Association Between False-Positive Results and Return to Screening Mammography in the Breast Cancer Surveillance Consortium Cohort.

BACKGROUND: False-positive results on screening mammography may affect women's willingness to return for future screening. OBJECTIVE: To evaluate the association between screening mammography results and the probability of subsequent screening. DESIGN: Cohort study. SETTING: 177 facilities participating in the Breast Cancer Surveillance Consortium (BCSC). PATIENTS: 3 529 825 screening mammograms (3 184 482 true negatives and 345 343 false positives) performed from 2005 to 2017 among 1 053 672 women aged 40 to 73 years without a breast cancer diagnosis. MEASUREMENTS: Mammography results (true-negative result or false-positive recall with a recommendation for immediate additional imaging only, short-interval follow-up, or biopsy) from 1 or 2 screening mammograms. Absolute differences in the probability of returning for screening within 9 to 30 months of false-positive versus true-negative screening results were estimated, adjusting for race, ethnicity, age, time since last mammogram, BCSC registry, and clustering within women and facilities. RESULTS: Women were more likely to return after a true-negative result (76.9% [95% CI, 75.1% to 78.6%]) than after a false-positive recall for additional imaging only (adjusted absolute difference, -1.9 percentage points [CI, -3.1 to -0.7 percentage points]), short-interval follow-up (-15.9 percentage points [CI, -19.7 to -12.0 percentage points]), or biopsy (-10.0 percentage points [CI, -14.2 to -5.9 percentage points]). Asian and Hispanic/Latinx women had the largest decreases in the probability of returning after a false positive with a recommendation for short-interval follow-up (-20 to -25 percentage points) or biopsy (-13 to -14 percentage points) versus a true negative. Among women with 2 screening mammograms within 5 years, a false-positive result on the second was associated with a decreased probability of returning for a third regardless of the first screening result. LIMITATION: Women could receive care at non-BCSC facilities. CONCLUSION: Women were less likely to return to screening after false-positive mammography results, especially with recommendations for short-interval follow-up or biopsy, raising concerns about continued participation in routine screening among these women at increased breast cancer risk. PRIMARY FUNDING SOURCE: National Cancer Institute.

Screening Mammography for 40-Year-Old Women-Whose Decision?

This Viewpoint discusses the potential risks and benefits for starting screening at 40 rather than 50 years of age and whether clinicians or patients should decide based on risk rather than age.

Breast Cancer Screening Using Mammography, Digital Breast Tomosynthesis, and Magnetic Resonance Imaging by Breast Density.

Importance: Information on long-term benefits and harms of screening with digital breast tomosynthesis (DBT) with or without supplemental breast magnetic resonance imaging (MRI) is needed for clinical and policy discussions, particularly for patients with dense breasts. Objective: To project long-term population-based outcomes for breast cancer mammography screening strategies (DBT or digital mammography) with or without supplemental MRI by breast density. Design, Setting, and Participants: Collaborative modeling using 3 Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation models informed by US Breast Cancer Surveillance Consortium data. Simulated women born in 1980 with average breast cancer risk were included. Modeling analyses were conducted from January 2020 to December 2023. Intervention: Annual or biennial mammography screening with or without supplemental MRI by breast density starting at ages 40, 45, or 50 years through age 74 years. Main outcomes and Measures: Lifetime breast cancer deaths averted, false-positive recall and false-positive biopsy recommendations per 1000 simulated women followed-up from age 40 years to death summarized as means and ranges across models. Results: Biennial DBT screening for all simulated women started at age 50 vs 40 years averted 7.4 vs 8.5 breast cancer deaths, respectively, and led to 884 vs 1392 false-positive recalls and 151 vs 221 false-positive biopsy recommendations, respectively. Biennial digital mammography had similar deaths averted and slightly more false-positive test results than DBT screening. Adding MRI for women with extremely dense breasts to biennial DBT screening for women aged 50 to 74 years increased deaths averted (7.6 vs 7.4), false-positive recalls (919 vs 884), and false-positive biopsy recommendations (180 vs 151). Extending supplemental MRI to women with heterogeneously or extremely dense breasts further increased deaths averted (8.0 vs 7.4), false-positive recalls (1088 vs 884), and false-positive biopsy recommendations (343 vs 151). The same strategy for women aged 40 to 74 years averted 9.5 deaths but led to 1850 false-positive recalls and 628 false-positive biopsy recommendations. Annual screening modestly increased estimated deaths averted but markedly increased estimated false-positive results. Conclusions and relevance: In this model-based comparative effectiveness analysis, supplemental MRI for women with dense breasts added to DBT screening led to greater benefits and increased harms. The balance of this trade-off for supplemental MRI use was more favorable when MRI was targeted to women with extremely dense breasts who comprise approximately 10% of the population.

