Impact of Artificial Intelligence System and Volumetric Density on Risk Prediction of Interval, Screen-Detected, and Advanced Breast Cancer.

PURPOSE: Artificial intelligence (AI) algorithms improve breast cancer detection on mammography, but their contribution to long-term risk prediction for advanced and interval cancers is unknown. METHODS: We identified 2,412 women with invasive breast cancer and 4,995 controls matched on age, race, and date of mammogram, from two US mammography cohorts, who had two-dimensional full-field digital mammograms performed 2-5.5 years before cancer diagnosis. We assessed Breast Imaging Reporting and Data System density, an AI malignancy score (1-10), and volumetric density measures. We used conditional logistic regression to estimate odds ratios (ORs), 95% CIs, adjusted for age and BMI, and C-statistics (AUC) to describe the association of AI score with invasive cancer and its contribution to models with breast density measures. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance. RESULTS: On mammograms between 2-5.5 years prior to cancer, a one unit increase in AI score was associated with 20% greater odds of invasive breast cancer (OR, 1.20; 95% CI, 1.17 to 1.22; AUC, 0.63; 95% CI, 0.62 to 0.64) and was similarly predictive of interval (OR, 1.20; 95% CI, 1.13 to 1.27; AUC, 0.63) and advanced cancers (OR, 1.23; 95% CI, 1.16 to 1.31; AUC, 0.64) and in dense (OR, 1.18; 95% CI, 1.15 to 1.22; AUC, 0.66) breasts. AI score improved prediction of all cancer types in models with density measures (PLRT values < .001); discrimination improved for advanced cancer (ie, AUC for dense volume increased from 0.624 to 0.679, Δ AUC 0.065, P = .01) but did not reach statistical significance for interval cancer. CONCLUSION: AI imaging algorithms coupled with breast density independently contribute to long-term risk prediction of invasive breast cancers, in particular, advanced cancer.

Leveling the Workload for Radiologists in Diagnostic Mammography: Application of Lean Principles and Heijunka.

To facilitate the delivery of accurate and timely care to patients in complex environments, process improvement methodologies such as Lean can be very effective. Lean is a quality improvement methodology that seeks to add value for patients and employees by continuously improving processes and eliminating waste. At our institution, Lean principles were applied to improve efficiency and minimize waste in the diagnostic breast imaging reading room. This paper describes how we applied Lean principles, including plan-do-study-act testing, level-loading (heijunka), and visual management, to level the workload of the diagnostic radiologists in our practice. Implementation of these principles to improve the diagnostic workflow in breast imaging is described along with examples from our practice, including challenges and future opportunities.

Breast MRI during Neoadjuvant Chemotherapy: Lack of Background Parenchymal Enhancement Suppression and Inferior Treatment Response.

Background Suppression of background parenchymal enhancement (BPE) is commonly observed after neoadjuvant chemotherapy (NAC) at contrast-enhanced breast MRI. It was hypothesized that nonsuppressed BPE may be associated with inferior response to NAC. Purpose To investigate the relationship between lack of BPE suppression and pathologic response. Materials and Methods A retrospective review was performed for women with menopausal status data who were treated for breast cancer by one of 10 drug arms (standard NAC with or without experimental agents) between May 2010 and November 2016 in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2, or I-SPY 2 TRIAL (NCT01042379). Patients underwent MRI at four points: before treatment (T0), early treatment (T1), interregimen (T2), and before surgery (T3). BPE was quantitatively measured by using automated fibroglandular tissue segmentation. To test the hypothesis effectively, a subset of examinations with BPE with high-quality segmentation was selected. BPE change from T0 was defined as suppressed or nonsuppressed for each point. The Fisher exact test and the Z tests of proportions with Yates continuity correction were used to examine the relationship between BPE suppression and pathologic complete response (pCR) in hormone receptor (HR)-positive and HR-negative cohorts. Results A total of 3528 MRI scans from 882 patients (mean age, 48 years ± 10 [standard deviation]) were reviewed and the subset of patients with high-quality BPE segmentation was determined (T1, 433 patients; T2, 396 patients; T3, 380 patients). In the HR-positive cohort, an association between lack of BPE suppression and lower pCR rate was detected at T2 (nonsuppressed vs suppressed, 11.8% [six of 51] vs 28.9% [50 of 173]; difference, 17.1% [95% CI: 4.7, 29.5]; P = .02) and T3 (nonsuppressed vs suppressed, 5.3% [two of 38] vs 27.4% [48 of 175]; difference, 22.2% [95% CI: 10.9, 33.5]; P = .003). In the HR-negative cohort, patients with nonsuppressed BPE had lower estimated pCR rate at all points, but the P values for the association were all greater than .05. Conclusions In hormone receptor-positive breast cancer, lack of background parenchymal enhancement suppression may indicate inferior treatment response. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Philpotts in this issue.

