Much of the existing literature reporting associations of breast density with breast cancer risk has evaluated the density of the entire breast. However, density is not homogeneously distributed throughout the breast, and tumors are more likely to arise in areas of dense tissue. This study describes novel measures of local breast density and evaluates their association with participant characteristics and risk of breast cancer. Among a cohort of women aged 40–65 years who underwent image-guided breast biopsy following an abnormal mammogram from 2007 to 2010 (n = 808), absolute fibroglandular volume (FGV, cm3) and percentage fibroglandular volume (

Purpose: To evaluate long-term trends in mammography screening rates and identify sociodemographic and breast cancer risk characteristics associated with return to screening after the COVID-19 pandemic. Materials and Methods: In this retrospective study, statewide screening mammography data of 222 384 female individuals aged 40 years or older (mean age, 58.8 years +/- 11.7 [SD]) from the Vermont Breast Cancer Surveillance System were evaluated to generate descriptive statistics and Joinpoint models to characterize screening patterns during 2000-2022. Log-binomial regression models estimated associations of sociodemographic and risk characteristics with post-COVID-19 pandemic return to screening. Results: The proportion of female individuals in Vermont aged 50-74 years with a screening mammogram obtained in the previous 2 declined from a prepandemic level of 61.3% (95% CI: 61.1%, 61.6%) in 2019 to 56.0% (95% CI: 55.7%, 56.3%) in 2021 before rebounding to 60.7% (95% CI: 60.4%, 61.0%) in 2022. Screening adherence in 2022 remained substantially lower than that observed during the 2007-2010 apex of screening adherence (66.1%-67.0%). Joinpoint models estimated an annual percent change of -1.1% (95% -1.5%, -0.8%) during 2010-2022. Among the cohort of 95 644 individuals screened during January 2018-March 2020, the probability returning to screening during 2020-2022 varied by age (eg, risk ratio [RR] = 0.94 [95% CI: 0.93, 0.95] for age 40-44 vs age 60-64 years), race and ethnicity (RR = 0.84 [95% CI: 0.78, 0.90] for Black vs White individuals), education (RR = 0.84 [95% CI: 0.81, 0.86] for less than high school degree vs college degree), and by 5-year breast cancer risk (RR = 1.06 [95% CI: 1.04, 1.08] for very high vs average risk). Conclusion: Despite a rebound to near prepandemic levels, Vermont mammography screening rates have steadily declined since 2010, with certain sociodemographic groups less likely to return to screening after the pandemic.

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.

Supplementary Figure 1. Average Percent Dense Area by Age Supplementary Figure 2. Average Percent Dense Volume by Age.

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Cybersecurity in healthcare is a very real threat with the potential to severely disrupt patient care, place extra burden on an already strained system, and result in significant financial losses for a hospital or healthcare network. In October 2020, on the backdrop of the ongoing COVID-19 pandemic, our institution experienced one of the most significant cyberattacks on a healthcare system to date, lasting for nearly 40 days. By sharing our experience in radiology, and specifically in breast imaging, including the downtime procedures we relied upon and the lessons that we learned emerging from this cyberattack, we hope to help future victims of a healthcare cyberattack successfully weather such an experience.

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.

Supplementary Table 1. Spearman partial rank-order correlations for TDLU measures among pre- and postmenopausal women Supplementary Table 2. Spearman partial rank-order correlations between global and peri-lesional volumetric mammographic density measures among pre- and postmenopausal women with benign breast disease Supplementary Tables 3 to 5: Association between TDLU and mammographic density measures (percent, absolute and nondense) among postmenopausal women with benign breast disease

BackgroundThere 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. MethodsA 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%. ResultsA 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). ConclusionsUltrasound 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.

<p>Supplementary Figure 1. Spearman's rank correlation coefficients (rs) for volume and area density measures, stratified by age.</p>

<p>Supplementary Table 1. Age- and BMI-adjusted linear regression results for the association between participant characteristics and standardized volume and area mammographic density measures. Supplementary Table 2. Spearman's rank correlation coefficients for volume and area density measures, unadjusted and adjusted for age and body mass index.</p>

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.

