Diagnosis Of Benign Breast Disease Research Articles

Abstract GS01-06: Advancing Evidence of the Associations Between Specific Benign Breast Diagnoses and Future Breast Cancer RIsk

Abstract Background: Benign breast disease (BBD) is a common breast biopsy finding encompassing a diverse spectrum of diagnoses. Breast cancer risk associated with many specific BBD diagnoses and their joint associations with breast density have not been extensively studied. We estimate the future risk of invasive breast cancer associated with specific BBD diagnoses typically categorized into the broad category of proliferative lesions without atypia (PWoA) and evaluate whether associations differ by breast density or by presence of calcifications. Methods: We included 1,313,943 women ages 40-79 years who underwent 5,282,063 mammograms in the Breast Cancer Surveillance Consortium from 1996 to 2019 with no prior history of breast cancer. We fit a Cox proportional hazards model to estimate hazard ratios associated with each combination of PWoA BBD diagnoses, whether calcifications were present on biopsy, and breast density. We used classification trees to group combinations of PWoA diagnoses, breast density, age groups, and presence of calcifications with similar magnitudes of associations with 5-year risk of invasive breast cancer. Results: Compared with women with a PWoA BBD diagnosis without calcifications, presence of calcifications significantly elevated risk for breast cancer (HR=1.19, 95% CI = 1.02 to 1.41, P=0.03). Considering specific PWoA diagnoses, classification trees identified groups of women with higher and lower invasive cancer risk than expected risk for all PWoA combined. Among women ages 60-79 years with heterogeneously or extremely dense breasts, the 2.6% of women with any PWoA diagnosis, except papillomatosis, were at high invasive breast cancer risk (5-year risk >2.5%) (Table 1). Among women ages 40-59 years with dense breasts, presence of calcifications with papillomas, usual ductal hyperplasia, columnar cell hyperplasia, or PWoA NOS diagnoses put these women at high risk (5-year risk >2.5%) compared to women with the same BBD diagnoses without calcifications who were at intermediate or average risk (1-2.49%) (Table 1). Among women ages 60-79 years with non-dense breasts, the 1.6% of women with papilloma, usual ductal hyperplasia, radial scar, or PWoA NOS diagnoses were at high breast cancer risk (Table 2). Among women ages 40-59 years with non-dense breasts, presence of calcifications with usual ductal hyperplasia or PwoA NOS diagnoses put these women at intermediate risk (1.67-2.49%) compared to women with these BBD diagnoses without calcifications who were at average risk (1-1.66%) (Table 2). Women 60-79 years with fatty breasts were at intermediate 5-year risk if they had papillomas, usual ductal hyperplasia, or PWoA NOS diagnoses. Women 40-59 years with fatty breasts were at low risk of breast cancer regardless of PWoA diagnosis (Table 2). Conclusion: Specific BBD diagnoses and the presence of calcifications can change a woman’s predicted 5-year breast cancer risk compared to broad BBD categories alone. This information could be incorporated into risk prediction models to improve model accuracy. Citation Format: Olivia Sattayapiwat, Karla Kerlikowske, Donald Weaver, Alexander Borowsky, Theresa Keegan, Brian Sprague, Diana Miglioretti. Advancing Evidence of the Associations Between Specific Benign Breast Diagnoses and Future Breast Cancer RIsk [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-06.

Breast cancer early diagnosis detection of breast cancer through education of primary healthcare providers in Côte D'Ivoire.

e18767 Background: In Côte d'Ivoire, > 70% of women with breast cancer present with stage III/IV disease. To improve early detection, we designed and implemented an educational curriculum (EC; the Breast Health Program) for primary healthcare providers (PCPs). Methods: We performed in-depth interviews with key stakeholders to identify barriers and facilitators of breast cancer early detection. Interviews were audio-recorded, transcribed, double-coded and analyzed via thematic analysis. The EC was designed based on interview results and implemented during a one-day educational session for PCPs. Participating PCPs completed pre- and post-session surveys to assess knowledge. Data were analyzed using Fisher’s exact test. All p-values were two-sided. Results: Eighteen stakeholders participated in the interviews: 7 (39%) physicians, 5 (28%) medical students, 3 nurses, 2 cancer survivors, and 1 midwife. Identified barriers to early detection included: lack of awareness-raising campaigns to encourage earlier presentation (50%), need for patient follow-up and support after presentation to primary healthcare centers (50%), financial barriers (39%), delays due to lack of coordination in diagnosis and treatment (22%), and lack of mammography and biopsy capacity outside of the private sector (11%). Based on the interviews, the following topics were included in the EC: breast cancer and benign breast disease diagnosis and treatment, patient communication/support, clinical breast exam (CBE), symptom management, and financial navigation to assist patients access diagnosis. A total of 36 PCPs from five healthcare centers attended the educational session: 75% were female; the mean age was 41.3 years (SD 7.2); Nine (28%) were physicians, 6 (17%) nurses, 18 (50%) midwives; the median years of work experience was 7 years (range 3-32). At baseline, 18 (50%) PCPs felt qualified to evaluate patients with breast complaints; 10 (28%) did not, vs. 32 (89%) and 2 (6%) respectively at follow-up (χ2 = 8.75 p = 0.003). 15 (42%) providers felt qualified to help patients overcome barriers to diagnosis, and eleven (31%) felt unqualified/neutral at baseline, vs. 31 (86%) and 4 (11%) respectively at follow-up (χ2 = 7.67, p = 0.006). There were no statistically significant differences between baseline-follow-up in feeling qualified to perform CBE (27 (75%) vs. 32 (89%)) or ability to refer patients for diagnostic workup (29 (81%) vs. 34 (94%)). Conclusions: We identified multiple barriers to early breast cancer detection in Côte d’Ivoire. The EC was effective in improving confidence among PCPs and evaluation of breast complaints and addressing barriers to cancer diagnosis. There were no differences in feeling qualified to perform CBE or ability to refer patients to diagnostic workup, which were high at baseline. Future work includes expanding the program reach and evaluating impact on time to diagnosis.