Mammographic Variation Measures, Breast Density, and Breast Cancer Risk.

OBJECTIVE. Our previous work showed that variation measures, which represent breast architecture derived from mammograms, were significantly associated with breast cancer. For replication purposes, we examined the association of three variation measures (variation [V], which is measured in the image domain, and P1 and p1 [a normalized version of P1], which are derived from restricted regions in the Fourier domain) with breast cancer risk in an independent population. We also compared these measures to volumetric density measures (volumetric percent density [VPD] and dense volume [DV]) from a commercial product. MATERIALS AND METHODS. We examined 514 patients with breast cancer and 1377 control patients from a screening practice who were matched for age, date of examination, mammography unit, facility, and state of residence. Spearman rank-order correlation was used to evaluate the monotonic association between measures. Breast cancer associations were estimated using conditional logistic regression, after adjustment for age and body mass index. Odds ratios were calculated per SD increment in mammographic measure. RESULTS. These variation measures were strongly correlated with VPD (correlation, 0.68-0.80) but not with DV (correlation, 0.31-0.48). Similar to previous findings, all variation measures were significantly associated with breast cancer (odds ratio per SD: 1.30 [95% CI, 1.16-1.46] for V, 1.55 [95% CI, 1.35-1.77] for P1, and 1.51 [95% CI, 1.33-1.72] for p1). Associations of volumetric density measures with breast cancer were similar (odds ratio per SD: 1.54 [95% CI, 1.33-1.78] for VPD and 1.34 [95% CI, 1.20-1.50] for DV). When DV was included with each variation measure in the same model, all measures retained significance. CONCLUSION. Variation measures were significantly associated with breast cancer risk (comparable to the volumetric density measures) but were independent of the DV.

Association of Daily Alcohol Intake, Volumetric Breast Density, and Breast Cancer Risk.

High alcohol intake and breast density increase breast cancer (BC) risk, but their interrelationship is unknown. We examined whether volumetric density modifies and/or mediates the alcohol-BC association. BC cases (n = 2233) diagnosed from 2006 to 2013 in the San Francisco Bay area had screening mammograms 6 or more months before diagnosis; controls (n = 4562) were matched on age, mammogram date, race or ethnicity, facility, and mammography machine. Logistic regression was used to estimate alcohol-BC associations adjusted for age, body mass index, and menopause; interaction terms assessed modification. Percent mediation was quantified as the ratio of log (odds ratios [ORs]) from models with and without density measures. Alcohol consumption was associated with increased BC risk (2-sided P trend = .004), as were volumetric percent density (OR = 1.45 per SD, 95% confidence interval [CI] = 1.36 to 1.56) and dense volume (OR = 1.30, 95% CI = 1.24 to 1.37). Breast density did not modify the alcohol-BC association (2-sided P > .10 for all). Dense volume mediated 25.0% (95% CI = 5.5% to 44.4%) of the alcohol-BC association (2-sided P = .01), suggesting alcohol may partially increase BC risk by increasing fibroglandular tissue.

Comparison of Clinical Performance Between Two Generations of Magnetic Resonance-guided Focused Ultrasound Systems in Treatments of Uterine Leiomyomas.

