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.

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.

Digital Breast Tomosynthesis versus Digital Mammography Screening Performance on Successive Screening Rounds from the Breast Cancer Surveillance Consortium.

Background Prior cross-sectional studies have observed that breast cancer screening with digital breast tomosynthesis (DBT) has a lower recall rate and higher cancer detection rate compared with digital mammography (DM). Purpose To evaluate breast cancer screening outcomes with DBT versus DM on successive screening rounds. Materials and Methods In this retrospective cohort study, data from 58 breast imaging facilities in the Breast Cancer Surveillance Consortium were collected. Analysis included women aged 40-79 years undergoing DBT or DM screening from 2011 to 2020. Absolute differences in screening outcomes by modality and screening round were estimated during the study period by using generalized estimating equations with marginal standardization to adjust for differences in women's risk characteristics across modality and round. Results A total of 523 485 DBT examinations (mean age of women, 58.7 years ± 9.7 [SD]) and 1 008 123 DM examinations (mean age, 58.4 years ± 9.8) among 504 863 women were evaluated. DBT and DM recall rates decreased with successive screening round, but absolute recall rates in each round were significantly lower with DBT versus DM (round 1 difference, -3.3% [95% CI: -4.6, -2.1] [P < .001]; round 2 difference, -1.8% [95% CI: -2.9, -0.7] [P = .003]; round 3 or above difference, -1.2% [95% CI: -2.4, -0.1] [P = .03]). DBT had significantly higher cancer detection (difference, 0.6 per 1000 examinations [95% CI: 0.2, 1.1]; P = .009) compared with DM only for round 3 and above. There were no significant differences in interval cancer rate (round 1 difference, 0.00 per 1000 examinations [95% CI: -0.24, 0.30] [P = .96]; round 2 or above difference, 0.04 [95% CI: -0.19, 0.31] [P = .76]) or total advanced cancer rate (round 1 difference, 0.00 per 1000 examinations [95% CI: -0.15, 0.19] [P = .94]; round 2 or above difference, -0.06 [95% CI: -0.18, 0.11] [P = .43]). Conclusion DBT had lower recall rates and could help detect more cancers than DM across three screening rounds, with no difference in interval or advanced cancer rates. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Skaane in this issue.

Breast Biopsy Recommendations and Breast Cancers Diagnosed during the COVID-19 Pandemic.

Background The COVID-19 pandemic reduced mammography use, potentially delaying breast cancer diagnoses. Purpose To examine breast biopsy recommendations and breast cancers diagnosed before and during the COVID-19 pandemic by mode of detection (screen detected vs symptomatic) and women's characteristics. Materials and Methods In this secondary analysis of prospectively collected data, monthly breast biopsy recommendations after mammography, US, or both with subsequent biopsy performed were examined from 66 facilities of the Breast Cancer Surveillance Consortium between January 2019 and September 2020. The number of monthly and cumulative biopsies recommended and performed and the number of subsequent cancers diagnosed during the pandemic period (March 2020 to September 2020) were compared with data from the prepandemic period using Wald χ2 tests. Analyses were stratified by mode of detection and race or ethnicity. Results From January 2019 to September 2020, 17 728 biopsies were recommended and performed, with 6009 cancers diagnosed. From March to September 2020, there were substantially fewer breast biopsy recommendations with cancer diagnoses when compared with the same period in 2019 (1650 recommendations in 2020 vs 2171 recommendations in 2019 [24% fewer], P < .001), predominantly due to fewer screen-detected cancers (722 cancers in 2020 vs 1169 cancers in 2019 [38% fewer], P < .001) versus symptomatic cancers (895 cancers in 2020 vs 965 cancers in 2019 [7% fewer], P = .27). The decrease in cancer diagnoses was largest in Asian (67 diagnoses in 2020 vs 142 diagnoses in 2019 [53% fewer], P = .06) and Hispanic (82 diagnoses in 2020 vs 145 diagnoses in 2019 [43% fewer], P = .13) women, followed by Black women (210 diagnoses in 2020 vs 287 diagnoses in 2019 [27% fewer], P = .21). The decrease was smallest in non-Hispanic White women (1128 diagnoses in 2020 vs 1357 diagnoses in 2019 [17% fewer], P = .09). Conclusion There were substantially fewer breast biopsies with cancer diagnoses during the COVID-19 pandemic from March to September 2020 compared with the same period in 2019, with Asian and Hispanic women experiencing the largest declines, followed by Black women. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Heller in this issue.