Abstract 776: Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease

Abstract Introduction: Benign breast disease (BBD) is associated with increased breast cancer risk, and the magnitude of this risk is characterized by the severity of the histological classification of the biopsy lesion. High mammographic density (MBD) is an independent risk factor for invasive breast cancer. Given that MBD is altered by endogenous and exogenous factors, its temporal changes may impact future breast cancer risk, but this is poorly studied, particularly among high risk BBD patients. In this study, we examined whether MBD changes following a BBD diagnosis were associated with subsequent breast cancer risk. Methods: We conducted a case-control study within a cohort of 15,395 women aged 18-86 years who were members of the Kaiser Permanente Northwest Region health care system, had a diagnosis of BBD between 1970 and 2012 and were followed through mid-2015. Cases (n=261) were BBD patients who developed invasive breast cancer at least one year after the index BBD diagnosis. Controls were matched (1:1), on age at BBD diagnosis and health plan membership duration and did not develop breast cancer during the follow-up duration. Standardized change in percent MBD per 2 years, categorized as an increase (≥0%), stable/minimal decrease (-5%< to <0) or decrease (≤-5%), was determined from baseline (pre-biopsy) and follow-up (prior to breast cancer diagnosis for cases or matched selection date for controls) mammograms, using computer-assisted software. Associations between MBD change and breast cancer risk overall and stratified by BBD diagnosis age and histology were determined using unconditional logistic regression adjusted for matching factors and other covariates. Results: At BBD diagnosis (median age (range)=54.6 years (32.4, 86.6)), 64.5% (n=329: n=151 cases and n=178 controls) of women had non-proliferative and 35.5% (n=181: n=110 cases and n=71 controls) had proliferative BBD with or without atypia. Compared to women with stable/minimal MBD decrease, those who experienced a decline ≥5% per 2 years were less likely to develop breast cancer (odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.38, 1.07). However, among women aged ≥50 years at BBD diagnosis, an MBD decrease ≥5% was significantly associated with reduced breast cancer risk (OR: 0.48; 95%CI: 0.25, 0.92), with the protective effect most apparent for those with proliferative (OR: 0.32; 95%CI: 0.11, 0.99) versus non-proliferative (OR: 0.70; 95%CI: 0.30, 1.64) BBD. Discussion: Temporal MBD declines were associated with reduced risk of subsequent breast cancer particularly among BBD patients aged ≥50 years and with proliferative BBD diagnoses. These findings suggest that monitoring MBD may be useful in determining risk and that strategies to actively reduce MBD may be helpful in reducing breast cancer risk among high-risk BBD patients. Funding: Dr. Rohan is supported in part by the Breast Cancer Research Foundation (BCRF-22-140). Citation Format: Maeve Mullooly, Shaoqi Fan, Ruth M. Pfeiffer, Erin Aiello Bowles, Máire A. Duggan, Roni T. Falk, Kathryn Richert-Boe, Terry Kimes, Jonine D. Figueroa, Thomas E. Rohan, Mustapha Abubakar, Gretchen L. Gierach. Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 776.

Abstract 5241: Association of polygenic risk scores with breast cancer risk among women with benign breast disease

Abstract Over one million biopsies are performed annually in the U.S. to evaluate suspicious breast lesions. Most biopsies lead to a diagnosis of benign breast disease (BBD) and these women have a 1.5- to fourfold increase in subsequent breast cancer (BC) risk compared with the general population. A polygenic risk score (PRS) including 313 common variants was developed to predict BC risk in the general population and has improved performance when added to existing BC prediction models. However, the value of PRS in risk prediction models among women with BBD has not been evaluated. To evaluate the role of the established PRS, BBD, and BC risk, we pooled data from 15,194 white women (6,706 BC cases and 8,488 controls) participating in five Breast Cancer Association Consortium case-control studies. BC risk associations were evaluated by self-reported BBD history and combinations of PRS expressed in tertiles using odds ratios (OR), considering the lowest category of PRS among women without BBD as the referent. Associations were also assessed in an independent case-cohort study (831 BC cases and 1,845 controls) using hazard ratios (HR). Among the case-control studies, the PRS was strongly associated with BC risk (OR=2.50 per standard deviation increase), and associations were similar in women with (OR=2.60) and without a history of BBD (OR=2.44, p-interaction=0.23). Women with BBD have a higher risk of BC than those without BBD within each level of PRS. Compared to women without BBD and in the lowest PRS category, those with BBD and PRS in the highest tertile had 5-fold increased odds of BC (OR = 5.38; 95% CI 4.73-6.13). Associations were similar in an independent case-cohort study. These findings indicate that BBD history and PRS are independent contributors to BC risk, and consideration of both simultaneously could improve breast cancer risk prediction. Future studies are needed to integrate PRS with other risk measures to refine absolute BC risk prediction among BBD patients. Associations of BC risk with combinations of PRS (tertiles) and history of BBD in five case-control studies and a case-cohort study from the Breast Cancer Association Consortium. Case-control studies Case-cohort study PRS score range History of BBD n BC cases n controls OR (95% CI)1 n BC cases n controls HR (95% CI)2 Tertile 1 (≤ -0.57) No 1009 2692 1.00 (Ref) 117 584 1.00 (Ref) Yes 508 902 1.54 (1.35-1.76) 69 163 2.05 (1.45-2.89) Tertile 2 (-0.58, -0.03) No 1469 2001 1.97 (1.78-2.17) 181 475 1.93 (1.48-2.51) Yes 760 798 2.65 (2.34-3.01) 108 170 2.99 (2.18-4.09) Tertile 3 (≥ -0.02) No 1910 1551 3.32 (3.01-3.67) 214 336 3.28 (2.52-4.26) Yes 1050 544 5.38 (4.73-6.13) 142 117 4.83 4.25-8.02) 1.Logistic regression analysis, adjusted for study site/genomic platform and age at enrollment. OR, odds ratio; CI, confidence interval.2.Cox proportional hazards regression analysis, accounting for the case-cohort study design and adjusted for age at enrollment. HR, hazard ratio; CI, confidence interval. Citation Format: Stacey J. Winham, Mark Sherman, Robert Vierkant, Bryan McCauley, Christopher Scott, Mia Gaudet, Melissa Troester, Sandhya Pruthi, Derek Radisky, Amy Degnim, Kristan Aronson, Rachel Murphy, Pascal Guenel, Therese Truong, Jenny Chang-Claude, Heiko Becher, Montserrat Garcia-Closas, Stephen Chanock, Thomas Ahearn, Xiaohong Yang, Doug Easton, Manjeet Bolla, Celine Vachon, Breast Cancer Association Consortium. Association of polygenic risk scores with breast cancer risk among women with benign breast disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5241.

