Search

Background: Inflammatory breast cancer (IBC) is the most aggressive locally advanced breast cancer subtype. It is associated with loco-regional recurrence rates of 12-25%, and neoadjuvant chemotherapy (NAC) followed by modified radical mastectomy and comprehensive chest wall and regional nodal radiotherapy remain the standard of care. As has been demonstrated in non-IBC, achievement of pathologic complete response (pCR) has been shown to be associated with improved loco-regional control, recurrence-free and overall survival. Advances in NAC for IBC have resulted in improved pCR rates in both the breast and the axilla, with overall axillary pCR rates of approximately 30%, reaching as high as 67% in patients with HER2-positive disease receiving HER2-directed therapy. Hypothesis: Sentinel lymph node biopsy (SLNB) may be feasible in IBC patients who experience a good clinical and pathologic response in the axilla to NAC. Primary Objective: To evaluate the sentinel lymph node (SLN) identification rate in stage III IBC patients who experience cN0 status at completion of NAC. Secondary Objective: To assess the incidence of lymphedema following standard local-regional therapy for IBC. Methods and Study procedures: In this feasibility study, 50 patients with cT4dN0-2M0 IBC will be enrolled in order to evaluate 40 patients whose axillary nodal status becomes cN0 upon completion of NAC. All patients will undergo a research breast biopsy and lymphoscintigram pre and post NAC to evaluate lymphatic drainage patterns and patency of breast and axillary lymphatics. Post NAC lymphoscintigraphy will be appropriately timed for pre-operative SLN mapping and all patients will undergo SLNB using dual tracers (Tc99 Sulfur colloid and blue dye) with immediate axillary lymph node dissection (ALND), at the time of mastectomy. The patient-reported Lymphedema Symptom Intensity and Distress Survey (LSIDS-A) will be collected at 6 timepoints. Patients will be followed for 2 years post-surgery for oncologic outcomes. Correlatives: We plan to evaluate genetic and phenotypic heterogeneity in IBC and to assess markers of angiogenesis and lymph-angiogenesis associated with IBC, as well as to explore immunologic aspects of the tumor microenvironment and their association with pCR. Statistics: The identification rate will be calculated as number of patients in whom SLNs were successfully identified over the number of patients with cN0 disease after NAC in whom SLN mapping was attempted. Using a Simon two-stage design (α=.10, β=.10), a SLN identification rate of ≥90% would result in considering this procedure feasible whereas an identification rate of ≤75% (null hypothesis) would lead to the conclusion that it is not feasible. In the first stage, if greater than 18 of 25 patients have SLNs identified, then a total of 40 patients will be enrolled. If fewer than 33 of 40 patients have SLN identified, then the null hypothesis is rejected. Citation Format: Faina Nakhlis, Meredith Regan, Heather Jacene, Beth Harrison, Jennifer Bellon, Jean Landry, Eren Yeh, Elizabeth Mittendorf, Beth Overmoyer, Tari King. Refining loco-regional therapy for inflammatory breast cancer protocol in progress [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 PS14-21.

Background: Given the clinical utility for diagnosis and treatment of hereditary breast cancer, the use of genetic testing is growing. However, few data exist on the association between genetic testing and subsequent clinical outcomes, healthcare utilization, and cost. Objective: To examine medical utilization, cost, and survival in individuals with breast cancer who were tested for genes with high evidence for predicting breast cancer risk, as compared to those who were untested. Methods: A retrospective observational study was conducted in commercial claims. Adult women with non-metastatic breast cancer during 2013-2017 were identified and divided into two groups: (1) a genetic testing group (GTG) that was tested during January 2014-June 2017 for high risk genes for hereditary breast cancer (BRCA, PTEN) and (2) a no genetic testing group (NGTG) that did not test for any genes or gene expression for hereditary breast cancer. Members in the NGTG were matched 1:1 to the GTG by propensity scores using age, region, baseline clinical variables (other cancer types, breast imaging, breast biopsy, Deyo-Charlson Comorbidity Index), and baseline all-cause and cancer-related costs. Utilization and cost outcomes were assessed during 1 year post-genetic testing. We also estimated survival and all-cause healthcare costs during full follow-up, in the main sample and in a “3-year” sample of women who took their first genetic test at least 3 years prior to study end. Variables remained unbalanced after matching were adjusted in regression modeling. Results: The study identified 12,236 patients in the GTG and 53,125 patients in the NGTG. All patient covariates, except baseline cancer-related costs, were balanced after 1:1 propensity score matching (n=10,887 matched patients in each group). In the GTG and NGTG, 18% and 1%, respectively, had follow-up genetic testing (p Conclusions: Increased treatment and healthcare costs are likely to follow genetic testing and should be discussed in the shared decision-making process. Survival analyses were inconclusive due to low rate of mortality. Citation Format: Shia T Kent, Xiaoxue Chen, David Debono, Karen Lewis, Abiy Agiro. Genetic testing for breast cancer and associated downstream utilization and costs [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-13.

Introduction: Current guidelines are for yearly mammograms in women with early-stage breast cancer. Among breast cancer survivors treated with lumpectomy, semi-annual compared to annual screening mammography of the ipsilateral breast has been associated with early detection of local recurrence. However, a potential harm of more frequent screening is false-positive breast biopsies that may lead to negative psychosocial effects and increased costs. Our objective was to investigate how frequency of screening mammograms affects rates of false-positive biopsy results and local recurrences among breast cancer survivors. Methods: We conducted a retrospective cohort study at Columbia University Medical Center (CUMC) in New York, NY of women diagnosed with stage 0-III breast cancer between 2007 and 2015, who were treated with lumpectomy and had at least 2 screening mammograms at CUMC within the first 3 years after diagnosis. Demographic and clinical information, including tumor characteristics and breast cancer treatments, were collected from the electronic health record. Frequency of mammography screening was defined as the median interval between 2 consecutive mammograms (every 6 months vs. yearly). Both false-positive biopsy results and local recurrences were identified by review of breast pathology reports. A false-positive biopsy was defined as a diagnostic breast biopsy without evidence of invasive or non-invasive cancer. Descriptive statistics and logistic regression models were conducted to examine relationships between covariates and either false-positive biopsy or local recurrence. Results: In our sample (n=1257), the median age at breast cancer diagnosis was 60 years (range, 24-93), including 47% non-Hispanic white, 14% non-Hispanic black, 31% Hispanic, and 7% Asian. Nearly 80% of women had semi-annual screening mammography of the ipsilateral breast during the first 3 years after breast cancer diagnosis. In univariate analysis, higher body mass index, more advanced stage disease, higher tumor grade, and receipt of chemotherapy, hormonal therapy, and radiation therapy were associated with more frequent screening. Comparing women who screened every 6 months vs. yearly, there was no difference in local recurrence rates (4.1% vs. 3.9%), including screen-detected or invasive/non-invasive breast cancer recurrences. In multivariable analysis, women who screened every 6 months compared to yearly had a greater than 2-fold increased risk of having a false-positive biopsy (OR: 2.40; 95% CI: 1.50-3.86). Also, younger age at diagnosis, higher tumor grade, and receipt of chemotherapy were associated with higher false positive rates, adjusting for covariates. Conclusions: We observed that women with early-stage breast cancer treated with lumpectomy who underwent semi-annual vs. annual screening mammography had more false-positive breast biopsies, but no difference in local recurrence rates. To date, there is no evidence that more frequent screening in breast cancer patients is associated with improved survival. Future studies are needed to determine optimal screening strategies for breast cancer survivors, including frequency of screening and use of supplemental breast imaging with ultrasound, MRI, or tomosynthesis. Citation Format: Yuan S, Manley HJ, Ha R, Yu A, Genkinger JM, Crew KD. Effect of mammography screening frequency on false-positive biopsy rates and detection of local recurrence among breast cancer survivors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD2-15.

Background The crucial point in making treatment decisions for breast cancer patients is the assessment of tumour aggressiveness. The established prognostic markers may be insufficient to stratify cancer patients into treatment relevant risk groups. Emerging evidence indicates that mechanical properties of cancer cells and their microenvironment that occur on a nanometre scale play a critical role in cancer invasion and metastases. Therefore, detecting these nanomechanical changes could serve as biomarker of cancer aggressiveness. Trial design We conduct a prospective, blinded study in a routine clinical setting. Using minimal invasive breast biopsies we measure the nanomechanical (stiffness) properties of human breast tissue with our atomic force microscope (AFM) based method known as ARTIDIS (Automated and Reliable Tissue Diagnostics). These properties can only be measured using fresh (non-fixed) tissue under physiological conditions (Custodiol transplant buffer). This novel method is based on the use of a micro-fabricated 20nm-sharp tip that indents several thousand individual locations across tissue specimens within 60-180 minutes. Each indentation effectively measures the stiffness of local structures (e.g. cancer cells, extracellular matrix) located under the tip. Thus we obtain a quantitative, biopsy-wide, nanomechanical profile. Post-AFM the same biopsy is used for routine histopathological diagnosis, the current diagnostic gold standard to which the nanomechanical profile is then correlated. Eligibility criteria All women undergoing a minimal invasive breast biopsy (core needle or vacuum assisted biopsy) at the breast centre of the University of Basel. Exclusion criteria: age younger than 18years, necrotic/disintegrated biopsy, and technical limitations Specific aims Our primary endpoint is to differentiate benign from cancerous breast lesions based on their nanomechanical properties. Our secondary endpoint is to subclassify biopsies with cancerous lesions into the current four main breast cancer subgroups (Luminal A, Luminal B, HER2+ and basal-like). Statistical analysis The full dataset will include all patients with valid AFM measurements. Primary analysis: the proportion of true positive results divided by the total number of patients with malignant tumour (sensitivity) will be estimated and presented together with its 95% confidence interval. The histological diagnosis of the same biopsy as analysed by AFM will serve as gold standard. Present accrual and target accrual Present accrual as of June 12, 2017: 200 breast tissue biopsies. Target accrual is 508 biopsies. This will allow for a power of 0.8 and a sensitivity of 90%. Contact information: Rosemarie.Burian@usb.ch Citation Format: Burian R, Appenzeller T, Oertle P, Raez C, Lim R, Forte S, Dellas S, Münst S, Obermann E, Plodinec M. Atomic force microscopy (AFM) - a novel nanotool for cancer diagnostics: A prospective, blinded study of nanomechanical profiling of human breast tissue as a potential biomarker for stratifying low- and high-risk breast cancer subtypes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-06-05.