Background: The coronavirus disease 2019 (COVID-19) pandemic led to a near-total cessation of mammography services in the United States in mid-March 2020. It is unclear if screening and diagnostic mammography volumes have recovered to prepandemic levels and whether use has varied by women's characteristics. Methods: We collected data on 461 083 screening mammograms and 112 207 diagnostic mammograms conducted during January 2019 through July 2020 at 62 radiology facilities in the Breast Cancer Surveillance Consortium. We compared monthly screening and diagnostic mammography volumes before and during the pandemic stratified by age, race and ethnicity, breast density, and family history of breast cancer. Results: Screening and diagnostic mammography volumes in April 2020 were 1.1% (95% confidence interval [CI] = 0.5% to 2.4%) and 21.4% (95% CI = 18.7% to 24.4%) of the April 2019 prepandemic volumes, respectively, but by July 2020 had rebounded to 89.7% (95% CI = 79.6% to 101.1%) and 101.6% (95% CI = 93.8% to 110.1%) of the July 2019 prepandemic volumes, respectively. The year-to-date cumulative volume of screening and diagnostic mammograms performed through July 2020 was 66.2% (95% CI = 60.3% to 72.6%) and 79.9% (95% CI = 75.4% to 84.6%), respectively, of year-to-date volume through July 2019. Screening mammography rebound was similar across age groups and by family history of breast cancer. Monthly screening mammography volume in July 2020 for Black, White, Hispanic, and Asian women reached 96.7% (95% CI = 88.1% to 106.1%), 92.9% (95% CI = 82.9% to 104.0%), 72.7% (95% CI = 56.5% to 93.6%), and 51.3% (95% CI = 39.7% to 66.2%) of the July 2019 prepandemic volume, respectively. Conclusions: Despite a strong overall rebound in mammography volume by July 2020, the rebound lagged among Asian and Hispanic women, and a substantial cumulative deficit in missed mammograms accumulated, which may have important health consequences.

Background: There is widespread interest in discriminating indolent from aggressive ductal carcinoma in situ (DCIS). We sought to evaluate collagen organization in the DCIS tumor microenvironment in relation to pathologic characteristics and patient outcomes. Methods: We retrieved fixed tissue specimens for 90 DCIS cases within the population-based Vermont DCIS Cohort. We imaged collagen fibers within 75 μm of the tumor/stromal boundary on hematoxylin and eosin–stained slides using multiphoton microscopy with second-harmonic generation. Automated software quantified collagen fiber length, width, straightness, density, alignment, and angle to the tumor/stroma boundary. Factor analysis identified linear combinations of collagen fiber features representing composite attributes of collagen organization. Results: Multiple collagen features were associated with DCIS grade, necrosis pattern, or periductal fibrosis (P < 0.05). After adjusting for treatments and nuclear grade, risk of recurrence (defined as any second breast cancer diagnosis) was lower among cases with greater collagen fiber width [hazard ratio (HR), 0.57 per one standard deviation increase; 95% confidence interval (CI), 0.39–0.84] and fiber density (HR, 0.60; 95% CI, 0.42–0.85), whereas risk was elevated among DCIS cases with higher fiber straightness (HR, 1.47; 95% CI, 1.05–2.06) and distance to the nearest two fibers (HR, 1.47; 95% CI, 1.06–2.02). Fiber length, alignment, and fiber angle were not associated with recurrence (P > 0.05). Five composite factors were identified, accounting for 72.4% of the total variability among fibers; three were inversely associated with recurrence (HRs ranging from 0.60 to 0.67; P ≤ 0.01). Conclusions: Multiple aspects of collagen organization around DCIS lesions are associated with recurrence risk. Impact: Collagen organization should be considered in the development of prognostic DCIS biomarker signatures.

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.

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.

Abstract 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.

The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40–65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.