Abstract 4213: Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico

Abstract Introduction: Benign breast disease (BBD) is an important breast cancer (BC) risk factor, which may be classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) for risk stratification. Data related to the frequency of specific types of BBD and their relationship to BC risk in the Hispanic American population are limited. To address this knowledge gap, we compared BBD and associated BC risk among Hispanic white (HW) and non-Hispanic white (NHW) in New Mexico (NM). Methodology: A retrospective IRB-approved study was performed of women 19 years or older residing in six counties in NM (Bernalillo, Sandoval, Sante Fe, Socorro, Torrance, Cibola/Valencia) between 1996 and mid-2007 to compare the frequency of BBD subtypes and BC risk among HW and NHW. We excluded women who had a history of BC prior to BBD diagnosis or who were diagnosed with BC within 6 months after BBD biopsy. Race and ethnicity were self-reported by women at the time of biopsy. BBD was categorized as NPD, PDWA, or AH based on medical records. Incident BC (in-situ or invasive) was ascertained via linkage to the NM Surveillance Epidemiology End Results (SEER) Registry and BC risk was assessed using standardized incidence ratios (SIRs), comparing the observed number of BC events to that expected based on the NM SEER six-county race- and ethnicity-specific incidence rates, accounting for age and calendar period. Results: Our analysis included 3,870 HW and 6,996 NHW women with BBD. The HW were younger (47.1 vs. 51 years) compared to NHW. HW women had slightly more NPD (69.4% vs. 66.6%) but less PDWA (26.2% vs. 29.4%) and similar frequency of AH (4.3% vs. 3.9%) as compared to NHW. Over a median post-BBD follow-up period of 13 years (range 6 months-17 years), 644 BCs were observed (4.81% in HW and 6.55% in NHW). The observed BC risk among women with BBD was higher than population-based expected rates (SIR 1.98, 95% CI 1.82-2.13, p<0.001) and showed expected increases in risk with increasing degrees of BBD abnormality: SIR=1.90 for NPD, 2.00 for PDWA, and 3.01 for AH. Comparing BC risk by ethnic subgroups, HW women had an overall risk of BC after BBD that was statistically indistinguishable from NHW women (SIR=2.17, 95% CI 1.86-2.48 in HW women, and SIR=1.91, 95% CI 1.73-2.08 in NHW women). Within the major subgroups of the BBD findings, there were no significant differences in risk of BC after BBD for HW versus NHW women. Conclusions: In this population-based study, benign breast disease subtypes and their associated breast cancer risk were similar among the Hispanic and non-Hispanic white women. Citation Format: Kush Raj Lohani, Andrea M. Nibbe, Robert A. Vierkant, Laura M. Pacheco-Spann, Lisa R. Seymour, Celine M. Vachon, Mark E. Sherman, Amy C. Degnim, Deirdre Hill. Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4213.