OBJECTIVES: The aim of this study was to evaluate the impact of technology improvements on the outcomes of magnetic resonance-guided focused ultrasound (MRgFUS) treatments of symptomatic uterine leiomyomas (uterine fibroids). The study compared ablation volumes and incidence of adverse events in patient groups treated with two generations of MRgFUS systems from a single vendor. METHODS: The present study describes the results of a retrospective comparative study of two groups of women with symptomatic uterine leiomyomas who were clinically treated with MRgFUS at a single institution. Group 1 (n = 130) was treated using the first-generation system between March 2005 and December 2009. Group 2 (n = 71) was treated using the second-generation between December 2013 and September 2019. RESULTS: The second-generation MRgFUS system resulted in significantly improved nonperfused volume ratios in both dark and bright T2 fibroid categories compared with the first-generation system (dark - 80% versus46 %, p = 0.00002 and bright - 46% versus 32%, p = 0.001). There have been no recorded hospital admissions, no skins burns, and no reported major adverse events since the introduction of this second-generation ExAblate 2100 system with advanced safety and treatment planning features. CONCLUSION: This study has demonstrated that improvements to current MRgFUS technology resulted in significantly increased efficacy and patient safety of clinical treatments of patients with symptomatic uterine leiomyomas.

Evaluation of LIBRA Software for Fully Automated Mammographic Density Assessment in Breast Cancer Risk Prediction.

Background The associations of density measures from the publicly available Laboratory for Individualized Breast Radiodensity Assessment (LIBRA) software with breast cancer have primarily focused on estimates from the contralateral breast at the time of diagnosis. Purpose To evaluate LIBRA measures on mammograms obtained before breast cancer diagnosis and compare their performance to established density measures. Materials and Methods For this retrospective case-control study, full-field digital mammograms in for-processing (raw) and for-presentation (processed) formats were obtained (March 2008 to December 2011) in women who developed breast cancer an average of 2 years later and in age-matched control patients. LIBRA measures included absolute dense area and area percent density (PD) from both image formats. For comparison, dense area and PD were assessed by using the research software (Cumulus), and volumetric PD (VPD) and absolute dense volume were estimated with a commercially available software (Volpara). Density measures were compared by using Spearman correlation coefficients (r), and conditional logistic regression (odds ratios [ORs] and 95% confidence intervals [CIs]) was performed to examine the associations of density measures with breast cancer by adjusting for age and body mass index. Results Evaluated were 437 women diagnosed with breast cancer (median age, 62 years ± 17 [standard deviation]) and 1225 matched control patients (median age, 61 years ± 16). LIBRA PD showed strong correlations with Cumulus PD (r = 0.77-0.84) and Volpara VPD (r = 0.85-0.90) (P < .001 for both). For LIBRA, the strongest breast cancer association was observed for PD from processed images (OR, 1.3; 95% CI: 1.1, 1.5), although the PD association from raw images was not significantly different (OR, 1.2; 95% CI: 1.1, 1.4; P = .25). Slightly stronger breast cancer associations were seen for Cumulus PD (OR, 1.5; 95% CI: 1.3, 1.8; processed images; P = .01) and Volpara VPD (OR, 1.4; 95% CI: 1.2, 1.7; raw images; P = .004) compared with LIBRA measures. Conclusion Automated density measures provided by the Laboratory for Individualized Breast Radiodensity Assessment from raw and processed mammograms correlated with established area and volumetric density measures and showed comparable breast cancer associations. © RSNA, 2020 Online supplemental material is available for this article.

Automated volumetric breast density measures: differential change between breasts in women with and without breast cancer.

BACKGROUND: Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls. METHODS: Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1-5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time. RESULTS: Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (- 0.26% and - 2.10 cm3) than the normal breast (- 0.39% and - 2.74 cm3) for a difference of 0.13% (p value < 0.001) and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (- 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV. CONCLUSION: There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.

Longitudinal Changes in Volumetric Breast Density in Healthy Women across the Menopausal Transition.