Abstract Introduction Elevated mammographic density (MD) is a strong and independent risk factor for breast cancer, though underlying mechanisms are unclear. Prior studies have suggested that increased cumulative exposure to sex-steroid hormones and growth factors may impact both MD and MD-related breast cancer risk; however, most studies have only evaluated individual hormones. In this study, we simultaneously explored the relationship between 29 circulating hormones and growth factors with MD among postmenopausal women undergoing diagnostic breast biopsy. Methods We used data from 89 postmenopausal women, aged 44-65, who had complete measurements of 29 serum hormones from a single pre-biopsy blood draw (i.e., sex-steroid hormones: 15 estrogen/estrogen metabolites, 7 progesterone/progesterone metabolites; and non-sex hormones: insulin-like growth factor I and binding proteins (IGFBPs) 2-7). Volumetric MD (% fibroglandular volume) was assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Sufficient dimension reduction methods were used to compute a composite marker score that accommodates correlations among hormones and their relationship to MD. Backward elimination was applied to select log-transformed hormones contributing to the score at α=0.05; multivariable linear regression was used to further examine associations between selected hormones and MD within a single model, adjusting for age and BMI. Results Pearson correlations between hormones were moderate-to-strong. Dimension reduction methods identified 6 hormones as associated with MD (p<0.05): estradiol, 2-hydroxyestradiol, 2-methoxyestrone, 16-ketoestradiol, IGFBP-2, and 17α-hydroxyprogesterone, in models that considered MD as either continuous or dichotomous (>median vs. ≤median); BMI was consistently identified as the most significant predictor of MD (P <0.0001). In a multivariable linear regression model that included these 6 hormones, in addition to age and BMI, higher levels of 2-methoxyestrone, IGFBP-2, and 17α-hydroxyprogesterone were significantly associated with increased MD, whereas higher levels of age and BMI were significantly associated with lower MD. Conclusions We identified 6 out of 29 correlated hormones that were significantly associated with MD among postmenopausal women. For several, the directions of their associations with MD were comparable to those observed in prior studies that have separately evaluated these hormones in relation to breast cancer risk. We plan to further explore how circulating hormones concurrently affect MD in premenopausal women, accounting for menstrual cycle phase. Incorporation of dimension reduction methods in studies of multiple correlated hormones can help uncover new etiologic insights into the role of hormones and growth factors in MD and breast carcinogenesis and inform strategies for prevention. Citation Format: Shaoqi Fan, Ruth M. Pfeiffer, Manila Hada, Roni T. Falk, Maeve Mullooly, Hannah Oh, Berta Geller, Pamela Vacek, Donald Weave, John Shepherd, Jeff Wang, Sally Herschorn, Louise A. Brinton, Xia Xu, Mark E. Sherman, Britton Trabert, Gretchen L. Gierach. Associations of circulating hormones with mammographic density in postmenopausal women referred to diagnostic breast biopsy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3488.