CLINICAL STUDY ON BENIGN BREAST DISEASES

introduction Benign breast disease is the most common cause of breast problems, upto 30 percent of women will suffer from a benign breast disorder requiring treatment at sometime in their lives. 2 The main problem from a women poin to view is fear that such lumpmay be a cancer. Aims And Objectives 1.To determine the common types of benign breast diseases in the study group 2.To study the age distribution of different benign breast diseases. 3.To study the modes of presentation and clinical features. 4.To note the response to treatment and complications a rising during follow-up. 5.To correlate clinical ndings with FNAC and Histopathology. Materials And Methods Inclusion criteria 1. Female patients above 12 years of age who attended the OPD and those admitted in Department of Surgery Santhiram Medical College and General Hospital with clinical diagnosis of benign breast disease and who were willing to undergo investigations and treatment. 2. Patients who are willing for followup on monthly basis fora total period of 12 months following excision or conservative management. 3. Patients who have given in form edconsentare included in the study. Exclusion criteria 1.Male patients 2.Cases of malign antbreast lumpsasper FNAC ndings. 3.All patients aged12 years andless. Results: A study was carried out on 50 female patients above 12years of age with benign breast disease at Santhiram General Hospital, Nandyal over a period of two years. The data obtained was tabulated and analysed. : Benign conditions of breast are most common betweenConclusion 20-45 years of age. Majority of patients were between 31-40 years of age. Breast abscess was seen in women aged 20 and 25 years of age. They presented with lump, pain in the breast and fever forless than 10days. It was common on the left side, upper quadrant. Fibroadenoma was most common between 20 and 34 years of age. The commonest presentation was lump. Most cases presented vwithin 6months of onset of symptoms. It was more common onleft side than right, unilateral common than bilateral. Upper outerquadrant followed by upper in nerquadrant were most commonly involved.

Abstract SY25-02: Double-edged “soil”: Stromal microenvironment in breast cancer development

Abstract SY25-02: Double-edged “soil”: Stromal microenvironment in breast cancer development

Update on the Recommendations on Breast Cancer Screening by the Cancer Expert Working Group on Cancer Prevention and Screening.

Breast cancer (BC) is the most common cancer among women in Hong Kong. The Food and Health Bureau commissioned The University of Hong Kong (HKU) to conduct the Hong Kong Breast Cancer Study (HKBCS) with the aim of identifying relevant risk factors for BC in Hong Kong and developing a locally validated BC risk assessment tool for Hong Kong Chinese women. After consideration of the most recent international and local scientific evidence including findings of the HKBCS, the Cancer Expert Working Group on Cancer Prevention and Screening (CEWG) has reviewed and updated its BC screening recommendations. Existing recommendations were preserved for women at high risk and slightly changed for women at moderate risk. The following major updates have been made concerning recommendations for other women in the general population: Women aged 44 to 69 with certain combinations of personalised risk factors (including presence of history of BC among first-degree relative, a prior diagnosis of benign breast disease, nulliparity and late age of first live birth, early age of menarche, high body mass index and physical inactivity) putting them at increased risk of BC are recommended to consider mammography screening every 2 years. They should discuss with their doctors on the potential benefits and harms before undergoing mammography screening. A risk assessment tool for local women (eg, one developed by HKU) is recommended to be used for estimating the risk of developing BC with regard to the personalised risk factors described above.

Long-Term Risk of Breast Cancer after Diagnosis of Benign Breast Disease by Screening Mammography.

Assessing the long-term risk of breast cancer after diagnosis of benign breast disease by mammography is of utmost importance to design personalised screening strategies. We analysed individual-level data from 778,306 women aged 50–69 years with at least one mammographic screening participation in any of ten breast cancer screening centers in Spain from 1996 to 2015, and followed-up until 2017. We used Poisson regression to compare the rates of incident breast cancer among women with and without benign breast disease. During a median follow-up of 7.6 years, 11,708 (1.5%) women had an incident of breast cancer and 17,827 (2.3%) had a benign breast disease. The risk of breast cancer was 1.77 times higher among women with benign breast disease than among those without (95% CI: 1.61 to 1.95). The relative risk increased to 1.99 among women followed for less than four years, and remained elevated for two decades, with relative risk 1.96 (95% CI: 1.32 to 2.92) for those followed from 12 to 20 years. Benign breast disease is a long-term risk factor for breast cancer. Women with benign breast disease could benefit from closer surveillance and personalized screening strategies.

Abstract P2-11-12: Benign breast disease and breast malignancy

Abstract Introduction: Women with specific types of benign breast disease (BBD) are at higher than average risk for breast cancer. Non-proliferative BBD are at lower risk (1.3-2, compared to women without BBD), proliferative without atypia (1.8), and atypical proliferative such as atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) are at highest risk (2.5-4). We sought to categorize BBD subtypes for inclusion in a study to evaluate follow up screening and preventative care provided in a real world setting, by leveraging electronic health record and claims databases with refined diagnosis coding. Methods: We used the Kaiser Permanente Mid-Atlantic States (KPMAS) Research Data Warehouse (RDW), capturing claims and encounter data, to search for BBD among female patients with diagnosis dates from 1-1-2004 to 1-04-2020 and with at least 30 days of membership during the study period. We first selected patients with ICD-9 codes (217, 233, 610.8, 610.9), ICD-10 (D05.00-02, D05.81-82, D05.90, D24.1-2, D24.9, N60.81-2, N60.89, N60.91-2, N60.99, N62, N64.89). Filtering on IDs that capture standard diagnosis names, we included the diagnoses: benign neoplasm, intraductal papilloma, phyllodes tumor, ductal and stromal hyperplasias, dysplasia, atypical ductal and lobular hyperplasias (ADH, ALH), LCIS, and excluded fibroadenoma, sebaceous cysts, and non-specific carcinoma in situ. We calculated the time between malignant disease (DCIS or breast cancer) and the earliest BBD diagnosis in intervals: prior malignancy 31 or more days before BBD, concurrent malignancy within 30 days prior or after, and developed malignancy 31 or more days after BBD. We calculated overall survival after BC diagnosis, censored at Jan. 4, 2020. Results: We included 8670 unique patients with increased risk BBD subtypes, aged 12-93 years (median 52) at diagnosis. Patients self-reported race/ethnicity as Black (37.5%), White (28%), Asian (6%), Hispanic (1.6%), other (0.6%) and missing/unknown (25%). BBD diagnoses were first reported usually by the department of Surgery (35%), and Pathology (20%): other reporting departments include Hospitals, Radiology, Breast Health, Primary care, Ob/Gyn, and other or missing departments. Patients had more than one diagnosis: 47% benign neoplasm, 30.4% LCIS/DCIS, 12.5% intraductal papilloma, 12.9% ADH, 4% LCIS, 1.9% ALH, and the remainder with dysplasia, and phyllodes tumor or stromal hyperplasias. The benign neoplasm diagnosis was reported in 37% without another more specific diagnosis. Sixty percent, 5205 patients had no history of DCIS or BC at the time of BBD diagnosis. There were 1895 patients with DCIS (26.8% prior, 45.1% concurrent and 28.1% developed after BBD) and 3886 with BC (42.1% prior, 41.8% concurrent and 16.1% developed after BBD). For those with a breast cancer diagnosis, five-year overall survival after BC was 93%, with 649 (16.7%) deaths, median follow-up time of 6.7 yrs. Conclusion: Identifying specific BBD from the EHR can be accomplished with ICD codes and filtering on diagnosis IDs. Those with malignant disease were often diagnosed prior to or concurrent with benign disease. Citation Format: Monica Ter-Minassian, Brinda Somasundaram, Kala Visvanathan. Benign breast disease and breast malignancy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-12.