Performance of Supplemental US Screening in Women with Dense Breasts and Varying Breast Cancer Risk: Results from the Breast Cancer Surveillance Consortium.

Background It is unclear whether breast US screening outcomes for women with dense breasts vary with levels of breast cancer risk. Purpose To evaluate US screening outcomes for female patients with dense breasts and different estimated breast cancer risk levels. Materials and Methods This retrospective observational study used data from US screening examinations in female patients with heterogeneously or extremely dense breasts conducted from January 2014 to October 2020 at 24 radiology facilities within three Breast Cancer Surveillance Consortium (BCSC) registries. The primary outcomes were the cancer detection rate, false-positive biopsy recommendation rate, and positive predictive value of biopsies performed (PPV3). Risk classification of participants was performed using established BCSC risk prediction models of estimated 6-year advanced breast cancer risk and 5-year invasive breast cancer risk. Differences in high- versus low- or average-risk categories were assessed using a generalized linear model. Results In total, 34 791 US screening examinations from 26 489 female patients (mean age at screening, 53.9 years ± 9.0 [SD]) were included. The overall cancer detection rate per 1000 examinations was 2.0 (95% CI: 1.6, 2.4) and was higher in patients with high versus low or average risk of 6-year advanced breast cancer (5.5 [95% CI: 3.5, 8.6] vs 1.3 [95% CI: 1.0, 1.8], respectively; P = .003). The overall false-positive biopsy recommendation rate per 1000 examinations was 29.6 (95% CI: 22.6, 38.6) and was higher in patients with high versus low or average 6-year advanced breast cancer risk (37.0 [95% CI: 28.2, 48.4] vs 28.1 [95% CI: 20.9, 37.8], respectively; P = .04). The overall PPV3 was 6.9% (67 of 975; 95% CI: 5.3, 8.9) and was higher in patients with high versus low or average 6-year advanced cancer risk (15.0% [15 of 100; 95% CI: 9.9, 22.2] vs 4.9% [30 of 615; 95% CI: 3.3, 7.2]; P = .01). Similar patterns in outcomes were observed by 5-year invasive breast cancer risk. Conclusion The cancer detection rate and PPV3 of supplemental US screening increased with the estimated risk of advanced and invasive breast cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Helbich and Kapetas in this issue.

Relative Timing of Mammography and MRI for Breast Cancer Screening: Impact on Performance Evaluation.

OBJECTIVE: Mammography and MRI screening typically occur in combination or in alternating sequence. We compared multimodality screening performance accounting for the relative timing of mammography and MRI and overlapping follow-up periods. METHODS: We identified 8,260 screening mammograms performed 2005 to 2017 in the Breast Cancer Surveillance Consortium, paired with screening MRIs within ±90 days (combined screening) or 91 to 270 days (alternating screening). Performance for combined screening (cancer detection rate [CDR] per 1,000 examinations and sensitivity) was calculated with 1-year follow-up for each modality, and with a single follow-up period treating the two tests as a single test. Alternating screening performance was calculated with 1-year follow-up for each modality and also with follow-up ending at the next screen if within 1 year (truncated follow-up). RESULTS: For 3,810 combined screening pairs, CDR per 1,000 screens was 6.8 (95% confidence interval [CI]: 4.6-10.0) for mammography and 12.3 (95% CI: 9.3-16.4) for MRI as separate tests compared with 13.1 (95% CI: 10.0-17.3) as a single combined test. Sensitivity of each test was 48.1% (35.0%-61.5%) for mammography and 79.7% (95% CI: 67.7%-88.0%) for MRI compared with 96.2% (95% CI: 85.9%-99.0%) for combined screening. For 4,450 alternating screening pairs, mammography CDR per 1,000 screens changed from 3.6 (95% CI: 2.2-5.9) to zero with truncated follow-up; sensitivity was incalculable (denominator = 0). MRI CDR per 1,000 screens changed from 12.1 (95% CI 9.3-15.8) to 11.7 (95% CI: 8.9-15.3) with truncated follow-up; sensitivity changed from 75.0% (95% CI 63.8%-83.6%) to 86.7% (95% CI 75.5%-93.2%). DISCUSSION: Updating auditing approaches to account for combined and alternating screening sequencing and to address outcome attribution issues arising from overlapping follow-up periods can improve the accuracy of multimodality screening performance evaluation.