BACKGROUND: Mammographic breast density declines during menopause. We assessed changes in volumetric breast density across the menopausal transition and factors that influence these changes. METHODS: Women without a history of breast cancer, who had full field digital mammograms during both pre- and postmenopausal periods, at least 2 years apart, were sampled from four facilities within the San Francisco Mammography Registry from 2007 to 2013. Dense breast volume (DV) was assessed using Volpara on mammograms across the time period. Annualized change in DV from pre- to postmenopause was estimated using linear mixed models adjusted for covariates and per-woman random effects. Multiplicative interactions were evaluated between premenopausal risk factors and time to determine whether these covariates modified the annualized changes. RESULTS: Among the 2,586 eligible women, 1,802 had one premenopausal and one postmenopausal mammogram, 628 had an additional perimenopausal mammogram, and 156 had two perimenopausal mammograms. Women experienced an annualized decrease in DV [-2.2 cm3 (95% confidence interval, -2.7 to -1.7)] over the menopausal transition. Declines were greater among women with a premenopausal DV above the median (54 cm3) versus below (DV, -3.5 cm3 vs. -1.0 cm3; P < 0.0001). Other breast cancer risk factors, including race, body mass index, family history, alcohol, and postmenopausal hormone therapy, had no effect on change in DV over the menopausal transition. CONCLUSIONS: High premenopausal DV was a strong predictor of greater reductions in DV across the menopausal transition. IMPACT: We found that few factors other than premenopausal density influence changes in DV across the menopausal transition, limiting targeted prevention efforts.

Body mass index, mammographic density, and breast cancer risk by estrogen receptor subtype.

BACKGROUND: Obesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status. METHODS: We conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup (normal/underweight, < 25 kg/m2 versus overweight/obese, ≥ 25 kg/m2). We used Wald chi-squared tests to assess for interactions between percent density and BMI. Our analysis was stratified by menopausal status and hormone therapy usage at the time of index mammogram. RESULTS: Percent density was associated with increased risk of overall breast cancer regardless of menopausal status or BMI. However, when analyzing breast cancer across ER subtype, we found a statistically significant (p = 0.008) interaction between percent density and BMI in premenopausal women only. Specifically, elevated percent density was associated with a higher risk of ER-negative than ER-positive cancer in overweight/obese premenopausal women [OR per standard deviation increment 2.17 (95% CI 1.50-3.16) vs 1.33 (95% CI 1.11-1.61) respectively, Pheterogeneity = 0.01]. In postmenopausal women, elevated percent density was associated with similar risk of ER-positive and ER-negative cancers, and no substantive differences were seen after accounting for BMI or hormone therapy usage. CONCLUSIONS: The combination of overweight/obesity and elevated breast density in premenopausal women is associated with a higher risk of ER-negative compared with ER-positive cancer. Eighteen percent of premenopausal women in the USA have elevated BMI and breast density and may benefit from lifestyle modifications involving weight loss and exercise.

Impact of short-term low-dose tamoxifen on molecular breast imaging background parenchymal uptake: a pilot study.