Abstract P2-11-01: Breast cancer (BC) risk among patients with benign breast disease (BBD) by NSAID use

Abstract Background: Approximately one million U.S women are diagnosed with benign breast disease (BBD) annually, which increases breast cancer (BC) risk between 1.5- and four-fold, depending on the pathologic characteristics of the lesion and other factors. BBD lesions are associated with inflammation and fibrosis, suggesting that inflammatory pathways may play a role in progression of BBD to BC. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are well tolerated, widely used drugs that block inflammation by inhibiting cyclooxygenase enzymes, which lowers prostaglandin synthesis, and by exerting numerous additional anti-inflammatory effects. NSAIDs are inversely associated with several types of cancer, including BC in some, but not all studies, and have been linked to lower BC risk among BBD patients in prior publications. We examined the association between NSAID use and BC risk, overall and by self-reported history of BBD, using data from the American Cancer Society Cancer Prevention Study II (CPS-II). Methods: The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is a study of approximately 189,000 U.S. men and women followed prospectively for cancer incidence and mortality. Study participants filled out a detailed questionnaire at baseline in 1992/1993 and follow-up surveys in 1997 and every two years until 2017. On each follow-up survey, participants reported type, quantity, and duration of NSAID use as well as diagnoses of BBD. Incident BCs were either self-reported and validated via medical records or cancer registry linkage, or identified via National Death Index linkage. Women in the analytic cohort were followed from date of 1997 survey until diagnosis of BC, reported use of tamoxifen, report of cancer other than BC, date of death, loss to follow-up or end of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) assessing associations of BBD and NSAID use with BC risk were estimated using Cox proportional hazards regression analysis. Statistical interactions between BBD and NSAID were evaluated by fitting and testing the corresponding cross-product terms, along with the main effects of each. Both NSAID use and BBD were modeled as time-dependent variables, allowing exposure status to change over the course of the multiple surveys returned. Results: Of the 60,517 women included in the study, 3,899 (6.4%) developed BC. Mean follow-up time was 12.7 years. A total of 23,661 women (39%) reported a diagnosis of BBD at some point during the study period, and 54,656 (90%) reported some NSAID use. Women self-reporting BBD were 46% more likely to develop BC than those without self-reported BBD (HR 1.46, 95% CI 1.36-1.57). Overall, BC risk was not increased among NSAID users versus non-users (HR 0.95, 95% CI 0.88-1.02). In contrast, BC risk was reduced among current NSAID users with a history of BBD (HR 0.87, 95% CI 0.78-0.97), but not among NSAID users who did not report a history of BBD (HR 1.02, 95% CI 0.92-1.13, p-interaction=0.04). Risk did not differ across number of pills per month (RR=0.84 for <15 pills/month, 0.89 for 15-29, 0.88 for 30-44, 0.78 for 45-59, 0.88 for 60+). Conclusion: In our study, NSAID use had a statistically-significant protective effect on BC risk among women with BBD, suggesting its potential use as a chemopreventive agent in this high-risk group of women, but not among those who did not report a history of BBD. Citation Format: Robert A Vierkant, Matthew Masters, Lauren R Teras, Mark E Sherman. Breast cancer (BC) risk among patients with benign breast disease (BBD) by NSAID use [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-01.

Abstract 789: Benign breast disease and all-cause and breast cancer-specific mortality among postmenopausal women in the Women's Health Initiative