Multivariate testing and effect size measures for batch effect evaluation in radiomic features.

While precision medicine applications of radiomics analysis are promising, differences in image acquisition can cause "batch effects" that reduce reproducibility and affect downstream predictive analyses. Harmonization methods such as ComBat have been developed to correct these effects, but evaluation methods for quantifying batch effects are inconsistent. In this study, we propose the use of the multivariate statistical test PERMANOVA and the Robust Effect Size Index (RESI) to better quantify and characterize batch effects in radiomics data. We evaluate these methods in both simulated and real radiomics features extracted from full-field digital mammography (FFDM) data. PERMANOVA demonstrated higher power than standard univariate statistical testing, and RESI was able to interpretably quantify the effect size of site at extremely large sample sizes. These methods show promise as more powerful and interpretable methods for the detection and quantification of batch effects in radiomics studies.

Breast density knowledge and willingness to delay treatment for pre-operative breast cancer imaging among women with a personal history of breast cancer.

BACKGROUND: Following a breast cancer diagnosis, it is uncertain whether women's breast density knowledge influences their willingness to undergo pre-operative imaging to detect additional cancer in their breasts. We evaluated women's breast density knowledge and their willingness to delay treatment for pre-operative testing. METHODS: We surveyed women identified in the Breast Cancer Surveillance Consortium aged ≥ 18 years, with first breast cancer diagnosed within the prior 6-18 months, who had at least one breast density measurement within the 5 years prior to their diagnosis. We assessed women's breast density knowledge and correlates of willingness to delay treatment for 6 or more weeks for pre-operative imaging via logistic regression. RESULTS: Survey participation was 28.3% (969/3,430). Seventy-two percent (469/647) of women with dense and 11% (34/322) with non-dense breasts correctly knew their density (p < 0.001); 69% (665/969) of all women knew dense breasts make it harder to detect cancers on a mammogram; and 29% (285/969) were willing to delay treatment ≥ 6 weeks to undergo pre-operative imaging. Willingness to delay treatment did not differ by self-reported density (OR:0.99 for non-dense vs. dense; 95%CI: 0.50-1.96). Treatment with chemotherapy was associated with less willingness to delay treatment (OR:0.67; 95%CI: 0.46-0.96). Having previously delayed breast cancer treatment more than 3 months was associated with an increased willingness to delay treatment for pre-operative imaging (OR:2.18; 95%CI: 1.26-3.77). CONCLUSIONS: Understanding of personal breast density was not associated with willingness to delay treatment 6 or more weeks for pre-operative imaging, but aspects of a woman's treatment experience were. CLINICALTRIALS: GOV : NCT02980848 registered December 2, 2016.

Collaborative Modeling to Compare Different Breast Cancer Screening Strategies: A Decision Analysis for the US Preventive Services Task Force.

Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

Predicting five-year interval second breast cancer risk in women with prior breast cancer.