BACKGROUND: High background parenchymal uptake (BPU) on molecular breast imaging (MBI) has been identified as a breast cancer risk factor. We explored the feasibility of offering a short-term intervention of low-dose oral tamoxifen to women with high BPU and examined whether this intervention would reduce BPU. METHODS: Women with a history of high BPU and no breast cancer history were invited to the study. Participants had an MBI exam, followed by 30 days of low-dose oral tamoxifen at either 5 mg or 10 mg/day, and a post-tamoxifen MBI exam. BPU on pre- and post-tamoxifen MBI exams was quantitatively assessed as the ratio of average counts in breast fibroglandular tissue vs. average counts in subcutaneous fat. Pre-tamoxifen and post-tamoxifen BPU were compared with paired t tests. RESULTS: Of 47 women invited, 22 enrolled and 21 completed the study (10 taking 5 mg tamoxifen, 11 taking 10 mg tamoxifen). Mean age was 47.7 years (range 41-56 years). After 30 days low-dose tamoxifen, 8 of 21 women (38%) showed a decline in BPU, defined as a decrease from the pre-tamoxifen MBI of at least 15%; 11 of 21 (52%) had no change in BPU (within ± 15%); 2 of 21 (10%) had an increase in BPU of greater than 15%. Overall, the average post-tamoxifen BPU was not significantly different from pre-tamoxifen BPU (1.34 post vs. 1.43 pre, p = 0.11). However, among women taking 10 mg tamoxifen, 5 of 11 (45%) showed a decline in BPU; average BPU was 1.19 post-tamoxifen vs. 1.34 pre-tamoxifen (p = 0.005). In women taking 5 mg tamoxifen, 2 of 10 (20%) showed a decline in BPU; average BPU was 1.51 post-tamoxifen vs.1.53 pre-tamoxifen (p = 0.99). CONCLUSIONS: Short-term intervention with low-dose tamoxifen may reduce high BPU on MBI for some patients. Our preliminary findings suggest that 10 mg tamoxifen per day may be more effective than 5 mg for inducing declines in BPU within 30 days. Given the variability in BPU response to tamoxifen observed among study participants, future study is warranted to determine if BPU response could predict the effectiveness of tamoxifen for breast cancer risk reduction within an individual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02979301 . Registered 01 December 2016.

Relationships Between Human-Extracted MRI Tumor Phenotypes of Breast Cancer and Clinical Prognostic Indicators Including Receptor Status and Molecular Subtype.

PURPOSE: The purpose of this study was to investigate if human-extracted MRI tumor phenotypes of breast cancer could predict receptor status and tumor molecular subtype using MRIs from The Cancer Genome Atlas project. MATERIALS AND METHODS: Our retrospective interpretation study utilized the analysis of HIPAA-compliant breast MRI data from The Cancer Imaging Archive. One hundred and seven preoperative breast MRIs of biopsy proven invasive breast cancers were analyzed by 3 fellowship-trained breast-imaging radiologists. Each study was scored according to the Breast Imaging Reporting and Data System lexicon for mass and nonmass features. The Spearman rank correlation was used for association analysis of continuous variables; the Kruskal-Wallis test was used for associating continuous outcomes with categorical variables. The Fisher-exact test was used to assess correlations between categorical image-derived features and receptor status. Prediction of estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor, and molecular subtype were performed using random forest classifiers. RESULTS: ER+ tumors were associated with the absence of rim enhancement (P = 0.019, odds ratio [OR] 5.5), heterogeneous internal enhancement (P = 0.02, OR 6.5), peritumoral edema (P = 0.0001, OR 10.0), and axillary adenopathy (P = 0.04, OR 4.4). ER+ tumors were smaller than ER- tumors (23.7 mm vs 29.2 mm, P = 0.02, OR 8.2). All of these variables except the lack of axillary adenopathy were also associated with progesterone receptor+ status. Luminal A tumors (n = 57) were smaller compared to nonLuminal A (21.8 mm vs 27.5 mm, P = 0.035, OR 7.3) and lacked peritumoral edema (P = 0.001, OR 6.8). Basal like tumors were associated with heterogeneous internal enhancement (P = 0.05, OR 10.1), rim enhancement (P = 0.05, OR6.9), and perituomral edema (P = 0.0001, OR 13.8). CONCLUSIONS: Human extracted MRI tumor phenotypes may be able to differentiate those tumors with a more favorable clinical prognosis from their more aggressive counterparts.

Breast Cancer Litigation in the 21st Century.