Purpose: miRNAs are non-coding RNAs that are abnormally expressed in breast cancer, with critical roles in cancer due to their regulation of large gene networks. miRNA expression in benign high-risk breast tissue has never been evaluated, but it may provide information about early dysregulation events that contribute to breast cancer risk. The contralateral unaffected breast (CUB) of women with unilateral breast cancer is in high-risk for the second primary cancer. Thus, we examined miRNA expression profiles in tumor and the matching CUBs to seek potential miRNA biomarkers for breast cancer risk. Methods: FFPE tissues of breast cancer and their matching CUB tissues were sectioned. The areas of tumor and normal ductal epithelium were outlined and then dissected using laser microdissection system. Total RNA was extracted for miRNA profiling studies. Expression profiles of 754 mature miRNAs were examined using TaqMan Low Density Arrays assays in 30 paired breast cancer and CUB samples (15 with ER+ tumors, 15 with ER- tumors) and 15 reduction mammoplasty (RM) controls, matched by age, race and menopausal status. ANOVA test was performed to examine the differential expression among groups and pairwise comparison with Sidak adjustment was used for multiple comparison. Seven candidate miRNAs were then examined in an independent CUB sample set (20 with ER+ tumors, 20 with ER- tumors) and 20 RM controls. Further independent validation was performed using qRT-PCR in 80 benign breast biopsy (BBB) samples: 40 from women who subsequently developed breast cancer (cases) and 40 from those who did not (controls). Logistic regression analysis and receiver operating characteristic (ROC) analysis were performed using combinations of the expression of multiple miRNAs to establish models discriminating cases from controls. Results: Seven miRNAs (miR-18a, miR-210, miR-214*, miR-124, miR-193a-3p, miR485-3p and miR-671-3p) were found to be differentially expressed in breast cancer and CUB samples vs. RM samples in the discovery sample set. Among them, miR-18a and miR-210 were validated in a second, independent CUB sample set. The expression of miR-18a and miR-210 were significantly higher in tumor (regardless ER status) compared to CUBs and RM controls. The expression levels in CUBs were significantly higher than in RM. We then examined miR expression in case BBB samples, and confirmed that expression of miR-18a and miR-210 were increased compared with controls. ROC analysis using miR-18a and miR-210 discriminated high-risk cases from standard-risk controls with OR 2.44, P = 0.022. Conclusion: The expression of miR-18a and miR-210 were elevated in breast cancer, in matched CUBs, and in BBB predating cancer diagnosis. These data provide strong support for the hypothesis that miR-18a and miR-210 expression in BBB is an indicator of increased risk of breast cancer. Given the high expression in tumors, they are also potential cancer detection biomarkers. Citation Format: Wang J, Shidfar A, Costa FF, Scholtens D, Bischof JM, Sullivan ME, Ivancic D, Soares MB, Khan SA. Expression of miR-18a and miR-210 in normal breast tissue as candidate markers of breast cancer risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-07-02.

Background: Stratified breast cancer (BC) prevention is a major option for the future but requires clinically meaningful internationally validated risk models. Non parametric models may be alternate methods for modeling in very large cohorts. We have previously shown that a non-parametric similarity-based k-nearest neighbors' (kNN) model performs better than the BCRAT/Gail model to on 65 000 women of the E3N French national cohort (Dartois et al 2015). We used this method to develop and validate a mammographic density-based model in larger general screening populations (pops). Methods: A modified version of a data-mining based algorithm, the kNN method, was implemented and adapted as previously described [ref Dartois]. Core concept of kNN algorithm is to gather similar profiles using a distance computation. We developed a BC risk prediction model on 629 229 women (wn) from the US Breast Cancer Research Consortium (BCSC), with 5 times random selection of learning and validation sets (75/25 %) within the cohort. 5 parameters were included: age, family history, previous breast biopsy, mammographic density and race. The model's performances (discrimination using c-stat (AUC) and calibration using E/0 ratio) were evaluated and compared to the parametric model developed on the same pop (param/BCSC)(Tice et al 2008). This kNN/BCSC model was then tested on two French screening pops after adjustment on French BC incidence: an urban area (Paris suburbs, N=316 775) and a rural area (Côte d'Or, N=32 930). Its performances were compared to those of a model directly developed (same methods) on the Paris cohort (kNN/Paris). Levels of individual risks assessed by the models were assigned into 4 risk categories. The sensitivity of the models was defined as the number of wn who had BC whose 5 yrs-risk category was intermediate (median risk at 50-yrs - 1.66%), high (> 1.66%) or very high (> 20% lifetime) divided by the total number of wn who had BC. Results: The performances of the different models are shown in Table 1. The kNN model developed on BCSC performed well (c-stat 0.653 and E/0 1.001). It had equivalent performances as the parametric model developed previously on the same pop. This kNN/BCSC had a good discrimination on French pops, although slightly lower than that on US pops. This is expected since French screening starts at 50 (vs 40 in BCSC) and French parameters do not include race. The calibration of such model was excellent on Paris, while it overestimated the risk on Côte d'Or, in which BC incidence is lower. It performed as well as the kNN/Paris model directly developed on Paris' pop. The sensitivity of the kNN/BCSC on US and French pops was good. Conclusions: A new non parametric kNN breast cancer risk model developed on an American screening cohort (BCSC) was successfully validated on two French screening cohorts. This new international model could allow stratified prevention. Performances of the models Param/BCSC on BCSCParam/BCSC on PariskNN/BCSC on BCSCkNN/BCSC on PariskNN/BCSC on Cote d'OrkNN/Paris on ParisN629 229313 817629 229313 81732 930313 817c-statistic0.6580.6020.6530.6020.5930.605E/0 global1.031.071.0011.061.521.00Sensitivity--76.18%72.87%72.58%- Citation Format: Ragusa S, Gauthier E, Dartois L, Tice J, Dancourt V, Arveux P, Brixi Z, Bernoux A, Soyer P, Delattre H, Brechenade S, Catajar N, Kaufmanis A, Hélin VM, Clavel F, Kerlikowske K, Miglioretti D, Delaloge S. Development and validation of a new non-parametric breast cancer risk assessment model on US and European screening populations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-06-05.

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 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.

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 (pmedian vs. ≤median); BMI was consistently identified as the most significant predictor of MD (P 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.

Breast cancer is the most frequent female cancer with 48 800 new cases each year in France. A French national screening program in women without genetic risk factors has been initiated in 2004. Women with BRCA 1 or 2 mutations are included in surveillance programs. Women without such mutations can be assessed for breast cancer risk using risk prediction models. The aim of this study is to compare the performance of three breast cancer risk prediction models: GAIL2, BODICEA and IBIS in a population of patients (pts) who developed breast cancer. Patients and Methods: The GAIL1 model was performed to 188 pts at high risk of breast cancer according to their family history and who developed breast cancer. Personal and familial data was regenerated at the day before the diagnosis of breast cancer and the three models were applied. From this population, 60 pts were selected: for whom all information necessary to use the 3 models was available and for whom the GAIL1 model provided sufficient variability in the relative risk of breast cancer. The GAIL2 model takes into account individual risk factors: age, menarches, parity, age at first birth, history of breast biopsy, atypical hyperplasia or in situ lobular carcinoma. The BODICEA model considers age and familial risk factors: number of related affected by breast ovarian, prostate and pancreas cancer and age at diagnosis. Both personal and familial risk factors are used for the IBIS model. We estimated lifetime breast cancer risk for each patient with the three models from the available software packages. We assessed Pearson's correlation coefficient between the three models. Results Median (range) age was 45 years (25-74). Risk prediction could not be evalauted by the GAIL2 model for 14 pts since they were less than 35 years of age. Lifetime breast cancer risk was 16.1% (4.4-38.7) for GAIL2, 11.6% (2.2-39.5) for BODICEA and 16.5% (3.5-36.3) for IBIS. Pearson's correlation coefficient between BODICEA and GAIL2, IBIS and GAIL2 and between BODICEA and IBIS were 0.36, 0.38 and 0.69 respectively. In most cases, IBIS risk predictions were higher than GAIL2's which were higher than BODICEA's as soon as lifetime risk was at least 20%. When the three models were applicable (46pts), IBIS estimated a higher risk in 31 cases (67%) versus 10 for GAIL2 (21.74%) and 5 for BODICEA (10.86%). The median (range) time for use of the tools per patient was 30 seconds (16-80) for GAIL2, 588 (198-1804) for BODICEA and 86 (46-135) for IBIS. Discussion Results in this selected population of pts who developed breast cancer show that IBIS seems to be the better performer to predict breast cancer risk:. Results are obtained faster and the risk predictions provide higher estimates. The GAIL2 model is quick and easy to use but with a limited number of items. Conversely, BODICEA requires a very large number of items, not always available, and does not consider incomplete data. In conclusion, IBIS model seems to be the most suitable for practical use in the evaluation of breast cancer risk. Citation Format: Mailliez A, Kramar A, Peyrat J-P, Revillion F, Bonneterre J. Comparison of prediction models of breast cancer in high risk populations?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-16.

Background: Tamoxifen and raloxifene are two selective receptor modulators (SERMs) that have been shown to reduce the risk of developing breast cancer in women at increased risk of the disease. Both drugs are infrequently used in the general U.S. population. Increased knowledge about the risks and benefits of SERM use for breast cancer risk reduction does not lead to increased uptake of chemoprevention. We know little about what influences decision-making regarding breast cancer risk reduction with SERMs. Methods: To better understand what influences SERM decision-making for breast cancer risk reduction we conducted a survey study assessing social, environmental, and psychological factors that may influence a woman's decision. Women who talked to a health care provider (HCP) about SERM use (N=1,023) received a questionnaire immediately after the HCP visit that asked about the counseling session, sociodemographics, experiences with breast cancer, breast cancer risk, and risk perception. After its completion a second survey was administered that inquired about issues surrounding medication intake such as attitudes about taking medicines in general, trust in pharmaceutical companies, and in their HCP. A statistical comparison of survey responses was performed between those who decided to take a SERM and those who decided not to take a SERM. Logistic regression was used to determine a key set of independent factors associated with the decision. Results: Of the 1,023 women, 716 made a decision about SERM intake (70%) and were included in the study. Of those, 324 (45%) decided to take a SERM and 392 (55%) decided not to take a SERM. Of SERM users 89.8% received a recommendation to take a SERM by the HCP compared to 44.4% of non-users. Only 15.7% of SERM users reported never having had a breast biopsy compared to 26.3% of non-users. Overall, SERM users had a higher breast cancer risk, risk perception, and worry about getting breast cancer. In multivariate analysis 11 factors were identified as having independent association with SERM use, including: recommendation from HCP, attitudes and perceptions regarding medication intake, influenced by someone's breast cancer diagnosis, breast cancer worry, trust in HCP, a diagnosis of atypical hyperplasia, and others' experiences with SERM intake. Women who had one or more first degree relatives with breast cancer were less likely to take a SERM. Neither breast cancer risk nor risk perception influenced SERM decision-making. Discussion: Factors that influence SERM decision-making are related to women's personal experiences with breast cancer, their HCP, and attitudes towards medications. Conclusions: Social, environmental, and psychological factors proved to be more important for SERM decision-making than breast cancer risk or risk perception. In addition to presenting risks and benefits in counseling, the importance of personal experiences and attitudes for decision-making need to be considered to understand and support women's decision-making on SERM use for breast cancer risk reduction. SUPPORT: U10CA37377, -69974; -180868, -180822; -189867. Citation Format: Holmberg C, Bandos H, Fagerlin A, Bevers TB, Battaglia TA, Wickerham DL, McCaskill-Stevens W. Results from NRG oncology/NSABP protocol DMP-1: Women's decision-making in breast cancer risk reduction. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-01.

Background Women with benign breast disease (BBD) have an increased risk for breast cancer (BC). Almost 30% of all BCs develop in women with prior BBD. Information about the features of the expected BCs after BBD would enable individualized surveillance and prevention strategies for these women. We sought to characterize BCs developing in a large cohort of women with BBD. Methods Our cohort includes 13,485 women who underwent breast biopsy for mammographic or palpable concern between 1967-2001. Biopsy slides were reviewed and classified as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. Results With a median follow-up of 15.8 years, 1273 women developed BC. Most BCs were invasive (81%), among which 61% were ductal, 13% mixed ductal/lobular, and 14% lobular. Two thirds were intermediate or high-grade, and 29% were node positive. Cancer characteristics were similar across the three histologic categories of BBD, with similar frequency of DCIS and invasive disease, tumor size, time to invasive BC, histologic type of BC, nodal positivity and HER2 positivity. Women with AH had a higher frequency of ER+ BC (91%) vs women with PD (80%) or NP (85%), p=0.02. Conclusion A substantial proportion of all BCs develop in women with prior BBD. We show that the majority of BCs after BBD are invasive tumors of ductal type, with a substantial proportion node positive. 84% of cancers were ER-positive. Chemoprevention should be strongly encouraged in higher-risk women with BBD. Citation Format: Visscher DW, Frost MH, Hartmanan LC, Frank RD, Vierkant RA, McCullough AE, Winham SJ, Vachon C, Ghosh K, Brandt KR, Farrell AM, Tarabishy Y, Hieken TJ, Haddad TC, Kraft RA, Radisky DC, Degnim AC. Clinicopathologic features of breast cancers that develop in women with previous benign breast disease. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-19.