BACKGROUND: Annual surveillance mammography is recommended for women with a personal history of breast cancer. Risk prediction models that estimate mammography failures such as interval second breast cancers could help to tailor surveillance imaging regimens to women's individual risk profiles. METHODS: In a cohort of women with a history of breast cancer receiving surveillance mammography in the Breast Cancer Surveillance Consortium in 1996-2019, we used Least Absolute Shrinkage and Selection Operator (LASSO)-penalized regression to estimate the probability of an interval second cancer (invasive cancer or ductal carcinoma in situ) in the 1 year after a negative surveillance mammogram. Based on predicted risks from this one-year risk model, we generated cumulative risks of an interval second cancer for the five-year period after each mammogram. Model performance was evaluated using cross-validation in the overall cohort and within race and ethnicity strata. RESULTS: In 173 290 surveillance mammograms, we observed 496 interval cancers. One-year risk models were well-calibrated (expected/observed ratio = 1.00) with good accuracy (area under the receiver operating characteristic curve = 0.64). Model performance was similar across race and ethnicity groups. The median five-year cumulative risk was 1.20% (interquartile range 0.93%-1.63%). Median five-year risks were highest in women who were under age 40 or pre- or perimenopausal at diagnosis and those with estrogen receptor-negative primary breast cancers. CONCLUSIONS: Our risk model identified women at high risk of interval second breast cancers who may benefit from additional surveillance imaging modalities. Risk models should be evaluated to determine if risk-guided supplemental surveillance imaging improves early detection and decreases surveillance failures.

Assessment of salivary cadmium levels and breast density in the Marin Women's Study.

BACKGROUND: We aimed to determine if salivary cadmium (Cd) levels had any association with breast density, hoping to establish a less invasive cost-effective method of stratifying Cd burden as an environmental breast cancer risk factor. METHODS: Salivary Cd levels were quantified from the Marin Women's Study, a Marin County, California population composite. Volumetric compositional breast density (BDsxa ) data were measured by single x-ray absorptiometry techniques. Digital screening mammography was performed by the San Francisco Mammography Registry. Radiologists reviewed mammograms and assigned a Breast Imaging-Reporting and Data System score. Early morning salivary Cd samples were assayed. Association analyses were then performed. RESULTS: Cd was quantifiable in over 90% of saliva samples (mean = 55.7 pg/L, SD = 29). Women with higher saliva Cd levels had a non-significant odds ratio of 1.34 with BI-RAD scores (3 or 4) (95% CI 0.75-2.39, p = 0.329). Cd levels were higher in current smokers (mean = 61.4 pg/L, SD = 34.8) than former smokers or non-smokers. These results were non-significant. Pilot data revealed that higher age and higher BMI were associated with higher BI-RAD scores (p < 0.001). CONCLUSION: Salivary Cd is a viable quantification source in large epidemiologic studies. Association analyses between Cd levels and breast density may provide additional information for breast cancer risk assessment, risk reduction plans, and future research directions. Further work is needed to demonstrate a more robust testing protocol before the extent of its usefulness can be established.

Supplemental magnetic resonance imaging plus mammography compared with magnetic resonance imaging or mammography by extent of breast density.

BACKGROUND: Examining screening outcomes by breast density for breast magnetic resonance imaging (MRI) with or without mammography could inform discussions about supplemental MRI in women with dense breasts. METHODS: We evaluated 52 237 women aged 40-79 years who underwent 2611 screening MRIs alone and 6518 supplemental MRI plus mammography pairs propensity score-matched to 65 810 screening mammograms. Rates per 1000 examinations of interval, advanced, and screen-detected early stage invasive cancers and false-positive recall and biopsy recommendation were estimated by breast density (nondense = almost entirely fatty or scattered fibroglandular densities; dense = heterogeneously/extremely dense) adjusting for registry, examination year, age, race and ethnicity, family history of breast cancer, and prior breast biopsy. RESULTS: Screen-detected early stage cancer rates were statistically higher for MRI plus mammography vs mammography for nondense (9.3 vs 2.9; difference = 6.4, 95% confidence interval [CI] = 2.5 to 10.3) and dense (7.5 vs 3.5; difference = 4.0, 95% CI = 1.4 to 6.7) breasts and for MRI vs MRI plus mammography for dense breasts (19.2 vs 7.5; difference = 11.7, 95% CI = 4.6 to 18.8). Interval rates were not statistically different for MRI plus mammography vs mammography for nondense (0.8 vs 0.5; difference = 0.4, 95% CI = -0.8 to 1.6) or dense breasts (1.5 vs 1.4; difference = 0.0, 95% CI = -1.2 to 1.3), nor were advanced cancer rates. Interval rates were not statistically different for MRI vs MRI plus mammography for nondense (2.6 vs 0.8; difference = 1.8 (95% CI = -2.0 to 5.5) or dense breasts (0.6 vs 1.5; difference = -0.9, 95% CI = -2.5 to 0.7), nor were advanced cancer rates. False-positive recall and biopsy recommendation rates were statistically higher for MRI groups than mammography alone. CONCLUSION: MRI screening with or without mammography increased rates of screen-detected early stage cancer and false-positives for women with dense breasts without a concomitant decrease in advanced or interval cancers.

