On Measures of risk (WISDOM) study. The tool integrates genetic, polygenic, and lifestyle factors, and quantifies the risk-reduction from undertaking medication and lifestyle interventions. The development and design process utilized feedback from clinicians, decision-making scientists, software engineers, and patient advocates. We piloted the tool with 17 study participants, collecting quantitative and qualitative feedback. Overall, participants felt they better understood their personalized breast cancer risk, were motivated to reduce their risk, and considered lifestyle interventions. The tool will be used to evaluate whether risk-based screening leads to more informed decisions and higher uptake of risk-reduction interventions among those most likely to benefit.