BACKGROUND: Approximately 15% of general surgeons practicing in the United States face a medical malpractice lawsuit each year. This study aimed to determine the reasons for litigation for breast cancer care during the past 17 years by reviewing a public legal database. METHODS: The LexisNexis legal database was queried using a comprehensive list of terms related to breast cancer, identifying all cases from 2000 to 2017. Data were abstracted, and descriptive analyses were performed. RESULTS: The study identified 264 cases of litigation pertaining to breast cancer care. Delay in breast cancer diagnosis was the most common reason for litigation (n = 156, 59.1%), followed by improperly performed procedures (n = 26, 9.8%). The medical specialties most frequently named in lawsuits as primary defendants were radiology (n = 76, 28.8%), general surgery (n = 74, 28%), and primary care (n = 52, 19.7%). The verdict favored the defendant in 145 cases (54.9%) and the plantiff in 60 cases (22.7%). In 59 cases (22.3%), a settlement was reached out of court. The median plaintiff verdict payouts ($1,485,000) were greater than the settlement payouts ($862,500) (p = 0.04). CONCLUSION: Failure to diagnose breast cancer in a timely manner was the most common reason for litigation related to breast cancer care in the United States. General surgery was the second most common specialty named in the malpractice cases studied. Most cases were decided in favor of the defendant, but when the plaintiff received a payout, the amount often was substantial. Identifying the most common reasons for litigation may help decrease this rate and improve the patient experience.

Evaluation of 2 breast cancer risk models in a benign breast disease cohort.

BACKGROUND: More than 1.5 million women per year have a benign breast biopsy resulting in concern about their future breast cancer (BC) risk. This study examined the performance of 2 BC risk models that integrate clinical and histologic findings in this population. METHODS: The BC risk at 5 and 10 years was estimated with the Breast Cancer Surveillance Consortium (BCSC) and Benign Breast Disease to Breast Cancer (BBD-BC) models for women diagnosed with benign breast disease (BBD) at the Mayo Clinic from 1997 to 2001. Women with BBD were eligible for the BBD-BC model, but the BCSC model also required a screening mammogram. Calibration and discrimination were assessed. RESULTS: Fifty-six cases of BC were diagnosed among the 2142 women with BBD (median age, 50 years) within 5 years (118 were diagnosed within 10 years). The BBD-BC model had slightly better calibration at 5 years (0.89; 95% confidence interval [CI], 0.71-1.21) versus 10 years (0.81; 95% CI, 0.70-1.00) but similar discrimination in the 2 time periods: 0.68 (95% CI, 0.60-0.75) and 0.66 (95% CI, 0.60-0.71), respectively. In contrast, among the 1089 women with screening mammograms (98 cases of BC within 10 years), the BCSC model had better calibration (0.94; 95% CI, 0.85-1.43) and discrimination (0.63; 95% CI, 0.56-0.71) at 10 years versus 5 years (calibration, 1.31; 95% CI, 0.94-2.25; discrimination, 0.59; 95% CI, 0.46-0.71) where discrimination was not different from chance. CONCLUSIONS: The BCSC and BBD-BC models were validated in the Mayo BBD cohort, although their performance differed by 5-year risk versus 10-year risk. Further enhancement of these models is needed to provide accurate BC risk estimates for women with BBD.

Automated and Clinical Breast Imaging Reporting and Data System Density Measures Predict Risk for Screen-Detected and Interval Cancers: A Case-Control Study.