BACKGROUND: The American College of Surgeons National Accreditation Program for Breast Centers, Standard 2.9, requires a palpation-guided or image-guided needle biopsy as the initial diagnostic approach for breast cancer rather than an open biopsy. In replacing excisional biopsies, this minimally invasive technique demonstrates accuracy and precision in determining tumor characteristics and allows for more optimal breast cancer care. Recent studies have suggested that needle biopsy is underused in the United States. In a recently published analysis of U.S. Medicare data from 2003-2007, needle biopsy was used in 68.4% of all patients with breast cancer surgery. In this single-institution study, we analyzed the utilization of image-guided preoperative breast biopsies and which patient and system related factors contributed to the underutilization of image-guided breast biopsies and clinical outcomes. MATERIALS AND METHODS: In this retrospective study, we analyzed all breast cancer cases diagnosed over a four year period at Mount Sinai Medical Center (MSMC) from January 1, 2009 to December 31, 2013 (n=485). We performed a detailed chart review of the surgical cases that did not meet breast biopsy standards to identify contributing patient and surgeon level factors. Descriptive statistics and univariate analysis were used to characterize breast biopsy patterns and outcomes as well as delineate the associations between patient and surgical covariates with needle biopsy receipt. RESULTS: Needle biopsy was used in 86% (n=419) of all breast cancer surgeries. The median age for the cohort of patients without needle biopsy was 68.0 years (range 35-94). There was no significant variation in utilization of needle biopsy by race or surgeon. The proportion of patients without needle biopsy decreased significantly over time from 2009-2013. The most common reason for the lack of preoperative breast biopsy was the surgeon's preference to proceed with surgery because of very suspicious imaging studies (including mammograms and MRI) (n=9). There were an additional nine cases where the biopsy was attempted but was non-diagnostic. The most common patient-related factors for lack of needle biopsy were advanced age, use of anticoagulation and noncompliance due to a psychiatric diagnosis and patient discomfort. Other factors identified include lack of surgeon consultation before biopsy, biopsy of axillary lymph nodes as a means of diagnosis and patient's inpatient status. CONCLUSIONS: In this single institution, the rate of needle biopsy for breast cancer diagnosis was above national benchmarks. The most common reason for lack of a preoperative breast biopsy was the surgeon's preference to proceed with surgery because of very suspicious imaging studies. Patients with advanced age, psychiatric history, and inpatient workup were also more likely to lack a preoperative breast biopsy. Citation Format: Fan T, Paramo J, Mesko T, Poppiti R, Ruiz A, Rodriguez E. Factors determining underutilization of core biopsy prior to breast surgery. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-04.

Objective: Changes in health care delivery and policies resulting from translational research efforts are intended to benefit a broad segment of the affected population. Yet, uptake of new approaches may not occur at the same level and/or pace in all groups, inadvertently increasing disparities in cancer outcomes. Our objective is to explore the impact of recently enacted legislation associated with routine mammography screening on Hispanic /Latino women living in Connecticut. Background: Breast densities are the non-fat (epithelial and stromal) breast tissue observable on screening mammograms. They are associated with a 4 to 6 fold increase in breast cancer risk and complicate the reading of screening mammograms, resulting in lowered sensitivity. Connecticut (CT) and many other states have enacted legislation requiring supplemental testing to be offered to women with dense breasts. Per CT statute, insurance companies must cover the cost of ultrasound screening of an entire breast/breasts for women with heterogeneously or extremely dense breasts. Additionally, personal information on breast density must be included in the mailed result following a screening mammogram. The intent is to improve early detection in women with dense breasts and to increase awareness of the greater risk of associated with dense breast tissue. Methods: After this law was enacted in 2008, we undertook a large prospective study of mammography screening in community based Hispanic/Latinas. We enrolled women seeking care in primary health care settings in the 4 CT cities with the largest H/L populations. Eligible women were ages 40-75, self-identified as H/L, and had negative history for breast cancer or breast biopsy. With 75% participation for baseline interview and 98% consent for medical record review, we report baseline interview data and mammography results (medical records) over a 2.5 - 4 year follow-up on 668 H/L women, ages 40-79, living in CT at the time of enrollment (2009-2011). Results: The women in this study were mostly foreign or Puerto Rican born (84%), lower socioeconomic status (51% with household incomes less than $10,000 per year; 54% less had than a high school education) than the general population; median age was 51. Nearly half (46.0%) reported no usual care provider. Only 14% reported speaking English "very well". Most women reported that they received a mammogram in the previous year (65.0%). 21.4% of women met the criteria for receiving additional bilateral ultrasound testing due to heterogeneously dense (19.2%) or extremely dense (2.3%) breast tissue on screening mammograms occurring during follow up. Of the 128 women eligible for follow-up ultrasound, 18 (14%) received this exam. Conclusion: Although state law requires patient notification of breast density and insurance coverage for supplementary bilateral ultrasound tests in women with moderate to extremely dense breasts, our results show low uptake in Hispanic/Latino women in CT. In this largely foreign born, English second language population, effective communication regarding breast cancer risk, breast density, and the availability of follow-up ultrasound or other testing may represent a significant cancer care challenge. Citation Format: Jones BA, Philpotts L, Cooley R, Silber A, Epstein L, Claye E. Impact of breast density legislation on Hispanic / Latinas in the Northeast, US. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD4-07.

Background: Stage II-III TNBC retains a poor outcome despite high chemosensitivity. Patients (pts) with pCR after neoadjuvant chemotherapy have a good prognosis whereas non-responding pts have a 25-40% risk of distant relapse at 5 years. pCR is thus a major goal in TNBC. We previously reported that TNLABC benefit the most of dose dense dose intense cyclophosphamide (C)-epirubicin (E) (S.Giacchetti; BJC, 2014) Aim: To confirm these results prospectively and analyze the predictive factors of response to high dose chemotherapy in TNBC. Patients and methods: From january 2009 to april 2015 non inflammatory TNLABC received high dose C (1200 mg/m2 d1 qw 2) with E (75 mg/m2/ d1 qw2) for 6 cycles. The pts had a breast biopsy with frozen tissue. We performed molecular studies: qRT-PCR for AR, FOXA1, PI3K and FASAY technic for p53 mutation.The percentage of stromal Tumor-infiltrating lymphocytes (TILs) was also evaluated by two independent pathologists and assessed as a continuous variable. A18F-FDG PET/CT was performed initially and after 2 courses of chemotherapy and the metabolic answer assessed as a variation of the tumor uptake (ΔSUVmax). We report here the pathological complete response (pCR) (absence of infiltrative carcinomas in the breast and in the lymph nodes) and the factors associated with pCR. Results: The characteristics of the 74 pts are listed in table 1. The median age is 48 years old, 48 pts (65.8%) are premenopausal and 79% did not have any family history of breast cancers. TIL was divided in 3 groups < 10 % (26 pts, 40 %); 10-50 % (30 pts, 46 %) > 50% (9 pts, 14 %). Pathological response was assessed in 66 pts, one pt progressed during chemotherapy and 6 pts did not undergo surgery yet. 28 pts were in pCR (42.4 %). With a median follow up of 25 months, 13 pts (17.8 %) progressed and 8 (11%) died. Table 1: Patients characteristics and pCR according to tumor features and metabolic responseCharacteristicsNumber of pts (%)N of pts evaluated for pCRpCR (%)OR [IC 95%]p-valueTumor size T2363519 (54)10.04T337319 (29)0.34 [0.12 ; 0.96]Nodal status N0363315 (46)10.62N1/N2/N3 24/11/33313 (39)0.78 [0.29 ; 2.07]Histological grade: 2660 (0) 0.04*3676028 (47)TILs Tumor size, tumor grade, percentage of TILs, the change in 18F-fluorodeoxyglucose tumor uptake (ΔSUVmax) were significantly associated with pCR at univariate analysis. Only one factor remained significant at multivariate analysis, the ΔSUVmax, OR: 0.04 [0.007- 0.27], p = 0.0008. Conclusion: In this prospective phase III trial we confirm the efficacy of a dose dense EC in TNBC. The metabolic response evaluated with 18 F-FDG PET/CT is a strong and reliable predictor of pCR and could allow an early change of treatment for the non responders. A clinical trial is planned to test this strategy. Citation Format: Giacchetti S, De Roquancourt A, Groheux D, Piron P, Lehmann-che J, Cuvier C, Resche-rigon M, Albiter M, Roche B, Frank S, Hamy A-S, Teixeira L, Marty M, Lalloum M, Espié M. Prediction of pathological response (pCR) to neoadjuvant dose dense and intense cyclophosphamide and anthracycline in a prospective series of triple negative locally advanced breast cancers (TNLABC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-08.

Background: A major area of innovation in breast cancer (BC) is improving risk models for screening efforts. The University of California Athena Breast Health Network uses several risk models, including the Gail model [PMID: 10491430]. The Breast Cancer Surveillance Consortium (BCSC) model [PMID: 18316752] which integrated information on breast density was developed and validated by UCSF investigators and reports Asian-specific risk. The Peking Union Medical College (PUMC) model [PMID: 22662004] is developed from a case-control study in China and reports BC risk in Chinese women. Risk factors and their respective weights included in these models are different. Methods: From December 2012 to April 2014, 2,305 women without previous history of BC and consented to research were enrolled in the UCSF Athena screening cohort. Questions asked included risk factors used in Gail, BCSC and PUMC model, such as age, age of menarche (AOM), age at first live birth, body mass index (BMI), breast biopsy, breast density, hormone replacement therapy (HRT), oral contraceptives (OCP). Women were considered high risk when: Gail > 1.67% 5-year risk, BCSC > 1.67% 5-year risk, PUMC score > 30 (equals >0.20% 1-year risk) respectively. The distribution of the risk factors and the high risk population percentage were compared between Chinese women versus non-Chinese Asian and Caucasian women. Results: 402 Asian women comprise 17.4% of all 2,305 Athena screening cases with 234 Chinese, and 168 non-Chinese Asian (NCA). Differences in risk factor distribution were observed for the following: positive family history was observed 23% for Caucasian, 15% for Chinese and 13% for NCA (p=0.001), and previous breast biopsy was 27%, 17% and 22% respectively (p=0.002). Ever use of HRT was 36% in Caucasian, 17% in Chinese and 11% in NCA (p Table 1 Percentage of high risk population by ethnicity for different risk modelsRisk modelsChinese (n=234)non-Chinese Asian (n=168)Caucasian (n=1,492)P ValueRisklowhighlowhighlowhighGail137 (58.6%)97 (41.4%)107 (63.7%)61 (36.3%)884 (59.2%)608 (40.8%)0.509BCSC211 (90.2%)23 (9.8%)152 (90.5%)16 (9.5%)864 (58.0%)626 (42.0%)0.000PUMC167 (71.7%)66 (28.3%)108 (64.7%)59 (35.3%)781 (52.6%)704 (47.4%)0.000 Conclusion: Chinese and NCA women have a lower proportion of high risk by the BCSC and PUMC model compared to the Caucasian women, whereas by Gail model these proportions appear to be similar. Citation Format: Bo Pan, Jeffrey Tice, Qiang Sun, Celia Kaplan, Zhou Yidong, Yali Xu, Songjie Shen, Changjun Wang, Alexandra Solomon, Lauren Ryan, Paige Kendall, Timothy Henderson, Laura Esserman, Beth Crawford, Athena Breast Health Network, Laura van 't Veer. The comparison of the distribution of breast cancer risk factor between Chinese women, non-Chinese Asian and Caucasian women in the screening cohort of Athena Breast Health Network [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-10.