Imaging Surveillance Options for Individuals With a Personal History of Breast Cancer: AJR Expert Panel Narrative Review.

Annual surveillance mammography is recommended for breast cancer survivors on the basis of observational studies and meta-analyses showing reduced breast cancer mortality and improved quality of life. However, breast cancer survivors are at higher risk of subsequent breast cancer and have a fourfold increased risk of interval breast cancers compared with individuals without a personal history of breast cancer. Supplemental surveillance modalities offer increased cancer detection compared with mammography alone, but utilization is variable, and benefits must be balanced with possible harms of false-positive findings. In this review, we describe the current state of mammographic surveillance, summarize evidence for supplemental surveillance in breast cancer survivors, and explore a risk-based approach to selecting surveillance imaging strategies. Further research identifying predictors associated with increased risk of interval second breast cancers and development of validated risk prediction tools may help physicians and patients weigh the benefits and harms of surveillance breast imaging and decide on a personalized approach to surveillance for improved breast cancer outcomes.

Mammary collagen architecture and its association with mammographic density and lesion severity among women undergoing image-guided breast biopsy.

BACKGROUND: Elevated mammographic breast density is a strong breast cancer risk factor with poorly understood etiology. Increased deposition of collagen, one of the main fibrous proteins present in breast stroma, has been associated with increased mammographic density. Collagen fiber architecture has been linked to poor outcomes in breast cancer. However, relationships of quantitative collagen fiber features assessed in diagnostic biopsies with mammographic density and lesion severity are not well-established. METHODS: Clinically indicated breast biopsies from 65 in situ or invasive breast cancer cases and 73 frequency matched-controls with a benign biopsy result were used to measure collagen fiber features (length, straightness, width, alignment, orientation and density (fibers/µm2)) using second harmonic generation microscopy in up to three regions of interest (ROIs) per biopsy: normal, benign breast disease, and cancer. Local and global mammographic density volumes were quantified in the ipsilateral breast in pre-biopsy full-field digital mammograms. Associations of fibrillar collagen features with mammographic density and severity of biopsy diagnosis were evaluated using generalized estimating equation models with an independent correlation structure to account for multiple ROIs within each biopsy section. RESULTS: Collagen fiber density was positively associated with the proportion of stroma on the biopsy slide (p < 0.001) and with local percent mammographic density volume at both the biopsy target (p = 0.035) and within a 2 mm perilesional ring (p = 0.02), but not with global mammographic density measures. As severity of the breast biopsy diagnosis increased at the ROI level, collagen fibers tended to be less dense, shorter, straighter, thinner, and more aligned with one another (p < 0.05). CONCLUSIONS: Collagen fiber density was positively associated with local, but not global, mammographic density, suggesting that collagen microarchitecture may not translate into macroscopic mammographic features. However, collagen fiber features may be markers of cancer risk and/or progression among women referred for biopsy based on abnormal breast imaging.

Identifying key barriers to effective breast cancer control in rural settings.

Breast cancer is the most common cancer and the second most common cause of cancer mortality among women in the United States. Efforts to promote breast cancer control in rural settings face specific challenges. Access to breast cancer screening, diagnosis, and treatment services is impaired by shortages of primary care and specialist providers, and geographic distance from medical facilities. Women in rural areas have comparable breast cancer mortality rates compared to women in urban settings, but this is due in large part to lower incidence rates and masks a substantial rural/urban disparity in breast cancer survival among women diagnosed with breast cancer. Mammography screening utilization rates are slightly lower among rural women than their urban counterparts, with a corresponding increase in late stage breast cancer. Differences in breast cancer survival persist after controlling for stage at diagnosis, largely due to disparities in access to treatment. Travel distance to treatment centers is the most substantial barrier to improved breast cancer outcomes in rural areas. While numerous interventions have been demonstrated in controlled studies to be effective in promoting treatment access and adherence, widespread dissemination in public health and clinical practice remains lacking. Efforts to improve breast cancer control in rural areas should focus on implementation strategies for improving access to breast cancer treatments.