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.

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.

Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.

Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.

Digital mammography and digital breast tomosynthesis for detecting invasive lobular and ductal carcinoma.

PURPOSE: Invasive lobular carcinoma (ILC) is a distinct histological subtype of breast cancer that can make early detection with mammography challenging. We compared imaging performance of digital breast tomosynthesis (DBT) to digital mammography (DM) for diagnoses of ILC, invasive ductal carcinoma (IDC), and invasive mixed carcinoma (IMC) in a screening population. METHODS: We included screening exams (DM; n = 1,715,249 or DBT; n = 414,793) from 2011 to 2018 among 839,801 women in the Breast Cancer Surveillance Consortium. Examinations were followed for one year to ascertain incident ILC, IDC, or IMC. We measured cancer detection rate (CDR) and interval invasive cancer rate/1000 screening examinations for each histological subtype and stratified by breast density and modality. We calculated relative risk (RR) for DM vs. DBT using log-binomial models to adjust for the propensity of receiving DBT vs. DM. RESULTS: Unadjusted CDR per 1000 mammograms of ILC overall was 0.33 (95%CI: 0.30-0.36) for DM; 0.45 (95%CI: 0.39-0.52) for DBT, and for women with dense breasts- 0.33 (95%CI: 0.29-0.37) for DM and 0.54 (95%CI: 0.43-0.66) for DBT. Similar results were noted for IDC and IMC. Adjusted models showed a significantly increased RR for cancer detection with DBT compared to DM among women with dense breasts for all three histologies (RR; 95%CI: ILC 1.53; 1.09-2.14, IDC 1.21; 1.02-1.44, IMC 1.76; 1.30-2.38), but no significant increase among women with non-dense breasts. CONCLUSION: DBT was associated with higher CDR for ILC, IDC, and IMC for women with dense breasts. Early detection of ILC with DBT may improve outcomes for this distinct clinical entity.

Impact of Surveillance Mammography Intervals Less Than One Year on Performance Measures in Women With a Personal History of Breast Cancer.

OBJECTIVE: When multiple surveillance mammograms are performed within an annual interval, the current guidance for one-year follow-up to determine breast cancer status results in shared follow-up periods in which a single breast cancer diagnosis can be attributed to multiple preceding examinations, posing a challenge for standardized performance assessment. We assessed the impact of using follow-up periods that eliminate the artifactual inflation of second breast cancer diagnoses. MATERIALS AND METHODS: We evaluated surveillance mammograms from 2007-2016 in women with treated breast cancer linked with tumor registry and pathology outcomes. Second breast cancers included ductal carcinoma in situ or invasive breast cancer diagnosed during one-year follow-up. The cancer detection rate, interval cancer rate, sensitivity, and specificity were compared using different follow-up periods: standard one-year follow-up per the American College of Radiology versus follow-up that was shortened at the next surveillance mammogram if less than one year (truncated follow-up). Performance measures were calculated overall and by indication (screening, evaluation for breast problem, and short interval follow-up). RESULTS: Of 117971 surveillance mammograms, 20% (n = 23533) were followed by another surveillance mammogram within one year. Standard follow-up identified 1597 mammograms that were associated with second breast cancers. With truncated follow-up, the breast cancer status of 179 mammograms (11.2%) was revised, resulting in 1418 mammograms associated with unique second breast cancers. The interval cancer rate decreased with truncated versus standard follow-up (3.6 versus 4.9 per 1000 mammograms, respectively), with a difference (95% confidence interval [CI]) of -1.3 (-1.6, -1.1). The overall sensitivity increased to 70.4% from 63.7%, for the truncated versus standard follow-up, with a difference (95% CI) of 6.6% (5.6%, 7.7%). The specificity remained stable at 98.1%. CONCLUSION: Truncated follow-up, if less than one year to the next surveillance mammogram, enabled second breast cancers to be associated with a single preceding mammogram and resulted in more accurate estimates of diagnostic performance for national benchmarks.