Abstract Introduction: The etiology of breast cancer remains an area of ongoing investigation. Improving our understanding of factors associated with breast cancer development will strengthen the utility of risk prediction strategies and improve risk stratification. Mammographic breast density remains one of the most influential breast cancer risk factors, with 4 to 6 fold elevated risk observed among women with the highest compared to the lowest levels. These associations have consistently been observed irrespective of the method (visual or automated), used to quantify breast density, showing the robustness of the associations. An understudied breast cancer risk factor is the bilateral asymmetry of mammographic features, with prior studies suggesting that women with higher levels of breast asymmetry may be at elevated breast cancer risk. Increasingly, studies are recognizing the potential of bilateral breast asymmetry defined by mammographic breast density in determining breast cancer risk. Recently, Eriksson and colleagues highlighted a strong influence of breast asymmetry within a model they developed to predict short-term breast cancer risk among women attending breast screening. They observed that the contribution to the model of asymmetry in mammographic breast density, microcalcifications, and masses between the breasts was as substantial as the total number of microcalcifications and masses found within a mammogram, indicating that differences between the breasts may be an important risk marker. To help further understand associations between breast cancer risk factors and asymmetry of breast density, particularly among women at elevated risk for breast cancer, we evaluated risk factor relationships with the bilateral asymmetry of volumetric measures of global and local breast density across the spectrum of premalignant and invasive breast cancer diagnoses. Methods: This study included 882 women enrolled as part of the National Cancer Institute's Breast Radiology Evaluation and Study of Tissues (BREAST)-Stamp Project (2007-2010). The BREAST-Stamp Project is a cross-sectional molecular epidemiologic study that aims to understand how novel breast density measures are related to breast cancer etiology. Women were enrolled if they were referred for diagnostic image-guided breast biopsy following an abnormal mammogram at the University of Vermont Medical Center, and had not previously been diagnosed or treated for cancer, undergone breast surgery within one year or received chemoprevention. Risk factor data were collected at study enrolment via interview and self-administered questionnaires. Breast density measures were estimated using Single X-ray Absorptiometry (SXA), a technique in which an SXA breast density phantom was affixed to the compression paddle of the mammography machine during routine mammography so that it was included in the X-ray field. It served as a reference standard to estimate volumetric breast density. Breast density was assessed using pre-biopsy craniocaudal full-field digital mammograms of both the ipsilateral (affected) and contralateral (unaffected) breast. Firstly, global density from each laterality was determined as percent fibroglandular volume (%FGV). Secondly, localized volumetric density measures were estimated following identification of the biopsy site on the ipsilateral pre-biopsy mammogram by the study radiologist and identifying the corresponding site on the contralateral mammogram. The SXA estimated %FGV in a perilesional volume twice the size of, but excluding, the biopsy target, centered at the biopsy site. Previous estimates of reproducibility for the SXA test phantoms demonstrated a repeatability SD of 2%, with a ±2% accuracy for the entire thickness and density ranges. Breast density asymmetry was defined as an absolute bilateral difference in measures when subtracting the breast density measures of the contralateral breast from the ipsilateral measures. Spearman's correlations (rho) examined associations between breast density measures of the left and right breasts. To determine relationships between breast cancer risk factors (defined as categorical variables) and measures of bilateral breast density asymmetry, analysis of covariance (ANCOVA) models (PROC GLM) were used. Analyses were conducted at the per woman level using SAS. Probability values of <0.05 were considered statistically significant, and all tests were two-tailed. Results:We initially investigated asymmetry within each woman by examining correlations between breast density measures in the left and right breasts. Strong, positive correlations between the ipsilateral and contralateral breast were observed for each breast density measure (rho for global %FGV=0.89, p-value<0.0001; rho for local %FGV=0.79, p-value<0.0001). Breast asymmetry was observed in the majority of the study population. For global %FGV, 76% of women had a bilateral difference ≥2%, with 43% of women having higher %FGV in their ipsilateral affected breast and 33% having higher in their contralateral unaffected breast. For localized %FGV, the majority of women had differences between their two breasts (89%), with 61% of women having higher localized %FGV in their ipsilateral affected breast compared to the remaining 28% who had higher localized breast density in their unaffected breast. We next examined relationships between breast cancer risk factors and breast asymmetry. Overall, no associations were observed between any of the risk factors examined, including age, race, body mass index, education, menopausal status, menopausal hormone therapy use with absolute bilateral differences in global or localized %FGV. Among the study population, most women had a benign breast disease diagnosis, with 33% and 43% being diagnosed with benign non-proliferative and benign proliferative lesions, respectively. Of the study population, 15% were diagnosed with invasive breast cancer. Overall, no differences were observed in bilateral differences in global %FGV according to diagnosis; however, higher mean bilateral differences in localized %FGV were observed for women with invasive compared to other diagnoses including benign and in-situ lesions (p=0.056). Discussion and conclusions: Our findings showed that breast asymmetry, defined by bilateral differences in global and localized mammographic breast density, was mostly unrelated to breast cancer risk factors among women undergoing an image guided breast biopsy. We observed that localized measures, defined according to within-woman bilateral differences in localized %FGV surrounding a suspicious lesion as compared with localized %FVG in a comparable location in the contralateral breast, may be an indication of cancer. This investigation is currently ongoing and efforts are underway to replicate findings using evolving image analysis methods such as Volpara Density Maps, an FDA-approved breast imaging tool which provides volumetric estimates of local glandular tissue distribution. Further, the ascertainment of 10-year follow-up data within this study population is in progress, which will facilitate prospective investigations of the relationship between breast asymmetry and breast cancer risk. Ongoing work will also extend our understanding of whether breast asymmetry is related to individualized breast cancer risk, defined using tailored breast cancer risk assessment tools. In conclusion, further understanding of breast asymmetry is needed to better exploit how bilateral differences in mammographic features may be used to inform breast cancer etiology as well as future breast cancer risk. Citation Format: Maeve Mullooly, Shaoqi Fan, Ruth M. Pfeiffer, Brian Sprague, Pamela M. Vacek, Donald L. Weaver, John A. Shepherd, Amir Pasha Mahmoudzadeh, Jeff Wang, Serghei Malkov, Jason M. Johnson, Sally D. Herschorn, Gretchen L. Gierach. Investigation of relationships between breast cancer risk factors and bilateral mammographic breast density asymmetry among women undergoing diagnostic image-guided breast biopsies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG15.