Multicenter Evaluation of Breast Cancer Screening with Digital Breast Tomosynthesis in Combination with Synthetic versus Digital Mammography.

BackgroundDigital breast tomosynthesis (DBT) combined with digital mammography (DM) is increasingly used in the United States instead of DM alone for breast cancer screening. Early screening outcomes incorporating synthetic mammography (SM) with DBT have suggested that SM is an acceptable non-radiation dose alternative to DM.PurposeTo compare multicenter outcomes from breast cancer screening with SM/DBT versus DM/DBT.Materials and MethodsThis was a retrospective study of consecutive screening mammograms obtained at two institutions. Eligible studies consisted of 34 106 DM/DBT examinations between October 3, 2011, and October 31, 2014, and 34 180 SM/DBT examinations between January 7, 2015, and February 2, 2018, at the University of Pennsylvania and 51 148 DM/DBT examinations between January 1, 2012, and May 31, 2016, and 31 929 SM/DBT examinations between June 1, 2016, and March 30, 2018, at the University of Vermont. Demographics of women who attended screening and results from screening were recorded. Recall rate, biopsy rate, false-negative rate, cancer detection rate, positive predictive value, sensitivity, and specificity were calculated according to modality and institution. Descriptive statistics, χ2 tests, and logistic regression were used in analysis.ResultsThe study included 151 363 screening examinations among 151 363 women (mean age, 58.1 years ± 10.9 [standard deviation]). The unadjusted recall rate was lower with SM/DBT than with DM/DBT (7.0% [4630 of 66 109 examinations] for SM/DBT vs 7.9% [6742 of 85 254 examinations] for DM/DBT; P < .01). However, after multivariable adjustment, SM/DBT was associated with a slightly higher recall rate compared with DM/DBT (adjusted odds ratio [OR], 1.06; adjusted 95% CI: 1.01, 1.11; P = .02). Similarly, after multivariable adjustment, SM/DBT was associated with slightly lower specificity compared with DM/DBT (adjusted OR, 0.95; adjusted 95% CI: 0.90, 0.99; P = .02). There was no statistically significant difference in biopsy rate (P = .54), false-negative rate (P = .38), cancer detection rate (P = .55), invasive or in situ cancer detection rate (P = .52 and P = .98, respectively), positive predictive value (P = .78), or sensitivity (P = .33) for SM/DBT versus DM/DBT overall or within either institution (P > .05 for all).ConclusionBreast cancer screening performance is maintained within benchmarks when synthetic mammography replaces digital mammography in digital breast tomosynthesis imaging.© RSNA, 2020Online supplemental material is available for this article.See also the editorial by Lång in this issue.

Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy.

BACKGROUND: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD. METHODS: Serum IGF measures were quantified in 296 women, ages 40-65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI2-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed. RESULTS: IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (ß = 1.49, p value = 0.02) and MD-A (ß = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (ß = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI < 25 kg/m2) (ß = 5.32, p = 0.0002; p interaction = 0.0003). CONCLUSIONS: In this comprehensive study of IGFBPs and MD, we observed a novel positive association between IGFBP-2 and MD, particularly among women with lower BMI. In concert with in vitro studies suggesting a dual role of IGFBP-2 on breast tissue, promoting cell proliferation as well as inhibiting tumorigenesis, our findings suggest that further studies assessing the role of IGFBP-2 in breast tissue composition, in addition to IGF-1 and IGFBP-3, are warranted.

Time-varying risks of second events following a DCIS diagnosis in the population-based Vermont DCIS cohort.