Abstract INTRODUCTION: Benign breast disease (BBD) describes a heterogeneous group of premalignant lesions associated with an increased risk of breast cancer development, especially in those with proliferative BBD with atypia. Whether BBD is associated with higher all-cause mortality is unsettled. Therefore, we examined the association between incident BBD, BBD histotypes and all-cause and breast cancer-specific mortality among WHI participants. METHODS: Included were 68,132 postmenopausal women enrolled in the WHI clinical trials from 1993-1998 at 40 US clinical centres, followed up through March 2019. In these trials, serial mammography was mandated and compliance was high. Cases were participants in the BBD ancillary study (AS)130 with incident BBD confirmed by central pathology review. The comparison group included all other clinical trial participants (intervention and control groups). Cox proportional hazard regression models, stratified by baseline age, clinical trial arms and WHI extension study participation, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause and breast cancer-specific mortality in association with BBD. Analyses were adjusted for age, race/ethnicity, education, income, smoking, BMI, waist circumference, energy intake, alcohol, physical activity, reproductive factors, family history of breast cancer, Gail model score, history of menopausal hormone therapy (MHT) use and history of comorbidities. RESULTS: Compared to women without incident BBD (n=43,439), women with incident BBD (n=3,467) were younger (p<0.001), more likely to have a higher education level (p=0.003), higher income (p<0.001), lower BMI (p=0.003) and waist circumference (p=0.002), a Gail risk score of >1.75 (p<0.001), a family history of breast cancer (p<0.001) and used MHT (p<0.001). There were 737 deaths among the BBD case group and 8,949 deaths among the non-case group. In adjusted analyses, no association was observed between incident BBD and all-cause mortality (HR:0.92, 95%CI: 0.83, 1.01). In adjusted analyses stratified by BBD, compared to women without BBD, no association for all-cause mortality was observed for women with non-proliferative BBD (n=374; HR:0.96; 95%CI: 0.84, 1.09), proliferative BBD without atypia (n=309; HR:0.91, 95%CI: 0.79, 1.05) or proliferative BBD with atypia (n=54; HR:0.72, 95% CI: 0.51, 1.03). In secondary analyses, compared to women without incident BBD, women with incident BBD had a statistically significantly higher breast cancer-specific mortality both for BBD overall and for each BBD histotype. CONCLUSIONS: In postmenopausal women, while a BBD diagnosis was associated with a statistically significant higher risk of breast cancer-specific mortality, irrespective of histotype, a BBD diagnosis was not associated with higher all-cause mortality. Citation Format: Maeve Mullooly, Kathy Pan, Sowmya Vasan, Gretchen L. Gierach, Dorothy S. Lane, Aladdin H. Shadyab, Juhua Luo, Lihong Qi, Kathleen E. Bennett, Thomas E. Rohan, Rowan Chlebowski. Benign breast disease and all-cause and breast cancer-specific mortality among postmenopausal women in the Women's Health Initiative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 789.

Benign breast disease and changes in mammographic breast density

BackgroundMammographic breast density (MBD) and benign breast disease (BBD) are two of the strongest risk factors for breast cancer. Understanding trends in MBD by age and parity in women with BBD is essential to the clinical management and prevention of breast cancer.MethodsUsing data from the Early Determinants of Mammographic Density (EDMD) study, a prospective follow-up study of women born in 1959–1967, we evaluated MBD in 676 women. We used linear regression with generalized estimating equations to examine associations between self-reported BBD and MBD (percent density, dense area, and non-dense area), assessed through a computer-assisted method.ResultsA prior BBD diagnosis (median age at diagnosis 32 years) was reported by 18% of our cohort. The median time from BBD diagnosis to first available study mammogram was 9.4 years (range 1.1–27.6 years). Women with BBD had a 3.44% higher percent MBD (standard error (SE) = 1.56, p-value = 0.03) on their first available mammogram than women without BBD. Compared with parous women without BBD, nulliparous women with BBD and women with a BBD diagnosis prior to first birth had 7–8% higher percent MBD (β = 7.25, SE = 2.43, p-value< 0.01 and β = 7.84, SE = 2.98, p-value = 0.01, respectively), while there was no difference in MBD in women with a BBD diagnosis after the first birth (β = −0.22, SE = 2.40, p-value = 0.93).ConclusionWomen with self-reported BBD had higher mammographic breast density than women without BBD; the association was limited to women with BBD diagnosed before their first birth.

Risk factors for breast cancer development by tumor characteristics among women with benign breast disease

BackgroundAmong women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown.MethodsUsing a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.ResultsBreast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14–14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21–3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.ConclusionMost tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.

The impact of mammographic screening on the subsequent breast cancer risk associated with biopsy-proven benign breast disease

Data on the risk of breast cancer following a benign breast disease (BBD) diagnosis were derived predominantly from populations of women biopsied before the widespread use of mammographic screening and in whom these lesions were mostly incidental findings. Whether or not similar risk associations are seen when these lesions are detected in mammographically screened populations is unknown. To address this, we examined the variation in BBD and breast cancer risk associations by the calendar time of BBD diagnosis (pre- vs. post-mammography era [before vs. 1985 and after]) in a nested case–control study within the Nurses’ Health Study (NHS) and NHSII BBD subcohort (488 cases; 1908 controls). We performed logistic regression analysis, adjusting for matching factors and potential confounders, to estimate odds ratio (ORs) and 95% confidence interval (CI) for the association between BBD subtype (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia (AH)) and subsequent breast cancer risk. When compared with non-proliferative lesions, both proliferative lesions without atypia (PWA) and AHs were associated with similar levels of risk in the pre-mammographic (pre) and post-mammographic (post) time periods (PWA: OR [95% CI] = 1.73 [1.27, 2.36] pre vs. 1.12 [0.73, 1.74] post; AH: 4.41 [2.90, 6.70] pre vs. 3.69 [2.21, 6.15] post). The interaction by mammography era was not statistically significant (p-interaction = 0.47). These results suggest that the risk associations reported for BBD subtypes in the pre-mammography era remain valid for BBD detected after the widespread implementation of mammographic screening.