Background Activating mutations in the PIK3CA gene represent the most common molecular aberration in luminal breast cancers. Three hot-spot mutations (E542K, E545K, H1047R) account for approximately 70% of the PIK3CA mutations identified. The presence of a mutation is likely to become an important predictive biomarker to select patients for treatment with PIK3CA inhibitors. Tumor-derived DNA can be detected in the systemic circulation in the form of cell-free plasma DNA (cfpDNA), and the ability to interrogate tumor-derived DNA from an easily acquired biospecimen like cfpDNA has practical advantages over analysis of tissue specimens. Furthermore, cfpDNA can be monitored serially and could provide a dynamic measure of tumor progression and response to therapy. Droplet digital PCR (ddPCR) is a high-throughput technique that provides highly precise and sensitive detection of rare alleles in samples with ultra-low abundance of target DNA. Methods A nested case-control study was conducted with plasma samples collected as part of a study to identify blood-based biomarkers. Blood was collected from women scheduled for a breast biopsy at one of seven participating mammography units. All blood samples were collected prior to the biopsy procedure and were processed using a standard protocol. Cases are women diagnosed with invasive ductal carcinoma, stage I-III, that is positive for the estrogen receptor (ER+) and negative for HER2/neu (0 or 1+ by IHC). Controls are women with a benign, non-proliferative lesion, matched by collection site, year of collection and age. cfpDNA was isolated using a commercial kit (Macherey-Nagel, Bethlehem, PA). DNA was extracted from FFPE biopsy specimens by standard techniques. Central pathologic review confirmed at least 10% tumor cellularity in biopsy specimens from cases. A ddPCR assay was developed on a BioRad QX100 Droplet Digital PCR instrument using standard TaqManR assays with probe pairs designed to detect the 3 PIK3CA hotspot mutations and corresponding wild type (wt) alleles. The assay was validated using DNA from four cell lines, each positive for one of the hotspot mutations or wt at all 3 loci (Horizon Diagnostics, Cambridge, UK). ddPCR was performed on cfpDNA and DNA extracted from FFPE biopsy specimens in cases and controls. Next generation DNA sequencing (NGS) of exons 9 and 20 of PIK3CA was performed on biopsy specimens from cases using an Ion Torrent Personal Genome Sequencer. Results Validation of the ddPCR assay with serial dilutions of cell line DNA demonstrated the assay is highly sensitive with mutant alleles detected at an allele frequency down to 25% when input DNA template is as low as 2 ng. With DNA template input of 20 ng (typical recovery of cfpDNA), mutations can be detected down to an allele frequency of 0.78%. We will present data on the rate of hotspot mutation detection with the ddPCR assay performed on cfpDNA and FFPE samples in cases (n=80) and controls (n=80), and we will report performance characteristics of the assay. Mutation status of tumors determined by NGS will serve as the gold standard. Conclusion We have developed a ddPCR assay to detect PIK3CA hotspot mutations in cfpDNA, and will report the performance characteristics of the assay in 80 cases of untreated, ER+ early breast cancer. Citation Format: Kent F Hoskins, Amer Sidani, Tiffany Jones, Stefan Green, Rajyasree Emmadi, Anjen Chenn. Detection of PIK3CA mutations in cell-free plasma DNA from women with early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-42.

Introduction: With a reported incidence of 2-12% in breast biopsy specimens, the appropriate management of atypical ductal hyperplasia (ADH) remains in evolution. At present, the optimal screening guidelines for patients with high-risk breast lesions such as ADH remain unclear. Current practices often parallel the surveillance of cancer patients and include a 6 month interval mammogram prior to resuming annual screening, which may result in unnecessary procedures and financial costs. This interval mammogram is typically a diagnostic study, which is an additional cost to the patient and healthcare system. The purpose of this study was to identify interval pathology following initial surgical resection and review associated costs. Methods: Following institutional review board approval, the pathology database from a single institution was queried for patients who underwent surgical excision for ‘atypical ductal hyperplasia’ from 2008 to 2013. Those who did not have follow-up data available were excluded. Subsequent clinical care was reviewed, including interval imaging and need for additional intervention. Based on a review of hospital charges from 2013, the average charge for a unilateral diagnostic mammogram (out-patient, digital) was $382. Results: There were 55 patients who underwent an excisional biopsy that were diagnosed with ADH and had subsequent follow-up. The median age was 57 years (range 38-82 years), and the median breast cancer risk assessment score was 2.3% at 5 years (range 0.5-17.9%) and 12.5% lifetime risk (range 2.2-37.6%). Pathology included concurrent lobular carcinoma in situ (n=1), atypical lobular hyperplasia (n=3), flat epithelial atypia (n=14), and papillary lesions (n=19). In addition to a routine clinical breast exam, a short-term follow-up diagnostic (ipsilateral) mammogram was performed in 35 patients. Of the 35 interval mammograms obtained, 31 yielded benign findings on initial imaging, while 4 patients required additional imaging that ultimately resulted in benign findings. The overall hospital charges for the 35 short interval mammograms alone during this 6 year period were roughly $13,370. For the patients that resumed annual surveillance, 3 had abnormal mammograms requiring additional imaging, and no malignancies were identified in this subset of patients. To date, the median physician follow-up is 3 years, and 52 patients have undergone at least one mammogram since their initial imaging; all subsequent findings have been benign for all patients. When extrapolated to national data, cost savings to the healthcare system from eliminating short interval mammograms would exceed $12 million annually without compromising clinical outcomes. Conclusions: Based on our findings, a 6 month follow-up mammogram is not recommended and incurs unnecessary costs to the patient and healthcare system. In the post-surgical breast, imaging may be misleading and result in additional procedures and significant charges that ultimately do not affect clinical outcomes. Although a clinical exam is still recommended at 6 months following surgical excision for a diagnosis of ADH, patients should forego short interval (6 month) imaging and resume annual mammogram surveillance. Citation Format: Jennifer K Plichta, Adrienne N Cobb, Gerard J Abood, Constantine Godellas, Claudia B Perez. Post-operative imaging after atypical ductal hyperplasia excision: The findings and costs [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-10-04.

Background: The gold standard for breast biopsy procedures is currently an open excision of the suspected lesion. However, an excisional biopsy inevitably makes a scar. The cost and morbidity associated with this procedure has prompted many physicians to evaluate less invasive, alternative procedures. More recently, image-guided percutaneous core-needle biopsy has become a frequently used method for diagnosing palpable and non-palpable breast lesions. Although sensitivity rates for core-needle biopsy are high, it has the disadvantage of histological underestimation, which renders the management of atypical ductal hyperplasia, papillary lesions, and fibroepithelial lesions somewhat difficult. Stereotactic vacuum assisted breast biopsy (VABB) was developed to overcome some of these negative aspects of core-needle biopsy. VABB allows for a sufficient specimen to be obtained with a single insertion and can provide a more accurate diagnosis and completely remove the lesion under real-time ultrasonic guidance. The advantage of complete lesion removal with VABB is to reduce or eliminate sampling error, to decrease the likelihood of a histological underestimation, to decrease imaging-histological discordance, to decrease the re-biopsy rate, and to diminish the likelihood of subsequent growth on follow-up, especially when stereotactic VABB is used to investigate microcalcifications. This method is expensive but cost effective when used to investigate microcalcifications classified as BI-RADS 4 and 5. Methodology: We performed a review in 1,354 patients with suspicious mammography microcalcifications, classified as BI-RADS 4 or 5 that were seen in Perola Byington Hospital from July 2012 to July 2017 in São Paulo-Brazil. We have used aHologic Lorad Multicare Platinum Stereotactic Prone Breast Biopsy and a Surus Pearl (Hologic, Malbolrough, Massachusetts, USA), with gauge 9 probe. Four to eight fragments (median of 6) were obtained with the placement of a metal clip in the bed that the biopsy was performed, and histopathological analysis was made. Results:The histopathological study of the lesions revealed benign alterations in 956 (68%) of our patients. The findings were positive for malignancy in 358 patients (29%) and the precursor lesions were diagnosed in 40 (3%). In 81 cases (5.9%) the findings were discordant. The sensitivity of the method was 84.4%, specificity was 96.1%, false negative rate was 4.5%, positive predictive value (PPV) was 89.8%, negative predictive value (NPV) was 93.8%. In literature review the sensitivity varies 91.5-100%, specificity 81.9-110%, false negative rate 0-3.3%, PPV 92.2-100% and NPV 80.5-99.5%. All patients with positive or discordant cases underwent surgical treatment to increase the margin or complete removal of the lesion. Conclusions: The VABB is an outpatient procedure that avoids hospital admissions for diagnostic elucidation in most of cases suspected of malignancy. It has high predictive value in both benign and malignant lesions, guiding therapeutic planning. In addition to presenting the cost lower than the surgical biopsy it indirect increases the supply of hospital beds for cancer treatment. Citation Format: Mattar A, Amorim AG, Ramos MdNM, Shida JY, Fonseca GR, Hegg R, Gebrim LH. The value of stereotactic vacuum-assisted biopsy in the investigation of microcalcifications in 1354 patients in public Brazilian hospital [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-04-01.

Background: The gold standard for breast biopsy procedures is currently an open excision of the suspected lesion. However, an excisional biopsy inevitably makes a scar. The cost and morbidity associated with this procedure has prompted many physicians to evaluate less invasive, alternative procedures. Stereotactic vacuum assisted breast biopsy (VASB) can provide a more accurate diagnosis and completely remove the lesion under real-time ultrasonic guidance. The advantage of complete lesion removal with VASB is to reduce or eliminate sampling error, to decrease the likelihood of a histological underestimation, to decrease imaging-histological discordance, to decrease the re-biopsy rate, and to diminish the likelihood of subsequent growth on follow-up, especially when stereotactic VASB is used to investigate microcalcifications. This method is expensive but cost effective when used to investigate microcalcifications classified as BI-RADS 4 and 5. Objectives: To evaluate the accuracy of VASB in the investigation of suspicious calcifications. Methods: We’ve performed a retrospective study from July, 2012 to June, 2019, in which 1,809 women with suspicious calcifications detected on mammography (BI-RADS 4 and 5) had VASB performed at Hospital Estadual Pérola Byington, a public Hospital in São Paulo, Brazil. The device used was Surus Pearl (Hologic, Malbolrough, Massachusetts, USA), with probe gauge 9. Fragments were obtained and sent to anatomopathological study; a metal clip was placed on the biopsy site. Four groups were analyzed, based on the biopsy results: benign, precursor lesions, Ductal Carcinoma In Situ (DCIS) and malignant. Most patients with positive or discordant cases underwent surgical treatment and the previous biopsy results were compared to surgery results. Results: patients median age was 55y (49-63). Pathology results on VASB and surgery were classified respectively as benign n=1,179 (65.1%), precursor lesions n=97 (5.4%), DCIS n=414 (22.9%) and malignant n=119 (6.6%). Benign and lesion precursor lesions results were clustered to form a new group (lower risk lesions) and so DCIS and malignant lesions (higher risk lesions). ROC curve and AUC were calculated to compare the results of lower and higher risk lesions groups according to VASB and surgery results (AUC=0,642). The X2 test was performed between the groups (p Keywords: Calcifications; Vacuum-assisted stereotactic biopsy; Breast cancer; Diagnosis Citation Format: Andressa Amorim, Marcellus N. M. Ramos, André Mattar, Maria Isabela B. A. C. Sawada, Jorge Y. Shida, Luiz H. Gebrim. Accuracy of stereotactic vacuum-assisted breast biopsy for investigating suspicious calcifications in 1,809 patients a public hospital in Brazil [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-03-03.