PURPOSE: Long-term disease-free survival patterns following surgical, radiation, and endocrine therapy treatments for ductal carcinoma in situ (DCIS) are not well characterized in general US practice. METHODS: We identified 1252 women diagnosed with DCIS in Vermont during 1994-2012 using data from the Vermont Breast Cancer Surveillance System, a statewide registry of breast imaging and pathology records. Poisson regression and Cox regression with time-varying hazards were used to evaluate disease-free survival among self-selected treatment groups. RESULTS: With 7.8 years median follow-up, 192 cases experienced a second breast cancer diagnosis. For women treated with breast-conserving surgery (BCS) alone, the annual rate of second events decreased from 3.1% (95% CI 2.2-4.2%) during follow-up years 1-5 to 1.7% (95% CI 0.7-3.5%) after 10 years. In contrast, the annual rate of second events among women treated with BCS plus adjuvant radiation therapy increased from 1.8% (95% CI 1.1-2.6%) during years 1-5 to 2.8% (95% CI 1.6-4.7%) after 10 years (P < 0.05 for difference in trend compared to BCS alone). Annual rates of second events also increased over time among women treated with BCS plus adjuvant radiation and endocrine therapy (P = 0.01 for difference in trend compared to BCS alone). The rate of contralateral events increased after 10 years for all groups with adjuvant treatments. The rate of second events did not vary over time among women who underwent ipsilateral mastectomy (P = 0.62). CONCLUSIONS: Long-term risk of a second event after DCIS varies over time in a manner dependent on initial treatment.

Digital Breast Tomosynthesis: Radiologist Learning Curve.

Background There is growing evidence that digital breast tomosynthesis (DBT) results in lower recall rates and higher cancer detection rates when compared with digital mammography. However, whether DBT interpretative performance changes with experience (learning curve effect) is unknown. Purpose To evaluate screening DBT performance by cumulative DBT volume within 2 years after adoption relative to digital mammography (DM) performance 1 year before DBT adoption. Materials and Methods This prospective study included 106 126 DBT and 221 248 DM examinations in 271 362 women (mean age, 57.5 years) from 2010 to 2017 that were interpreted by 104 radiologists from 53 facilities in the Breast Cancer Surveillance Consortium. Conditional logistic regression was used to estimate within-radiologist effects of increasing cumulative DBT volume on recall and cancer detection rates relative to DM and was adjusted for examination-level characteristics. Changes were also evaluated by subspecialty and breast density. Results Before DBT adoption, DM recall rate was 10.4% (95% confidence interval [CI]: 9.5%, 11.4%) and cancer detection rate was 4.0 per 1000 screenings (95% CI: 3.6 per 1000 screenings, 4.5 per 1000 screenings); after DBT adoption, DBT recall rate was lower (9.4%; 95% CI: 8.2%, 10.6%; P = .02) and cancer detection rate was similar (4.6 per 1000 screenings; 95% CI: 4.0 per 1000 screenings, 5.2 per 1000 screenings; P = .12). Relative to DM, DBT recall rate decreased for a cumulative DBT volume of fewer than 400 studies (odds ratio [OR] = 0.83; 95% CI: 0.78, 0.89) and remained lower as volume increased (400-799 studies, OR = 0.8 [95% CI: 0.75, 0.85]; 800-1199 studies, OR = 0.81 [95% CI: 0.76, 0.87]; 1200-1599 studies, OR = 0.78 [95% CI: 0.73, 0.84]; 1600-2000 studies, OR = 0.81 [95% CI: 0.75, 0.88]; P < .001). Improvements were sustained for breast imaging subspecialists (OR range, 0.67-0.85; P < .02) and readers who were not breast imaging specialists (OR range, 0.80-0.85; P < .001). Recall rates decreased more in women with nondense breasts (OR range, 0.68-0.76; P < .001) than in those with dense breasts (OR range, 0.86-0.90; P ≤ .05; P interaction < .001). Cancer detection rates for DM and DBT were similar, regardless of DBT volume (P ≥ .10). Conclusion Early performance improvements after digital breast tomosynthesis (DBT) adoption were sustained regardless of DBT volume, radiologist subspecialty, or breast density. © RSNA, 2019 See also the editorial by Hooley in this issue.

Detection Rates for Benign and Malignant Diagnoses on Breast Cancer Screening With Digital Breast Tomosynthesis in a Statewide Mammography Registry Study.