Background: In 30 states, women who have had screening mammography are informed of their breast density on the basis of Breast Imaging Reporting and Data System (BI-RADS) density categories estimated subjectively by radiologists. Variation in these clinical categories across and within radiologists has led to discussion about whether automated BI-RADS density should be reported instead. Objective: To determine whether breast cancer risk and detection are similar for automated and clinical BI-RADS density measures. Design: Case-control. Setting: San Francisco Mammography Registry and Mayo Clinic. Participants: 1609 women with screen-detected cancer, 351 women with interval invasive cancer, and 4409 matched control participants. Measurements: Automated and clinical BI-RADS density assessed on digital mammography at 2 time points from September 2006 to October 2014, interval and screen-detected breast cancer risk, and mammography sensitivity. Results: Of women whose breast density was categorized by automated BI-RADS more than 6 months to 5 years before diagnosis, those with extremely dense breasts had a 5.65-fold higher interval cancer risk (95% CI, 3.33 to 9.60) and a 1.43-fold higher screen-detected risk (CI, 1.14 to 1.79) than those with scattered fibroglandular densities. Associations of interval and screen-detected cancer with clinical BI-RADS density were similar to those with automated BI-RADS density, regardless of whether density was measured more than 6 months to less than 2 years or 2 to 5 years before diagnosis. Automated and clinical BI-RADS density measures had similar discriminatory accuracy, which was higher for interval than screen-detected cancer (c-statistics: 0.70 vs. 0.62 [P < 0.001] and 0.72 vs. 0.62 [P < 0.001], respectively). Mammography sensitivity was similar for automated and clinical BI-RADS categories: fatty, 93% versus 92%; scattered fibroglandular densities, 90% versus 90%; heterogeneously dense, 82% versus 78%; and extremely dense, 63% versus 64%, respectively. Limitation: Neither automated nor clinical BI-RADS density was assessed on tomosynthesis, an emerging breast screening method. Conclusion: Automated and clinical BI-RADS density similarly predict interval and screen-detected cancer risk, suggesting that either measure may be used to inform women of their breast density. Primary Funding Source: National Cancer Institute.

Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics.

BACKGROUND: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. METHODS: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women. RESULTS: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05). CONCLUSION: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.

Stroma modifies relationships between risk factor exposure and age-related epithelial involution in benign breast.

Delayed age-related lobular involution has been previously associated with elevated breast cancer risk. However, intraindividual variability in epithelial involution status within a woman is undefined. We developed a novel measure of age-related epithelial involution, density of epithelial nuclei in epithelial areas using digital image analysis in combination with stromal characteristics (percentage of section area comprising stroma). Approximately 1800 hematoxylin and eosin stained sections of benign breast tissue were evaluated from 416 participants having breast surgery for cancer or benign conditions. Two to sixteen slides per woman from different regions of the breast were studied. Epithelial involution status varied within a woman and as a function of stromal area. Percentage stromal area varied between samples from the same woman (median difference between highest and lowest stromal area within a woman was 7.5%, but ranged from 0.01 to 86.7%). Restricting to women with at least 10% stromal area (N = 317), epithelial nuclear density decreased with age (-637.1 cells/mm2 per decade of life after age 40, p < 0.0001), increased with mammographic density (457.8 cells/mm2 per increasing BI-RADs density category p = 0.002), and increased non-significantly with recent parity, later age at first pregnancy, and longer and more recent oral contraceptive use. These associations were attenuated in women with mostly fat samples (<10% stroma (N = 99)). Thirty-one percent of women evaluated had both adequate stroma (≥10%) and mostly fat (<10% stroma) regions of breast tissue, with the probability of having both types increasing with the number breast tissue samplings. Several breast cancer risk factors are associated with elevated age-related epithelial content, but associations depend upon stromal context. Stromal characteristics appear to modify relationships between risk factor exposures and breast epithelial involution.

Tissue-based associations of mammographic breast density with breast stem cell markers.

BACKGROUND: Mammographic breast density is a well-established, strong breast cancer risk factor but the biology underlying this association remains unclear. Breast density may reflect underlying alterations in the size and activity of the breast stem cell pool. We examined, for the first time, associations of CD44, CD24, and aldehyde dehydrogenase family 1 member A1 (ALDH1A1) breast stem cell markers with breast density. METHODS: We included in this study 64 asymptomatic healthy women who previously volunteered for a unique biopsy study of normal breast tissue at the Mayo Clinic (2006-2008). Mammographically identified dense and non-dense areas were confirmed/localized by ultrasound and biopsied. Immunohistochemical analysis of the markers was performed according to a standard protocol and the staining was assessed by a single blinded pathologist. In core biopsy samples retrieved from areas of high vs. low density within the same woman, we compared staining extent and an expression score (the product of staining intensity and extent), using the signed rank test. All tests of statistical significance were two-sided. RESULTS: A total of 64, 28, and 10 women were available for CD44, CD24, and ALDH1A1 staining, respectively. For all three markers, we found higher levels of staining extent in dense as compared to non-dense tissue, though for CD24 and ALDH1A1 the difference did not reach statistical significance (CD44, 6.3% vs. 2.0%, p < 0.001; CD24, 8.0% vs. 5.6%, p = 0.10; and ALDH1A1, 0.5% vs. 0.3%, p = 0.12). The expression score for CD44 was significantly greater in dense as compared to non-dense tissue (9.8 vs.3.0, p < 0.001). CONCLUSIONS: Our findings suggest an increased presence and/or activity of stem cells in dense as compared to non-dense breast tissue.