Background and objectives: Pathological complete response after neoadjuvant chemotherapy for women with primary breast cancer is achieved in up to 60%. Identification of these women by imaging is imprecise – even clear residual tumors on breast imaging after neoadjuvant chemotherapy frequently show pathologic complete response. Thus, pathologic evaluation of the surgical specimen is the gold standard. However, having women to undergo breast-conserving or even ablative breast surgery to diagnose pathologic complete response could be considered overtreatment. To potentially avoid these surgeries, we first evaluated the accuracy of an image-guided vacuum-assisted biopsy (i.g.VAB) alone to diagnose and rule out residual disease in the breast. Second, we assessed the accuracy of the combination of i.g.VAB with breast imaging results after neoadjuvant chemotherapy. Methods: This multicenter, prospective, diagnostic trial took place at 21 trial sites in Germany (March 2017 to May 2019). 398 women consented, presented with initial clinical tumor stage 1-3 breast cancer of all biological subtypes with partial or complete response by imaging after neoadjuvant chemotherapy and underwent i.g.VAB and guideline-adherent breast surgery. First, we compared i.g.VAB alone - guided either by ultrasound or mammography – with the gold standard evaluation of the surgical specimen to detect pathological residual disease. A pathologically confirmed residual tumor in the surgical specimen but no residual tumor in the i.g.VAB defines a false-negative finding. The study was powered to detect a false-negative rate of the i.g.VAB below 10% (primary efficacy analysis). Second, we combined the results of the i.g.VAB and the breast imaging exams (ultrasound and mammography) after neoadjuvant chemotherapy. A positive test (=residual tumor) was either a residual tumor in the i.g.VAB OR tumor seen on the imaging exam. Thus, a false-negative finding is a pathologically confirmed residual tumor in the surgical specimen but no residual tumor in i.g.VAB AND no residual tumor on the breast imaging exam (secondary explorative analysis). The study was stopped for futility after planned interim analysis. Results: For the whole cohort (n=398) and primary efficacy analysis, i.g.VAB alone failed to detect a residual tumor in 37 of 208 cases with a residual tumor in the surgical specimen (false-negative rate (FNR) = 17.8% (95% CI: 12.8-23.7%)). Only the subgroup in which i.g.VAB used 7 G needles showed a FNR < 10%. The secondary explorative analysis detected residual tumor with a FNR of 6.2% (3.4-10.5%) – 13 out of the 208 cases with a residual tumor in the surgical specimen were false-negative. While this approach increased sensitivity, it decreased specificity but still identified 95 of 190 (50.0%) pathologic tumor-free women. Conclusion The i.g.VAB alone did not reach the anticipated diagnostic accuracy in this study. However, combining the results of i.g.VAB and breast imaging after neoadjuvant chemotherapy detects residual disease in women with breast cancer with a FNR This finding will guide ongoing and future trials aiming for tailoring, de-escalating, and potentially avoiding unnecessary surgery in women without residual disease after neoadjuvant chemotherapy. Trial registration: NCT02948764 Protocol publication: DOI: 10.1186/s12885-018-4760-4 Table 1Primary efficacy analysisSecondary, explorative analysisresidual disease in i.g.VAB specimenno residual disease in i.g. VAB specimenresidual disease in i.g.VAB specimen OR imaging after NACTno residual disease in i.g.VAB specimen AND no tumor on imaging after NACTresidual disease in surgery specimen(n=208)1713719513no residual disease in surgery specimen(n=190)3*1879595FNR (95% CI)17.8% (12.8-23.7)6.2% (3.4-10.5)NPV (95% CI)81.4% (75.3-86.6)88.0% (80.3-93.4)PPV (95% CI)85.9% (80.3-90.4)67.2% (61.5-72.6)*whole tumor was removed by i.g.VAB, thus not false positiveNACT=neoadjuvant chemotherapyi.g.VAB=image-guided vacuum-assisted biopsyFNR=false-negative rateNPV=negative predictive valuePPV=positive predictive value Citation Format: Joerg Heil, André Pfob, Hans-Peter P Sinn, Geraldine Rauch, Paul Bach, Benedikt Schaefgen, Walter Weber, Sherko Kuemmel, Toralf Reimer, Markus Hahn, Marc Thill, Jens-Uwe Blohmer, Michael Golatta, RESPONDER Investigators. Diagnosing residual disease and pathologic complete response after neoadjuvant chemotherapy in breast cancer patients by image-guided vacuum-assisted breast biopsy: Results of a prospective multicenter trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-03.

Background: Image-guided biopsy of the residual imaging abnormality / tumor bed at the end of neoadjuvant chemotherapy (NAC) is increasingly used to assess residual disease in the breast, facilitate risk-adaptive surgery and potentially identify exceptional responders who may not require surgical intervention. The aim of this pooled analysis was to further assess the accuracy of post-NAC, image-guided biopsy to predict residual disease in the breast. The findings could help define an optimal post-NAC biopsy protocol to support trials omitting surgery in selected groups of patients. Methods: Multi-institutional, individual patient data on post-NAC image-guided biopsy was collected and pooled following Institutional Review Board (IRB) approval from each centre (Royal Marsden Hospital, Seoul National University Hospital, MD Anderson Cancer Center). Biopsy sampling accuracy was defined as representative if pathology features suggestive of tumor bed or residual cancer were identified. Pathologic complete response (pCR) was defined as no residual disease in the breast (ypT0). Biopsy predictive accuracy was calculated using final surgical pathology as the reference standard. Simple descriptive statistics and non-parametric analyses were performed. Results: Data were analyzed from 166 women who underwent post-NAC image-guided biopsy. Median age was 49 years (range: 25-76). The majority (n=160) had invasive ductal carcinoma (IDC) with phenotype distribution of 31 (18.7%), 47 (28.3%), 29 (17.5%) and 59 (35.5%) respectively for hormone receptor (HR) positive / Human Epidermal Growth Factor Receptor (HER)-2 negative, HR and HER2 positive, HR negative / HER2 positive and triple negative (TN). Median tumor size on pre-treatment imaging was 33.5 mm (range: 12-100). The overall pCR rate was 51.2% [16.1% for HR positive / HER2 negative, 44.7% for HR positive / HER2 positive, 69% for HR negative / HER2 positive and 66.1% for TN]. The majority (n=143) underwent vacuum assisted biopsy (VAB) and 23 had core cut (CC) biopsy. Median size of the biopsy needle was 10 gauge (range: 7-14) and median number of samples was 6 (range: 2-18). The biopsy was performed under ultrasound (n=129) or stereo guidance (n=37) and in 159 cases was representative of the tumor bed. When the image-guided biopsy (VAB and CC) was representative, the false negative rate (FNR) across the whole cohort was 18.7% (95% CI 9.8-26.8). Exploratory analysis of accuracy of VAB in cases with a residual imaging abnormality < 2 cm to allow adequate sampling and at least 6 representative biopsies taken (n=76) showed a FNR of 3.2% (95% CI 0-8.8), a negative predictive value (NPV) of 97.4% (95% CI 84.6-99.6) and an overall accuracy of 89.5% (95% CI: 80.3-95.3). Subgroup analysis in patients with HER2 positive or TN cancer (n=66) who are the most likely to be exceptional responders and achieve pCR showed similar accuracy of the technique with a FNR of 4.2% (95% CI 0-10.7), a negative predictive value (NPV) of 97.2% (95% CI 83.6-99.6) and an overall accuracy of 87.9% (95% CI: 77.5-94.6). Conclusions: This large pooled multicenter data suggests that a standardized protocol using image-guided VAB of a tumor bed measuring up to 2 cm with at least 6 samples allows reliable prediction of residual disease and pCR. These results should inform the design of de-escalation trials in NAC exceptional responders testing the safety of eliminating surgery. Citation Format: Marios Konstantinos Tasoulis, Han-Byoel Lee, Wei Yang, Romney Pope, Savitri Krishnamurthy, Soo-Yeon Kim, Nariya Cho, Victoria Teoh, Gaiane M Rauch, Benjamin D Smith, Vicente Valero, Wonshik Han, Royal Marsden Hospital MDT, Fiona MacNeill, Henry M Kuerer. Accuracy of post-neoadjuvant chemotherapy image-guided breast biopsy to predict the presence of residual cancer: A multi-institutional pooled analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-04.

Background: WISDOM is a 100,000 healthy women preference-tolerant, pragmatic study comparing traditional annual screening to personalized risk-based breast screening. The novelty of WISDOM personalized screening is the integration of previously validated genetic and clinical risk factors (age, family history, breast biopsy results, ethnicity, mammographic density) into a single risk assessment model that directs the starting age, timing, and frequency of screening. The goal of WISDOM is to determine if personalized screening, compared to annual screening, is as safe, less morbid, enables prevention, and is more accepted by women. The study is registered on ClinicalTrials.gov, NCT02620852. Methods: Women aged 40-74 years with no history of breast cancer or DCIS, and no previous double mastectomy can join the study online at wisdomstudy.org. Participants can either elect randomization or self-select a study arm. Then, they can provide electronic consent and sign the Release for Medical Information via DocuSign. For all participants, 5-year risk of developing breast cancer is calculated according to the Breast Cancer Screening Consortium (BCSC) model. Participants in the personalized arm undergo panel-based mutation testing (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, ATM, PALB2, and CHEK2), and their 5-year risk is calculated using the BCSC score combined with a Polygenic Risk Score (BCSC-PRS) that includes 75 single nucleotide polymorphisms (SNPs) known to increase breast cancer risk (will increase to 229). The SNPs and mutations are assessed by saliva-based testing through Color Genomics. 5-year risk level thresholds are used to stratify for low-, moderate- and high risk. Risk stratification determines age to start, stop, and frequency of screening. Accrual: As of July 2019, the WISDOM study is open to all eligible women in California, North Dakota, South Dakota, Minnesota, Iowa, Illinois, and New Jersey. To date, 30,392 eligible women have registered, and 21,392 women have consented to participate in the trial. The median age was 56 years. 85% of participants were Caucasian, 2% African-American, and 5% Asian. 6% self-reported Hispanic ethnicity. WISDOM is actively partnering with Blue Cross Blue Shield Association for national coverage, self-insured companies (Salesforce, Genentech, Qualcomm, CalPERS) and Medi-Cal (Inland Empire Health Plan) using a coverage with evidence progression approach. Accrual expansion and diversity: To strengthen generalizability, the WISDOM Study is enhancing the diversity of our potential participant population by expanding to other states (Alabama, Louisiana), and partnering with other health insurers and self-insured companies. Future expansion regions include Texas, Florida, South Carolina, Oklahoma, Montana, and New Mexico. Additionally, we have translated the whole study experience to Spanish to further reach Spanish-speaking communities. With the engagement of patient advocates and community partnerships, expanding diversity recruitment will strengthen our scientific knowledge of breast cancer risk and increase access to personalized breast cancer screening recommendations for all women. WISDOM enrollment will continue through 2020. Conclusions: Results at 5 years will enable us to demonstrate that personalized screening improves healthcare value by reducing screen volumes and costs without jeopardizing outcomes. Citation Format: Mandy Che, Allison Stover Fiscallini, Irene Acerbi, Yiweh Shieh, Lisa Madlensky, Jeffrey Tice, Elad Ziv, Martin Eklund, Amie Blanco, Barry Tong, Deborah Goodman, Lamees Nassereddine, Nancy Anderson, Heather Harvey, Steele Fors, Hannah L Park, Antonia Petruse, Skye Stewart, Janet Wernisch, Larissa Risty, Ian Hurley, Barbara Koenig, Celia Kaplan, Robert Hiatt, Neil Wenger, Vivian Lee, Diane Heditsian, Susie Brain, Leah Sabacan, Barbara Parker, Alexander Borowsky, Hoda Anton-Culver, Hoda Anton-Culver, Arash Naeim, Andrea Kaster, Melinda Talley, Laura van't Veer, Andrea LaCroix, Olufunmilayo I Olopade, Deepa Sheth, WISDOM Study and Athena Breast Health Network Investigators and Advocate Partners and Laura Esserman. Personalized breast cancer screening in a population-based study: Women informed to screen depending on measures of risk (WISDOM) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-03-02.