OBJECTIVE: The objective of our study was to determine whether detection rates of specific benign and malignant diagnoses differ for breast cancer screening with digital breast tomosynthesis (DBT) versus full-field digital mammography (FFDM) alone. MATERIALS AND METHODS: We analyzed observational data from the Vermont Breast Cancer Surveillance System, including 86,349 DBT screening examinations and 97,378 FFDM screening examinations performed at eight radiology facilities in Vermont that adopted DBT screening during 2012-2016. We determined the most severe diagnosis made within 6 months after positive screening examinations. Multivariable-adjusted logistic regression was used to compare detection rates for specific diagnoses on DBT versus FFDM. RESULTS: Compared with FFDM, DBT had a lower recall rate (adjusted odds ratio [OR], 0.81; 95% CI, 0.77-0.85) but comparable biopsy rate (OR = 1.05; 95% CI, 0.93-1.17), benign biopsy rate (OR = 1.12; 95% CI, 0.97-1.29), and cancer detection rate (OR = 0.94; 95% CI, 0.78-1.14). Among benign diagnoses, DBT and FFDM had comparable detection rates for nonproliferative lesions (OR = 1.19; 95% CI, 0.92-1.53), fibroepithelial proliferations (OR = 1.24; 95% CI, 0.85-1.81), proliferative lesions without atypia (OR = 1.13; 95% CI, 0.90-1.42), atypical lesions (OR = 0.77; 95% CI, 0.43-1.38), and lobular carcinoma in situ (LCIS) (OR = 0.92; 95% CI, 0.53-1.61). Among malignant diagnoses, DBT and FFDM had comparable detection rates for ductal carcinoma in situ (OR = 1.05; 95% CI, 0.70-1.57) and invasive breast cancer (OR = 0.92; 95% CI, 0.74-1.13), with no statistically significant differences in detection of invasive ductal carcinoma (OR = 0.83; 95% CI, 0.66-1.06), invasive lobular carcinoma (OR = 1.11; 95% CI, 0.59-2.07), or invasive mixed ductal-lobular carcinoma (OR = 1.49; 95% CI, 0.65-3.39). CONCLUSION: Compared with FFDM, breast cancer screening with DBT has a lower recall rate while detecting a similar distribution of benign and malignant diagnoses.

Comparative effectiveness of incorporating a hypothetical DCIS prognostic marker into breast cancer screening.

PURPOSE: Due to limitations in the ability to identify non-progressive disease, ductal carcinoma in situ (DCIS) is usually managed similarly to localized invasive breast cancer. We used simulation modeling to evaluate the potential impact of a hypothetical test that identifies non-progressive DCIS. METHODS: A discrete-event model simulated a cohort of U.S. women undergoing digital screening mammography. All women diagnosed with DCIS underwent the hypothetical DCIS prognostic test. Women with test results indicating progressive DCIS received standard breast cancer treatment and a decrement to quality of life corresponding to the treatment. If the DCIS test indicated non-progressive DCIS, no treatment was received and women continued routine annual surveillance mammography. A range of test performance characteristics and prevalence of non-progressive disease were simulated. Analysis compared discounted quality-adjusted life years (QALYs) and costs for test scenarios to base-case scenarios without the test. RESULTS: Compared to the base case, a perfect prognostic test resulted in a 40% decrease in treatment costs, from $13,321 to $8005 USD per DCIS case. A perfect test produced 0.04 additional QALYs (16 days) for women diagnosed with DCIS, added to the base case of 5.88 QALYs per DCIS case. The results were sensitive to the performance characteristics of the prognostic test, the proportion of DCIS cases that were non-progressive in the model, and the frequency of mammography screening in the population. CONCLUSION: A prognostic test that identifies non-progressive DCIS would substantially reduce treatment costs but result in only modest improvements in quality of life when averaged over all DCIS cases.

Using deep convolutional neural networks to identify and classify tumor-associated stroma in diagnostic breast biopsies.

The breast stromal microenvironment is a pivotal factor in breast cancer development, growth and metastases. Although pathologists often detect morphologic changes in stroma by light microscopy, visual classification of such changes is subjective and non-quantitative, limiting its diagnostic utility. To gain insights into stromal changes associated with breast cancer, we applied automated machine learning techniques to digital images of 2387 hematoxylin and eosin stained tissue sections of benign and malignant image-guided breast biopsies performed to investigate mammographic abnormalities among 882 patients, ages 40-65 years, that were enrolled in the Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project. Using deep convolutional neural networks, we trained an algorithm to discriminate between stroma surrounding invasive cancer and stroma from benign biopsies. In test sets (928 whole-slide images from 330 patients), this algorithm could distinguish biopsies diagnosed as invasive cancer from benign biopsies solely based on the stromal characteristics (area under the receiver operator characteristics curve = 0.962). Furthermore, without being trained specifically using ductal carcinoma in situ as an outcome, the algorithm detected tumor-associated stroma in greater amounts and at larger distances from grade 3 versus grade 1 ductal carcinoma in situ. Collectively, these results suggest that algorithms based on deep convolutional neural networks that evaluate only stroma may prove useful to classify breast biopsies and aid in understanding and evaluating the biology of breast lesions.