Racial and Ethnic Variation in Diagnostic Mammography Performance among Women Reporting a Breast Lump.

BACKGROUND: We evaluated diagnostic mammography among women with a breast lump to determine whether performance varied across racial and ethnic groups. METHODS: This study included 51,014 diagnostic mammograms performed between 2005 and 2018 in the Breast Cancer Surveillance Consortium among Asian/Pacific Islander (12%), Black (7%), Hispanic/Latina (6%), and White (75%) women reporting a lump. Breast cancers occurring within 1 year were ascertained from cancer registry linkages. Multivariable regression was used to adjust performance statistic comparisons for breast cancer risk factors, mammogram modality, demographics, additional imaging, and imaging facility. RESULTS: Cancer detection rates were highest among Asian/Pacific Islander [per 1,000 exams, 84.2 (95% confidence interval (CI): 72.0-98.2)] and Black women [81.4 (95% CI: 69.4-95.2)] and lowest among Hispanic/Latina women [42.9 (95% CI: 34.2-53.6)]. Positive predictive values (PPV) were higher among Black [37.0% (95% CI: 31.2-43.3)] and White [37.0% (95% CI: 30.0-44.6)] women and lowest among Hispanic/Latina women [22.0% (95% CI: 17.2-27.7)]. False-positive results were most common among Asian/Pacific Islander women [per 1,000 exams, 183.9 (95% CI: 126.7-259.2)] and lowest among White women [112.4 (95% CI: 86.1-145.5)]. After adjustment, false-positive and cancer detection rates remained higher for Asian/Pacific Islander and Black women (vs. Hispanic/Latina and White). Adjusted PPV was highest among Asian/Pacific Islander women. CONCLUSIONS: Among women with a lump, Asian/Pacific Islander and Black women were more likely to have cancer detected and more likely to receive a false-positive result compared with White and Hispanic/Latina women. IMPACT: Strategies for optimizing diagnostic mammography among women with a lump may vary by racial/ethnic group, but additional factors that influence performance differences need to be identified. See related In the Spotlight, p. 1479.

Breast cancer risk characteristics of women undergoing whole-breast ultrasound screening versus mammography alone.

BACKGROUND: There are no consensus guidelines for supplemental breast cancer screening with whole-breast ultrasound. However, criteria for women at high risk of mammography screening failures (interval invasive cancer or advanced cancer) have been identified. Mammography screening failure risk was evaluated among women undergoing supplemental ultrasound screening in clinical practice compared with women undergoing mammography alone. METHODS: A total of 38,166 screening ultrasounds and 825,360 screening mammograms without supplemental screening were identified during 2014-2020 within three Breast Cancer Surveillance Consortium (BCSC) registries. Risk of interval invasive cancer and advanced cancer were determined using BCSC prediction models. High interval invasive breast cancer risk was defined as heterogeneously dense breasts and BCSC 5-year breast cancer risk ≥2.5% or extremely dense breasts and BCSC 5-year breast cancer risk ≥1.67%. Intermediate/high advanced cancer risk was defined as BCSC 6-year advanced breast cancer risk ≥0.38%. RESULTS: A total of 95.3% of 38,166 ultrasounds were among women with heterogeneously or extremely dense breasts, compared with 41.8% of 825,360 screening mammograms without supplemental screening (p < .0001). Among women with dense breasts, high interval invasive breast cancer risk was prevalent in 23.7% of screening ultrasounds compared with 18.5% of screening mammograms without supplemental imaging (adjusted odds ratio, 1.35; 95% CI, 1.30-1.39); intermediate/high advanced cancer risk was prevalent in 32.0% of screening ultrasounds versus 30.5% of screening mammograms without supplemental screening (adjusted odds ratio, 0.91; 95% CI, 0.89-0.94). CONCLUSIONS: Ultrasound screening was highly targeted to women with dense breasts, but only a modest proportion were at high mammography screening failure risk. A clinically significant proportion of women undergoing mammography screening alone were at high mammography screening failure risk.

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.