Clinical limitations of the International Federation of Gynecology and Obstetrics (FIGO) classification of uterine fibroids.

OBJECTIVE: To determine the reproducibility of classifying uterine fibroids using the 2011 International Federation of Gynecology and Obstetrics (FIGO) staging system. METHODS: The present retrospective cohort study included patients presenting for the treatment of symptomatic uterine fibroids at the Gynecology Fibroid Clinic at Mayo Clinic, Rochester, USA, between April 1, 2013 and April 1, 2014. Magnetic resonance imaging of fibroid uteri was performed and the images were independently reviewed by two academic gynecologists and two radiologists specializing in fibroid care. Fibroid classifications assigned by each physician were compared and the significance of the variations was graded by whether they would affect surgical planning. RESULTS: There were 42 fibroids from 23 patients; only 6 (14%) fibroids had unanimous classification agreement. The majority (36 [86%]) had at least two unique answers and 4 (10%) fibroids had four unique classifications. Variations in classification were not associated with physician specialty. More than one-third of the classification discrepancies would have impacted surgical planning. CONCLUSION: FIGO fibroid classification was not consistent among four fibroid specialists. The variation was clinically significant for 36% of the fibroids. Additional validation of the FIGO fibroid classification system is needed.

Mammographic breast density and risk of breast cancer in women with atypical hyperplasia: an observational cohort study from the Mayo Clinic Benign Breast Disease (BBD) cohort.

BACKGROUND: Atypical hyperplasia (AH) and mammographic breast density (MBD) are established risk factors for breast cancer (BC), but their joint contributions are not well understood. We examine associations of MBD and BC by histologic impression, including AH, in a subcohort of women from the Mayo Clinic Benign Breast Disease Cohort. METHODS: Women with a diagnosis of BBD and mammogram between 1985 and 2001 were eligible. Histologic impression was assessed via pathology review and coded as non-proliferative disease (NP), proliferative disease without atypia (PDWA) and AH. MBD was assessed clinically using parenchymal pattern (PP) or BI-RADS criteria and categorized as low, moderate or high. Percent density (PD) was also available for a subset of women. BC and clinical information were obtained by questionnaires, medical records and the Mayo Clinic Tumor Registry. Women were followed from date of benign biopsy to BC, death or last contact. Standardized incidence ratios (SIRs) compared the observed number of BCs to expected counts. Cox regression estimated multivariate-adjusted MBD hazard ratios. RESULTS: Of the 6271 women included in the study, 1132 (18.0%) had low MBD, 2921 (46.6%) had moderate MBD, and 2218 (35.4%) had high MBD. A total of 3532 women (56.3%) had NP, 2269 (36.2%) had PDWA and 470 (7.5%) had AH. Over a median follow-up of 14.3 years, 528 BCs were observed. The association of MBD and BC risk differed by histologic impression (p-interaction = 0.03), such that there was a strong MBD and BC association among NP (p < 0.001) but non-significant associations for PDWA (p = 0.27) and AH (p = 0.96). MBD and BC associations for AH women were not significant within subsets defined by type of MBD measure (PP vs. BI-RADS), age at biopsy, number of foci of AH, type of AH (lobular vs. ductal) and body mass index, and after adjustment for potential confounding variables. Women with atypia who also had high PD (>50%) demonstrated marginal evidence of increased BC risk (SIR 4.98), but results were not statistically significant. CONCLUSION: We found no evidence of an association between MBD and subsequent BC risk in women with AH.