Breast cancer screening in patients with cancers other than breast.

BACKGROUND: Screening mammography can detect early breast cancers and reduce subsequent cancer mortality. However, there is a lack of consensus as to when to discontinue screening. The absence of clear-cut guidelines on when not to screen means that many patients with advanced malignancies continue screening despite unclear benefit. METHODS: We performed a retrospective cohort study of female patients diagnosed with a non-breast malignancy to explore the incidence and effects of screening mammography. Female patients diagnosed with a non-breast malignancy stage II or higher between 2007 and 2012 were identified through the Vermont Cancer Registry and cross-referenced with mammography screening logs from January 1, 2007 to September 30, 2014. Additional data were collected through chart review, in May 2016. RESULTS: Twenty-six percent of women (398/1501) with a stage II or greater cancer (other than breast) diagnosed between 2007 and 2012 had a screening mammogram within the first 5 years of their diagnosis. Of these 398 women, 193 (48.5%) were alive without cancer, 132 (33.2%) had died, and 73 (18.3%) were alive with cancer at the time of chart review. Of those who died, 84 (63.6%) had a stage III or IV cancer. Eighteen (4.5%) had a breast biopsy following a screening mammogram suspicious for cancer, resulting in 13 (3.3%) benign diagnoses and 5 (1.3%) breast cancer diagnoses. No patient died of breast cancer. CONCLUSIONS: Except for highly curable cancers, female patients diagnosed with an advanced non-breast malignancy experienced mortality that outweighs a breast cancer mortality benefit from screening mammography as estimated from prior studies.

Relationship between preoperative breast MRI and surgical treatment of non-metastatic breast cancer.

BACKGROUND AND OBJECTIVES: More extensive surgical treatments for early stage breast cancer are increasing. The patterns of preoperative MRI overall and by stage for this trend has not been well established. METHODS: Using Breast Cancer Surveillance Consortium registry data from 2010 through 2014, we identified women with an incident non-metastatic breast cancer and determined use of preoperative MRI and initial surgical treatment (mastectomy, with or without contralateral prophylactic mastectomy (CPM), reconstruction, and breast conserving surgery ± radiation). Clinical and sociodemographic covariates were included in multivariable logistic regression models to estimate adjusted odds ratios and 95% confidence intervals. RESULTS: Of the 13 097 women, 2217 (16.9%) had a preoperative MRI. Among the women with MRI, results indicated 32% higher odds of unilateral mastectomy compared to breast conserving surgery and of mastectomy with CPM compared to unilateral mastectomy. Women with preoperative MRI also had 56% higher odds of reconstruction. CONCLUSION: Preoperative MRI in women with DCIS and early stage invasive breast cancer is associated with more frequent mastectomy, CPM, and reconstruction surgical treatment. Use of more extensive surgical treatment and reconstruction among women with DCIS and early stage invasive cancer whom undergo MRI warrants further investigation.

Variation in Mammographic Breast Density Assessments Among Radiologists in Clinical Practice: A Multicenter Observational Study.