Introduction Annual mammography screening is recommended for women diagnosed with breast cancer for the early detection of local recurrence and new breast primaries. Younger women have higher breast density, which lowers the sensitivity of mammography for early detection. The American Cancer Society recommends breast MRI as an adjunct to mammography for women with known hereditary breast cancer syndromes. However, there is insufficient evidence on the use of breast MRI or ultrasound as an adjunct to screening mammography among young women with a personal history of breast cancer. Our objective was to investigate factors associated with use of supplemental screening among young breast cancer patients and the impact of supplemental screening on detection of breast cancer recurrence and false positive biopsy rates. Methods We conducted a retrospective analysis of women diagnosed with stage 0-III breast cancer at age 50 years or younger at Columbia University Irving Medical Center in New York, NY between 2007 and 2017. Patients were excluded if they had stage IV disease at diagnosis, bilateral mastectomy, or no breast imaging available in the CUIMC electronic health record (EHR). All clinical data was extracted from the EHR and tumor registry, including receipt and results of genetic testing. Supplemental screening was defined as use of breast ultrasound or MRI in the absence of breast symptoms and in the setting of a normal mammogram. Breast cancer recurrence and false positive biopsy were defined as any breast biopsy which did or did not show ductal carcinoma in situ (DCIS) or invasive carcinoma, respectively. Univariate and multivariate analyses were performed to assess the association between demographic and clinical factors and our main outcomes of supplemental screening and false positive biopsy. Results Among 681 evaluable women, mean age at diagnosis was 44 years (SD, 4.9) with 41.6% white, 28.2% Hispanic, 12.6% black, 11.7% Asian, and 5.9% other race/ethnicity. About 62.7% had private insurance and 23.1% Medicaid, and 47% had undergone genetic testing, including 20 (2.9%) with pathogenic variants. Over half (51%) had supplemental screening with either breast MRI or ultrasound, 130 (19.1%) had a false positive biopsy, and 52 (7.6%) had a breast cancer recurrence, with about half (51.9%) screen-detected. In multivariate analysis, supplemental screening was less likely among black and Hispanic women compared to whites (odds [OR]=0.56, 95% confidence interval [CI]=0.33-0.97 and OR=0.46, 95% CI=0.30-0.72, respectively), those with Medicaid compared to private insurance (OR=0.46, 95% CI=0.30-0.71), and women with lower breast density (OR=0.63, 95% CI=0.43-0.92). False positive biopsies were more frequent among women who underwent supplemental screening compared to those who did not (26.4% vs. 11.4%, p Citation Format: Vicky Ro, Ziyi Zhao, Samuel Pan, Katherine D. Crew. Impact of genetic testing for hereditary breast cancer on supplemental breast imaging and false positive biopsy rates among young breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-02-03.

Background: The majority of breast cancer cases are considered to be sporadic and occur in women without a strong family history. Accurate estimation of a woman's risk of developing breast cancer is essential for guiding decisions regarding surveillance and prevention. The Breast Cancer Risk Assessment Tool (BCRAT) uses only clinical factors and has been shown to be of marginal value for individual risk counseling. Even though the BCRAT risks for women without a biopsy and no first degree relative with breast cancer are low, a significant fraction of cases occur in these women. OncoVue® is a logistic regression model developed from individual genetic and personal factor data from a large case-control study. In three independent validation populations, including a blinded validation, OncoVue has been shown to significantly outperform BCRAT. Here we compare OncoVue to the BCRAT in stratifying risk in women without a first degree relative with breast cancer that have never had a breast biopsy. Materials and Methods: Absolute risks for Caucasian participants ranging in age from 35 to 89 were analyzed for a case-control study conducted in six distinct geographic regions of the United States. This analysis focused on participants that had never had a biopsy and reported no first degree relatives with breast cancer (cases prior to diagnosis/controls at time of enrollment). DNAs from a total of 2729 women (842 cases and 1887 controls) were genotyped for 22 SNP variants and genotype information was combined with clinical risk information to calculate 5-year and lifetime risks. Clinical factor information alone was used to calculate BCRAT risk scores for comparison to OncoVue. Results: The 5-year risks for OncoVue ranged from 0.10 to 5.0% (50-fold) compared to 0.20 to 3.0% (15-fold) for BCRAT risks. OncoVue lifetime risks ranged from 2.4 to 25.0% (11-fold) compared to 4 to 16% (4-fold) for BCRAT risks. The OncoVue model 5-year risk placed 11% of this sub-population of controls at ≥ 2.0% risk compared to the BCRAT which placed only 3.5% at this risk. The BCRAT did not place anyone at a lifetime risk over 16% while OncoVue placed 10% of this sub-population of controls above 16%. The Odds Ratio (OR) was determined at increasing model risk output levels. Over comparable ranges, OncoVue 5-year risks exhibited statistically significant ORs while BCRAT ORs did not reach significance. OncoVue associations for lifetime risk reach high levels. For example, an OR of 5.0 (p = 0.03) was observed at a risk level ≥ 23%. Conclusion: The OncoVue model stratifies risk over a much wider range than the BCRAT in this group of women at low risk by traditional methods. In the 5-year risk frame OncoVue exhibited improved performance in estimating individual risk compared to the BCRAT. Due to the lack of any elevated lifetime risks generated by the BCRAT, a direct comparison of lifetime risks for OncoVue to the BCRAT was not possible. The OncoVue model which uses both genetics and clinical factors significantly improves individualized breast cancer risk estimation. These results demonstrate the importance of the genetic component of the OncoVue model in accurately estimating individual risk of sporadic breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-05.

Background The Avon Breast Health Outreach Program (BHOP) supports community-based organizations to conduct education and outreach to link low-income and uninsured women to routine breast cancer screening. Women under age 40 with breast health issues may not be eligible for low-cost or free screening programs that target women age 40 and older. Objective Describe demographic and health characteristics of clients under age 40 served by Avon BHOP-funded organizations compared with clients of other age groups. Methods We analyzed CY2012 client intake data for females aged 20-75 years (N = 100,418). We conducted univariate and multivariate analysis of client demographics (race/ethnicity, annual household income, education, and geographic setting of client's residence) and health history (health insurance status, personal history of breast cancer, family history of breast cancer, prior breast biopsy, and prior mammogram). Results were stratified by age group. Results Overall, 5.7% (n = 5,719) of female clients were aged 20-39, 36.9% (n = 37,041) were aged 40-49, and 57.4% (57,658) were aged 50-75 years. A majority of clients (64.6%) identified as a racial and/or ethnic minority; this percentage was lowest among women under age 40 (58.8%), and highest among women aged 40-49 (69.2%). Overall, 78.4% of women reported an annual household income of $25,000 or less, with little variation across age groups. Women under age 40 were more likely to report having some college or an associate degree (27.2%) versus 21.3% of clients overall. Nearly two-thirds (64.5%) of clients reported no health insurance, with higher rates among women aged 20-39 (73.1%) and 40-49 (70.8%) compared with women aged 50 and older (59.6%). A majority of clients reported living in an urban setting (57.1%) or rural areas (31.4%); women under age 40 were more likely to report living in rural (40.8%) or frontier areas (4.6%). Current symptoms (lump, nipple discharge, rash, or unusual pain) were reported by 40.1% of women under age 40, compared with 12.0% of clients overall. Women aged 20-39 were less likely to have ever had a mammogram (34.8% versus 85.8% of all clients). However, white clients were almost twice as likely to have had a mammogram before the age of 40, even when controlling for breast symptoms and a family history of breast cancer. Conclusion Avon BHOP clients under age 40 were more likely to be white, to reside in rural areas, and to be uninsured despite higher levels of education. More than 40% of clients under age 40 reported current breast symptoms. Discussion Characteristics of Avon BHOP clients under age 40 are influenced by the location and target population of funded organizations. Low-income and uninsured women under age 40 may require specialized outreach and education to ensure timely access to breast cancer screening services. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-11.

African American (AA) women have higher mortality rates from breast cancer (BrCa) and are diagnosed at younger ages than their Caucasian counterparts. Women who have had a benign breast biopsy are at increased risk of the disease, although less is known about the risk of BrCa associated with benign breast disease in AA women. We examined 1428 breast biopsies from AA women which occurred from 1997–2000 and assessed various pathologic markers including: apocrine metaplasia, ductal hyperplasia including atypia, evidence of cysts, duct ectasia, fibrosis, intra-ductal papilloma, sclerosing adenosis, columnar alteration, and involution (atrophy). These women were followed for later BrCa through the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology and End Results (SEER) program through 2008. Women who developed BrCa were compared to those in the cohort who did not, and to other AA women with BrCa in the SEER registry. AA women in our study were also compared to Caucasian women in the Mayo Clinic cohort. Differences in variables were assessed by chi-squared tests and 95% confidence intervals. Of the 1428 biopsies, 52 (3.6%) subsequent incident breast cancers were reported in SEER. The mean age at diagnosis was 59, and the mean time from biopsy to BrCa diagnosis was 6.1 years. Individuals with atypical ductal hyperplasia at biopsy (n=37, 2.6%) were more likely to develop breast cancer (n=7, 13.5%, p Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-16.

Background Acquisition of additional breast tissue for research has become integral to breast oncology research but no data exists regarding patient attitudes to additional, non-diagnostic biopsies. Baseline research biopsies may be obtained as part of the diagnostic process as extra passage(s) of the needle through a ‘generic consent’ process, or as an additional biopsy event after carcinoma diagnosis has been confirmed and eligibility for a specific study has been established. This study sought to explore patient perspectives to such biopsies. Patients and Methods Patients attending breast clinics were recruited to complete a questionnaire prior to their consultation (and any interaction with researchers or clinicians seeking consent for research biopsies) which examined willingness to undergo an extra fine needle aspirate (FNA) and/or core needle biopsy (CNB) for research either at time of the diagnostic biopsy (B1) or after diagnosis (B2). Descriptions of FNA and CNB procedures were supplied to those with no prior experience. Patient perspectives towards donating surplus tissue left over from a diagnostic procedure and/or surgery for storage for future research was also explored. Results: 100 patients were recruited, 42% with a prior history of breast carcinoma, 23% with family history of breast carcinoma and 65%/ 42% with previous experience of CNB/FNA respectively for either benign or malignant disease. Willingness to undergo additional biopsy was greater for the B1 than the B2 time point, but equivalent for CNB and FNA (willingness CNB B1 50% vs B2 26%, willingness FNA B1 50% vs B2 29%). A statistically significant increase in willingness to undergo CNB and FNA at B1 and/or B2 was seen in association with prior diagnosis of breast cancer, family history of breast cancer, previous visit to breast clinic and prior experience of breast biopsy. Reasons for willingness or unwillingness were recorded. 83% of patients expressed a willingness to allow surplus tissue to be stored in a biobank for future research. Conclusions: When asked by questionnaire prior to clinic consultation, additional research biopsy was much more acceptable if undertaken at time of initial diagnostic biopsy rather than at a later time point. Acceptability was equivalent for CNB and FNA. Previous experience of biopsy, previous attendance to breast clinic, a prior history of breast cancer or family history of breast cancer increased acceptability suggesting that willingness is increased with knowledge of the biopsy procedure. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-21-04.