Abstract PS7-11: Benign breast disease: Temporal trends from 1967 to 2013

Abstract Background: Women with benign breast disease (BBD) are at increased risk of breast cancer (BC). Classic studies based on film-based mammographic screening and pathology diagnosis of surgical biopsies conducted in the 1980s established a hierarchy of increasing BC risk: non-proliferative (NP) BBD, proliferative BBD without atypia (PDWA) and atypical hyperplasia (AH). Given changes in epidemiological BC risk factors and introduction of percutaneous core needle biopsy (CNB) in mid-1990s, and later, digital mammography, we hypothesized that the patient characteristics and relative frequency of BBD diagnoses have changed over time. Accordingly, we performed a longitudinal analysis of the frequency of patient characteristics and BBD diagnoses in the Mayo BBD cohort. Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had a BBD biopsy between 1/1/67 and 12/31/13 were identified. Breast pathologists reviewed biopsies masked to diagnoses of incident BC diagnosed in follow-up. Demographic characteristics and BC events were obtained by query of institutional data sources and participant surveys. Trends were evaluated for the following eras: 1: pre-mammogram (1967-1981), 2: pre-CNB (1982-1992), 3: CNB Transition (1993-2001), and 4: CNB (2002-2013). Demographics were formally compared across eras using chi-square tests for categorical variables and analyses of variance (ANOVAs) for continuous variables. Results: From 1967-2013, the cohort includes 19,582 unique women with BBD. The frequency of CNB increased from eras 1-4: 0.04%, 0.6%, 51.3 %, and 88.9%, respectively. Mean age at BBD diagnosis was younger in era 1 (48.0 years) vs eras 2-4 (53.2, 52.0, and 51.8, respectively, p&amp;lt;0.001). The percentage of biopsies diagnosed as PDWA increased from era 1-4 (25.7%, 34.3%, 35.2%, 46.2%, p&amp;lt;0.001), as did the percentage with AH (2.4%, 5.1%, 8.6%, 12.3%, p&amp;lt;0.001). Over eras 1-4, the percentages of women with a strong family history of BC increased (9.9%, 12.7%, 17.1%, and 29.0%, p&amp;lt;0.001) as did mean BMI (24.8, 26.4, 27.4, and 28.6, p&amp;lt;0.001). With a median follow-up of 10.9 years, 1,719 breast cancers have developed, with increasing proportion of noninvasive (DCIS-only) disease across eras 1-4: 15.0%, 21.1%, 21.2%, and 33.2%, p&amp;lt; 0.001. Conclusions: Analysis of this large, single institution BBD cohort for the 46 year period 1967-2013 demonstrates that BC risk factors among BBD patients has changed over time, with subjects demonstrating increasing age, BMI, and family history, and that the percentages of BBD classified as PDWA and AH have increased. Impact on BC risk will be further investigated. Citation Format: Amy Degnim, Karthik Ghosh, Jodi M Carter, Robert A Vierkant, Matthew R Jensen, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Teresa M Allers, Denise L Gehling, Mindy J Kern, Laura M Pacheco-Spann, Celine M Vachon, Derek C Radisky, Daniel W Visscher, Mark E Sherman. Benign breast disease: Temporal trends from 1967 to 2013 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-11.

Infiltrating immune cells in benign breast disease and risk of subsequent invasive breast cancer

BackgroundIt is well established that tumors are antigenic and can induce an immune response by the host, entailing lymphocytic infiltration of the tumor and surrounding stroma. The extent and composition of the immune response to the tumor, assessed through evaluation of tumor-infiltrating lymphocyte counts, has been shown in many studies to have prognostic and predictive value for invasive breast cancer, but currently, there is little evidence regarding the association between infiltrating immune cell counts (IICCs) in women with benign breast disease (BBD) and risk of subsequent invasive breast cancer.MethodsUsing a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest, we conducted a nested case-control study in which cases were women who developed a subsequent invasive breast cancer during follow-up and controls were individually matched to cases on age at BBD diagnosis. We assessed IICCs in normal tissue and in the BBD lesions, and we used unconditional logistic regression to estimate the multivariable odds ratios (OR) and 95% confidence intervals (CI) for the associations between IICCs and breast cancer risk.ResultsThere was no association between the IICC in normal tissue (multivariable OR per 5% increase in IICC = 1.05, 95% CI = 0.96–1.16) or in the BBD lesion (OR per 5% increase in IICC = 1.06, 95% CI = 0.96–1.18) and risk of subsequent invasive breast cancer. Also, there were no associations within subgroups defined by menopausal status, BBD histology, BMI, and history of smoking.ConclusionThe results of this study suggest that IICCs in BBD tissue are not associated with altered risk of subsequent invasive breast cancer.

Abstract 2113: Discrimination of benign breast disease from normal lobules using an automated computational pathology algorithm