Background: About half of the United States has legislation requiring radiology facilities to disclose mammographic breast density information to women, often with language recommending discussion of supplemental screening options for women with dense breasts. Objective: To examine variation in breast density assessment across radiologists in clinical practice. Design: Cross-sectional and longitudinal analyses of prospectively collected observational data. Setting: 30 radiology facilities within the 3 breast cancer screening research centers of the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. Participants: Radiologists who interpreted at least 500 screening mammograms during 2011 to 2013 (n = 83). Data on 216 783 screening mammograms from 145 123 women aged 40 to 89 years were included. Measurements: Mammographic breast density, as clinically recorded using the 4 Breast Imaging Reporting and Data System categories (heterogeneously dense and extremely dense categories were considered "dense" for analyses), and patient age, race, and body mass index (BMI). Results: Overall, 36.9% of mammograms were rated as showing dense breasts. Across radiologists, this percentage ranged from 6.3% to 84.5% (median, 38.7% [interquartile range, 28.9% to 50.9%]), with multivariable adjustment for patient characteristics having little effect (interquartile range, 29.9% to 50.8%). Examination of patient subgroups revealed that variation in density assessment across radiologists was pervasive in all but the most extreme patient age and BMI combinations. Among women with consecutive mammograms interpreted by different radiologists, 17.2% (5909 of 34 271) had discordant assessments of dense versus nondense status. Limitation: Quantitative measures of mammographic breast density were not available for comparison. Conclusion: There is wide variation in density assessment across radiologists that should be carefully considered by providers and policymakers when considering supplemental screening strategies. The likelihood of a woman being told she has dense breasts varies substantially according to which radiologist interprets her mammogram. Primary Funding Source: National Institutes of Health.

Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis.

BACKGROUND: Women with high levels of mammographic density (MD) have a four- to six-fold increased risk of developing breast cancer; however, most neither have a prevalent tumor nor will they develop one. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is related to increased breast cancer risk. Correlations of microvessel density (MVD) in tissue, MD and biopsy diagnosis have not been defined, and we investigated these relationships among 218 women referred for biopsy. METHODS: MVD was determined by counting CD31-positive vessels in whole sections of breast biopsies in three representative areas; average MVD was transformed to approximate normality. Using digital mammograms, we quantified MD volume with single X-ray absorptiometry. We used linear regression to evaluate associations between MVD and MD adjusted for age and body mass index (BMI) overall, and stratified by biopsy diagnosis: cases (in situ or invasive cancer, n = 44) versus non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression adjusted for age, BMI, and MD was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between MVD and biopsy diagnosis. We also assessed whether the MVD-breast cancer association varied by MD. RESULTS: MVD and MD were not consistently associated. Higher MVD was significantly associated with higher odds of in situ/invasive disease (ORAdjusted = 1.69, 95 % CI = 1.17-2.44). MVD-breast cancer associations were strongest among women with greater non-dense volume. CONCLUSIONS: Increased MVD in tissues is associated with breast cancer, independently of MD, consistent with MRI findings suggestive of its possible value as a radiological cancer biomarker.

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.

BACKGROUND: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. METHODS: Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. RESULTS: Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. CONCLUSIONS: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system.

Emerging trends in surgical and adjuvant radiation therapies among women diagnosed with ductal carcinoma in situ.

BACKGROUND: The use of surgery and radiation therapy in treating ductal carcinoma in situ (DCIS) is directed by treatment guidelines and evidence from research. This study investigated recent patterns in DCIS treatment by demographic factors. METHODS: Data for women diagnosed with DCIS between 1998 and 2011 (n = 416,232) in the National Cancer Data Base were assessed for trends in treatment patterns by age group, calendar year, ancestral/ethnic group, and geographic region. The likelihood of receiving specific treatment modalities was analyzed with multivariable logistic regression. RESULTS: DCIS cases were most frequently treated with breast-conserving surgery (BCS) and adjuvant radiation (45.6%). After an initial rise, the use of adjuvant radiation after BCS plateaued at approximately 70% after 2007, with increasing utilization of mastectomy beyond 2005. In addition, there was an increasing trend in postmastectomy reconstruction over time, and women of African ancestry (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.66-0.72) and Hispanic women (OR, 0.83; 95% CI, 0.78-0.89) were less likely to undergo reconstruction in comparison with women of European ancestry. A similar trend was observed in contralateral risk-reducing mastectomy utilization, with women of European ancestry having a more rapid rise in the utilization of contralateral risk-reducing mastectomy in comparison with all other ancestral/ethnic groups. CONCLUSIONS: Recent trends demonstrate a plateau in radiation therapy administration after BCS along with increasing utilization of mastectomy, reconstruction, and contralateral risk-reducing mastectomy. There are substantial differences in treatment utilization according to ancestry/ethnicity and geographical region. Further studies examining patient-physician decision making surrounding DCIS treatment are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2810-2818. © 2016 American Cancer Society.