Introduction: The NMPOA cohort started in 2004 with the purpose of testing a breast screening model for underserved women in limited resource countries. In the city of Porto Alegre (South Brazil with 1.5 million population), breast cancer incidence rate is 127/100.000 (Brazilian NCI,2010) with increasing mortality due to 45% of Stage III and IV and no public health care early detection program, it was mandatory to test the feasibility of an organized screening program for women with very low income and level of education (64% under 6 years of schooling). In this scenario, there was always a concern of over diagnosis that will increase costs (more biopsies and surgeries) and under diagnosis by the radiologists involved in the program. We present here the results of all breast biopsies performed in this period, and its correlation with the attributed BI-RADS classification in order to optimize care and costs. Also, this study has a long term proposal and other results have been published concerned to the baseline profile of the population (Cancer Epidemiol Biomarkers Prev. 2010 Oct;19(10):2673–9. Epub 2010 Aug 17). Methods:Since April 2004, 5592 women from 40 to 69 years were enrolled in the program and underwent to clinical breast exam and annual mammography screening at NMPOA. Initially, lesions were classified as B1, B2 or B0. After complementary views or exams, B0 was classified as B3, B4 (A, B or C) or B5. B4 and B5 were considered positive tests and immediately submitted to biopsy (open surgical or ultrasound guided core biopsy). B3 was followed according to recommended in BI-RADS fourth edition, and subsequently classified as benign (annual follow up) or suspicious findings (biopsy performed). The evaluation included histological analysis of breast biopsy specimens by two independent pathologists. Predictive positive value (PPV), predictive negative value (PNV) and accuracy (Acc) were calculated. Results: A total of 259 breast lesions were initially classified as BI-RADS 0 (recall rate of 2.8%), and further classification of these was: 166 B3 (64.1%), 60 B4 (23.2%) and 33 B5 (12.7%). Thirty seven B3 (14.3%) were considered suspicious after 6 months and submitted to biopsy. Correlation results of the 130 biopsies performed are summarized on [Table1]. PPV of 63.4% (52.8%-73.1%), PNV of 97.3% (85.8%-99.9%) and an Acc of 73.1% were observed. In this sample, 71.7% of BC were ductal invasive carcinoma, 11.7% ductal carcinoma in situ, 5% lobular invasive carcinoma and 11.6% were other types of neoplasia. Conclusion: Recall rate is in accordance with the medical audit benchmarks recommended of less than 10% published in BI-RADS fourth edition. NMPOA is model for limited resource countries in breast cancer imaging diagnosis. The radiologists involved in the program are classifying breast lesions in accordance with the established parameters, with a high accuracy in diagnosis. Even though we are dealing with a poorly educated cohort not used to any form of screening, our adherence is 57% in 12 months and 71% in 24 months. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-09-01.

Background Recently, ultrasonography guided vacuum-assisted breast biopsy (US-guided VABB) has been widely used as alternative to surgical open biopsy. Enough breast tissue samples obtained by US-guided VABB are important because of increasing neoadjuvant treatment. Although the information obtained from US-guided VABB may be the only information available for determining the candidates for neoadjuvant treatment, only few studies evaluated the concordance of histological type, estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor-2 (HER2) status, and Ki67 level between US-guided VABB and surgical specimen. The aim of this study was to evaluate the accuracy of preoperative US-guided VABB. Materials and Methods: In 439 breast cancer patients without neoadjuvant treatment who underwent US-guided VABB and surgical resection from April 2004 and March 2011 at Aichi Cancer Center hospital, we examined the concordance of Histological type, ER status, PgR status, HER2 status, and Ki67 level between US-guided VABB and surgical specimen. All the US-guided VABB were performed using 11-gauge Mammotome® or 10-gauge VACORA®. The ER and PgR status were assessed using Allreds scoring system by IHC. These statuseswere categorized as positive when the total score was more than two. HER2 expression status was tested by IHC and FISH. HER2 3+ by IHC, or 2+ and FISH positive were judged as HER2 positive. In this study, the Ki67 cut-off level for positivity was defined at 20% (Penault-Llorca et al, JCO 2009). The agreement on histological type, ER status, PgR status, HER2 status, and Ki67 level were tested using the absolute concordance rate and the kappa statistic values. Results: The concordance rate of histological types between US-guided VABB and surgical specimens was 93.4% (410 of 439 cases) with a Kappa statistic value of 0.82. In 115 cases diagnosed as DCIS by US-guided VABB, 28 cases (24.3%) were subsequently diagnosed as invasive cancer by surgical specimens. However, among these cases, 78.6% (22/28) were T1mic and T1a. And one case (0.3%, 1/324) diagnosed as invasive cancer by US-guided VABB changed DCIS by surgical specimens. The concordance rate of ER, PgR, and HER2 status were 96.6% (112/116), 89.5% (102/116), and 97.4%(113/116), respectively (kappa statistic value of 0.99, 0.76, and 0.90). In HER2 status, the concordance rate between US-guided VABB and surgical specimens was better than between core needle biopsy and surgical specimens (the concordance rate: 88%, kappa statistic value: 0.65, Usami et al, Jpn J Clin Oncol 2007). The agreement of Ki67 level was 85.7% (24/28) with a Kappa statistic value of 0.71. Conclusions: The judgment of histological type, ER status, and HER2 status by preoperative US-guided VABB can be used with confidence due to determine the treatment strategies according to molecular subtype. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-01.

Background BI-RADS Category 4 patients have a 2–95% risk for malignancy and are generally recommended for breast biopsy with little discrimination for risk level or distinction between risk of invasive or in situ disease. Our study sought to determine if higher thresholds for biopsy based on stratifying for risk and distinguishing between risk of invasive cancer and DCIS could reduce biopsy rates and increase cancer-to-biopsy yields without missing cancers urgent for resolution. Methods 108 BI-RADS 4 cases with final outcomes data were evaluated from a prospective cohort of 215 consecutive patients seen at a same-day multidisciplinary breast clinic for women with mammograms categorized as BI-RADS 0, 4, or 5 in 2006–07. Final outcomes were determined from pathologic diagnosis or two-year follow-up. Risk estimates (RE) for DCIS and invasive cancer were collected prospectively and re-assessed by a radiologist blinded to outcomes and prior reading assessments. Cases were stratified according to the risk ranges of the BI-RADS 4 subcategories and risk of invasive or in situ disease. Biopsy rates, cancer-to-biopsy yields, and number of malignancies missed were calculated for various thresholds for intervention. Results A ROC curve for invasive cancer risk for the radiologist demonstrated a 98.5% level of accuracy (95% confidence interval [CI]: 96.9%, 100%). 60 cases had some risk for invasive cancer and 48 had some risk for DCIS. There were 14 invasive cancer and 11 DCIS outcomes, 3 of which were high-grade. Pathologic assessment from biopsy or surgery was available for 100 patients. The outcomes of 8 cases were determined by benign two-year follow-up. There are several strategies for intervention that improve biopsy yield and reduce biopsies for benign disease as shown in Table 1. If cases with RE between 2–10% for DCIS or invasive cancer were not biopsied, 23% of biopsies would be avoided and the yield would increase to 30%. If cases with invasive cancer RE between 10–95% and DCIS RE between 50–95% were biopsied, 52% of biopsies would be avoided and the yield would increase to 39%. One invasive ductal carcinoma (3 mm, Grade 2) would be missed, although with six-month follow-up, this would not be a problem. Limitations Small sample size; one radiologist providing RE may not be representative of general mammographic assessment. Conclusion Setting higher biopsy thresholds for BI-RADS 4 lesions can safely reduce biopsy rates and increase biopsy yields. Given evidence suggesting that low/intermediate grade DCIS may be overdiagnosed, distinguishing between DCIS and invasive cancer risk at screening by offering active surveillance as an alternative to biopsy for BI-RADS 4 lesions suspicious for non-high-grade DCIS may be a promising approach for reducing biopsies. This will be prospectively tested in a reader study using several radiology readers in a series of 750 cases in the Athena Breast Health Network. New biopsy thresholds can be set if the results of our study can be validated. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-09-02.

Background Regardless of the result, women that have undergone a breast biopsy are considered at increased risk due to the clinical circumstances leading to the need for the procedure. Both the number and outcome of biopsy are considered in the widely used Breast Cancer Risk Assessment Tool (BCRAT) also known as the Gail model. Accurately estimating individualized risk of developing breast cancer is useful for early detection and cancer prevention. Although the BCRAT has been demonstrated to accurately estimate the number of breast cancers likely to emerge in a population of women seeking regular mammography screening, it does not produce accurate individualized risk estimates for patient counseling. We have simultaneously analyzed gene polymorphism and clinical factor data in breast cancer cases and matched controls to develop a polyfactorial risk model (OncoVue) to improve estimation of individual risk. In three independent patient populations, OncoVue has been shown to significantly outperform both the BCRAT and composite risk scores produced by combining GWAS SNP risks with the BCRAT. Here we have characterized the performance of OncoVue in stratifying risk in women that have had one or more breast biopsies. Materials and Methods: Risk scores were analyzed for participants ranging in age from 35 to 89 for a subset of participants that had enrolled in a larger case-control study conducted in six distinct geographic regions of the United States. The current study focused on the analysis of participants that had reported one or more biopsies (cases prior to diagnosis/controls at time of enrollment) amounting to 1265 Caucasian women (537 cases and 728 controls) in a model building set and 303 women in an independent validation set (134 cases and 169 controls). DNAs were genotyped for 22 SNP variants and genotype information was combined with clinical risk factor information to calculate the risk scores for the individual participants. Clinical factor information was also used to calculate BCRAT risk scores. The performance of OncoVue was examined in comparison to the BCRAT alone. Results: For both models, positive likelihood ratios (PLR) were calculated as the proportion of patients with breast cancer with an elevated lifetime risk estimate (≥20%) divided by the proportion of disease-free individuals with an elevated risk estimate. In both the model building and validation sets, OncoVue exhibited approximately a 2.0-fold improvement compared to the BCRAT in more accurately assigning elevated risk estimates to breast cancer cases. In these women that are already considered at increased risk because of a history of biopsy, the observed level of improved performance of OncoVue was similar to that in our previous overall studies. Conclusions: The OncoVue polyfactorial risk model incorporating both genetics and clinical factors improves on individualized breast cancer risk estimation compared to the BCRAT which uses only clinical factors. The performance in biopsied women further supports the potential utility of OncoVue for directing prevention and screening decisions. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-05.