Abstract Background: Biopsy diagnosis of benign breast disease (BBD) based on the most severe lesion in a sample predicts future breast cancer risk and has implications for screening and management. Lobules are the functional unit of the breast and the structures from which BBD arises. We developed and preliminarily validated an automated computational pathology algorithm to discriminate normal from BBD breast lobules as a step toward automated comprehensive characterization of benign biopsies. Methods: 152 BBD biopsies (27 training, 125 validation) from the Mayo Clinic were examined using scanned digital images of H&amp;E stained sections. For each image, a pathologist annotated up to 10 representative lobules as normal or BBD using standard pathology criteria. A deep learning algorithm to quantify lobular features was developed using 129 lobules from 27 subjects. Nine features were identified that discriminate normal vs BBD lobules, expressing lobule size, acini size and number, acinar lumen size, proportion of lobular stroma, and capillaries. Here, we validate their performance to discriminate normal vs BBD lobules in a set of 1250 lobules from 125 subjects using area under the ROC curve (AUC) analysis. Random forest analysis was used for multivariable modeling; model performance was assessed with a tenfold cross-validation approach. Results: Median subject age was 52 years. Among the 125 validation subjects, BBD findings were nonproliferative in 39%, proliferative in 45%, and atypical hyperplasia in 16%. Sections included 552 (44%) normal lobules and 698 BBD (56%) lobules, with representation of both lobule types on each section. In univariate analyses, four individual features showed good discrimination between normal vs. BBD lobules, yielding the following AUCs: lobule size= 0.74, mean acini size= 0.75, epithelial area= 0.75, and number of acini with large lumens= 0.76. Lobule size and epithelial area were highly correlated (Spearman rank correlation r = 0.95), but both of these features showed lower correlation with mean acini size and number of acini with large lumens (each r &amp;lt; 0.5). With random forest modeling, number of acini with large lumens was the strongest discriminating feature, followed by mean acini size, lobule size, and epithelial area. With ten-fold cross validation of the multivariable random forest model, the overall AUC was 0.82 (95% CI: 0.79-0.85). Conclusion: Our validation showed that automated quantitative computational pathology assessment of breast lobules can discriminate normal versus BBD on a per lobule basis. This finding supports the feasibility of developing automated algorithms to classify every lesion in breast biopsies, expanding beyond visual assessment. Further studies using deep learning may reveal novel pathology features for classifying BBD biopsies with the potential to strengthen estimation of breast cancer risk. Citation Format: Amy C. Degnim, Thomas de Bel, Mark E. Sherman, Derek C. Radisky, Stacey J. Winham, Tanya L. Hoskin, Melody L. Stallings Mann, Marlene Frost, Robert A. Vierkant, Brendan T. Broderick, Ethan P. Heinzen, Rushin Brahmbhatt, Muhammad Arshad, Celine M. Vachon, Jodi M. Carter, Lori A. Denison, Daniel W. Visscher, Jeroen van der Laak. Discrimination of benign breast disease from normal lobules using an automated computational pathology algorithm [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 2113.

Abstract 4632: Automated quantitative measures of terminal duct lobular unit involution and breast cancer risk

Abstract Background Terminal duct lobular units (TDLUs) involute with age. Prior studies using qualitative or semi-quantitative measures of TDLU involution found inverse associations with breast cancer (BC) risk. We applied our validated deep learning computational method to yield quantitative measures of TDLU involution in normal breast tissue and then assessed their association with established BC risk factors and BC risk. Materials and Methods This study used a nested case-control design within the Nurses' Health Study cohorts. Cases and controls were diagnosed with benign breast disease (BBD) and cases subsequently developed BC (median 7.75 years later). Cases and controls were matched on year of BBD diagnosis, age at BC diagnosis (or index date for controls), and years between BBD and BC diagnosis (or index date). We applied our computational method to 3951 whole slide images of normal breast tissue from BBD biopsies (287 cases and 1083 controls; median 3 images per woman). Quantitative estimates of TDLU involution were derived for 3 standardized measures (median TDLU span, TDLU count per non-adipose tissue area, median acini count) and 5 novel measures (median TDLU area, TDLU area as a percentage of total tissue area, TDLU area as a percentage of total non-adipose tissue area, acini count per non-adipose tissue area, median acini density). TDLU involution was also manually categorized in 177 cases and 857 controls. Associations between TDLU involution measures and risk factors were evaluated among controls using Spearman's rho or Chi-squared tests. The relationship between each measure and BC risk was evaluated using logistic regression models controlling for the matching factors and BBD histological subtypes. Results All 8 TDLU measures were significantly inversely correlated with age at BBD biopsy (range: rho -0.07 to -0.42; p&amp;lt;0.05) and menopausal status (p&amp;lt;0.05). Parity was positively associated with 6 metrics (p&amp;lt;0.05); birth index was inversely associated with another 6 metrics (p&amp;lt;0.05). Select TDLU measures were also significantly associated with BBD histological subtype, BMI, age at first birth, and/or length of total breastfeeding (p&amp;lt;0.05). No metric was significantly correlated with body size at ages 5-10 years or age of menarche. No quantitative TDLU involution measure was associated with subsequent BC risk; results remained null within strata of parity and menopausal status. Qualitative categorizations of TDLU involution were also not associated with BC risk (predominant lobule type 1 no type 3 versus no type 1, adjusted OR=0.95, 95%CI 0.54-1.71). Conclusion Quantitative measures of TDLU involution were associated with age and reproductive BC risk factors. However, automated and manual assessments of TDLU involution in normal tissue were not associated with BC risk. Further work will include applying our method to assess TDLU involution and BC risk in other cohorts. Citation Format: Kevin H. Kensler, Emily Z. Liu, Suzanne C. Wetstein, Allison M. Onken, Christina I. Luffman, Gabrielle M. Baker, Laura C. Collins, Stuart J. Schnitt, Vanessa C. Bret-Mounet, Mitko Veta, Josien P. Pluim, Ying Liu, Graham A. Colditz, Rulla M. Tamimi, Yu Jing Jan Heng. Automated quantitative measures of terminal duct lobular unit involution and breast cancer risk [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 4632.

Abstract NG15: Investigation of relationships between breast cancer risk factors and bilateral mammographic breast density asymmetry among women undergoing diagnostic image-guided breast biopsies

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 Institute9s 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. Spearman9s 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 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.