PURPOSE To evaluate imaging characteristics, outcome of surgical excision or imaging follow-up on high-risk lesions diagnosed at MRI-guided vacuum-assisted breast biopsy (MRI-VAB). MATERIALS AND METHODS We retrospectively reviewed 581 lesions, to include benign, high-risk and malignant lesions, undergoing 9-gauge MRI-VAB from January 2015 to April 2018. We collected patient demographics, risk factors and indications, breast MRI BI-RADS descriptors, histopathological diagnosis at MRI-VAB and surgical excision, frequency of upgrade to malignancy and imaging follow-up of high-risk lesions found in this period. RESULTS 101 patients with 107/581 (18.4% of all lesions) had high risk lesions at MRI-VAB, including atypical ductal hyperplasia (ADH)(n=19/107, 17.8%), lobular neoplasia (n=35/107, 32.7) including atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), ALH plus LCIS, papillary lesions (n=44/107, 41.1%), radial scar/complex sclerosing lesion (RS/CSL)(n=8/107, 7.5%) and flat epithelial atypia (FEA)(n=1/107, 1%). 71/107 (66.4%) high risk lesions were excised. 16/71 (22.5%) were upgraded to malignancy (4 invasive cancer, 12 DCIS). The upgrade rate for ADH and lobular neoplasia was 5 /16 (31.3%) and 8/26 (30.8%) respectively. The upgrade rate for RS/CSL was 1/6 (16.7%). Of the 22 papillary lesions excised, 2 (9.1%) demonstrated pathologic atypia and were upgraded to DCIS. The other 20 papillary lesions had no upgrade or atypia. Excised high risk lesions showing upgrade varied from 0.4 to 6 cm in length (average 2.1 cm). Increasing size correlated with tendency towards increased upgrade to malignancy, but there were no other specific imaging features to predict malignancy upgrade. CONCLUSION There were no specific MRI imaging characteristics of high-risk lesions to predict malignancy upgrade. Therefore, surgical excision is recommended for high risk lesions especially ADH or lobular neoplasia. Additionally, non-atypical papillomas did not demonstrate malignancy upgrade in our small study. And further larger studies may demonstrate that these lesions may not need to be surgically excised. Citation Format: Okamoto S, Covelli JD, DeMartini WB, Daniel BL, Ikeda DM. High-risk lesions diagnosed at MRI-guided vacuum-assisted breast biopsy: Imaging characteristics, outcome of surgical excision or imaging follow-up [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-02-06.

Introduction: Defining the histologic correlates of mammographic breast density (MD) may provide insights into why elevated MD is related to increased breast cancer risk. Studies suggest that reduced terminal ductal lobular (TDLU) involution is associated with elevated MD, and both are independent breast cancer risk factors among women who have undergone a biopsy for benign breast disease (BBD). Prior digital histologic analyses of normal breast tissues revealed epithelial nuclear density (END) and TDLU involution are correlated. Accordingly, we examined associations of END with TDLU involution and MD in clinical biopsies. Methods: We analyzed 262 image-guided breast biopsies diagnosed as BBD from 224 women. TDLU involution was visually assessed as TDLU count/mm2 and TDLU span (inversely related to level of involution) in background normal tissue, evaluated using digitized images. The Genie Classifier (Aperio) was applied to images to estimate nuclei count per unit epithelial area, (END). Single X-ray Absorptiometry of pre-biopsy craniocaudal digital mammograms was applied to measure global MD (percent fibroglandular volume (%FGV)). Analysis of covariance, adjusted for age and body mass index, examined mean END differences across tertiles of TDLU/MD measures. Analyses were conducted at the biopsy level using SAS PROC GENMOD to account for within-woman correlations. All tests were two-tailed. Results: Overall, 67% of BBD biopsies were proliferative. Higher END was observed among proliferative than non-proliferative BBD (median END: 10,187 vs. 9,953 respectively; p=0.04). Among all women, END significantly increased with increasing tertiles of TDLU measures (p-trends: TDLU count/100mm2=0.0001, TDLU span=0.046). Whereas TDLU metrics were positively associated with %FGV, no relationship was observed between END and %FGV. In analyses stratified by BBD severity, however, END and %FGV were positively associated among women with non-proliferative disease (p-trend=0.04), findings not observed with proliferative disease. Conclusions: Automated END and visually assessed TDLU involution metrics were positively associated with each other and with MD. However, associations were diluted for proliferative lesions, suggesting that applying automated digital pathology tools to unsegmented digital images of whole sections of BBD biopsies does not demonstrate the same associations with MD as visual assessment of TDLU involution. Citation Format: Maeve Mullooly, Samantha Puvanesarajah, Shaoqi Fan, Ruth M. Pfeiffer, Linnea Olsson, Manila Hada, Erin L. Kirk, Pamela M. Vacek, Donald L. Weaver, John A. Shepherd, Amir P. Mahmoudzadeh, Jeff Wang, Stephen M. Hewitt, Sally D. Herschorn, Mark E. Sherman, Melissa A. Troester, Gretchen L. Gierach. Utilizing digital pathology to understand breast epithelial characteristics of benign breast disease among women undergoing diagnostic image-guided breast biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3260.

Purpose: The Imagio™ OA/US breast imaging system, a diagnostic opto-acoustic (OA) imaging device bearing the CE Mark, is in the U.S. FDA Premarket Approval process. OA/US provides both functional (relative oxygenation/de-oxygenation) and anatomic (angiogenesis) information that is co-registered and temporally interleaved in real time with gray-scale ultrasound that may improve discrimination between benign and malignant masses. We recently reported correlation studies demonstrating tumor-zone specific OA attributes in histopathologic grade I versus grade III malignancies. The relationship between OA attributes (individual feature scores or summed feature results) and pathologically-determined prognostic markers (PDPM) in malignant lesions is the subject of this report. Materials and Methods: In this HIPAA-compliant, IRB-approved prospective multi-center trial across 16 U.S clinical sites; 1,808 masses in 1,739 subjects assessed as BI-RADS 3, 4 or 5 were imaged with OA/US. Of these, 655 were invasive malignancies and the subject of this analysis. Each mass was scored by 8 blinded readers on 3 internal zone features of the tumor nidus and 2 external features (0-5, 6) of the tumor boundary and peripheral zones (OA attributes). Pathologic diagnoses were confirmed by an experienced central breast pathologist blinded to the OA assessment. Tumor histologic classification and grading was performed in all subjects.Evaluation of tumor estrogen receptor (ER) and progesterone receptor (PR) were performed at each site by immunohistochemistry (IHC) and was reported as percent of tumor cells expressing the receptor or, as positive if greater than 1%. Tumor HER2-neu expression was reported by IHC as 0, 1+ (negative, not over-expressed), 2+ (indeterminate) and 3+ (over-expressed). All 2+ results reflexed to fluorescence in-situ hybridization (FISH) and reported as over-expressed or not over-expressed. Tumor Ki-67 expression was evaluated with IHC and reported as percent of tumor cells positive for the antigen. Statistical analysis of categorical measures of PDPM is in process and will be performed using a two-way Analysis of Variance (ANOVA) and Tukey HSD (honest significant difference) test for pairwise comparisons. This ANOVA will be repeated for each PDPM to test which specific PDPM sub-categories are related to OA attributes. Correlation coefficients will be generated for PDPM that are continuous, not categorical. All statistical testing will be done at a 5% significance level. Results: A total of 655 invasive and 22 DCIS were scored for internal (nidus) and external (boundary and periphery) OA attributes and compared with PSBC as defined by ER, PR, Her2 and Ki-67 expression. Of these, 108 were Luminal-A (LA), 153 Luminal-B (LB), 80 Triple-negative (TN), 23 Her2-enriched (HER2) and 314 unclassified (including 22 DCIS). OA attributes differentiated LA (99%CI 2.8,3.1) from TN (99%CI 3.1,3.4), p=0.027 and HER2 (99%CI 3.1,3.6), p=0.036. OA features strongly suggested LA vs. LB (99%CI 3.1,3.3) subtype, p=0.060. LB vs.TN(p=0.59) and HER2(p=0.41) were non-significant. TNBC vs. HER2 was p=0.62. Citation Format: Grobmyer SR, Butler R, Neuschler EI, Stavros AT, Aitchison RD, Lavin PT, Tucker FL. Opto-acoustic imaging of breast masses: Correlation with breast biopsy prognostic indicators [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-02-04.

[INTRODUCTION] Mammography is the principal non-invasive imaging method of screening for breast cancer around the world. Mammography has been shown to be effective in reducing breast cancer deaths in randomized studies (Tabar et al., 2011 and Duffy et al., 2002). However, screening mammography can result in false positives that require subsequent interventions such as biopsy or interval repeat mammography. Recently, circulating micro RNAs (miRNAs) have been cited as promising minimally invasive markers for breast cancer as well as for various other types of malignancies (Shimomura et al., 2016; Lawrie et al., 2008; Wang et al., 2009; Zhang et al., 2010; Mitchell et al., 2008). In this study, we have developed a new molecular diagnostic platform for the measurement of circulating (serum) miRNAs to assist with the management of women with abnormal screening mammograms. [METHODS] Peripheral venous blood samples were collected in BD Red/Gray gel barrier tubes from patients with untreated breast cancer, patients with benign breast diseases and healthy individuals with no cancer history. The processing from blood to serum was done within six hours of collection and stored at -80°C. Total RNA was extracted from 300uL of the resulting serum using 3D-Gene®RNA extraction reagent (Toray Industries, Inc). Comprehensive miRNA expression analysis was then performed using 3D-Gene® Human miRNA Oligo Chip (Toray Industries, Inc). The average of three pre-selected internal control miRNA (miR-149-3p, miR-2861 and miR-4463) was used to normalize the signals across the different microarrays tested. [RESULTS] RESULTS] All serum specimens used in this study were from subjects enrolled at US clinical sites (83% Caucasian, 15% African American, 2% Asian and others). One hundred fifteen (115) specimens (breast cancer: 40, healthy: 45, benign breast lesions: 30) were selected as a training cohort and used to develop comprehensive discriminants with 1–5 miRNAs using Fisher's linear discriminant analysis. The analysis identified a combination of five miRNAs that could detect breast cancer, and the resulting discriminant equation showed a sensitivity of 90.5%, specificity of 89.5% and accuracy of 89.8%. As test cohorts, (A) 381 subjects (breast cancer: 63, healthy: 160, benign breast lesions: 152), independent from subjects in the training cohort, and (B) 35 subjects who had been referred for breast biopsy were tested. The discrimination performance of the equation for each breast cancer stage (Stage 0: 1, Stage 1: 20, Stage 2: 17, Stage 3: 14, Stage 4: 11) was examined in the test cohorts. Also, information from breast cancer types as well as from benign breast lesions have been used to assess the performance of the discriminant score. The results of these analyses along with a discussion of the potential significance and plans for expanded clinical trials will be presented. Citation Format: Akiyama H, Manlapaz V, Wong C, Yamazaki Y, Knapp M, Ohara S. Differences in serum miRNA signatures in women with pathology-confirmed breast cancer, benign breast diseases and healthy individuals with no cancer history [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-11.

Introduction Currently, risk management options for BRCA1 mutation carriers include risk-reducing mastectomies (RRM), and selective oestrogen receptor modulators (SERMs). However, the majority of BRCA1-associated tumours are oestrogen receptor negative (ER-ve). SERMs do not reduce the incidence of ER-ve tumours, therefore are unlikely to be effective in this group of women. Oestrogen and its metabolites have been shown to cause DNA damage, resulting in genomic instability in BRCA1 deficient breast cells, an early hallmark of BRCA1-related cancers. Based on this, we hypothesise that oestrogen suppression in BRCA1 carriers may reduce DNA damage in breast tissue, and thereby potentially reducing breast cancer risk. Trial Design The study is an interventional, non-randomised, crossover study without masking. The primary purpose is to assess the impact of these drugs on suppression of DNA damage and therefore their potential for use as chemopreventive agents in this setting. Pre-menopausal BRCA1 mutation carriers will be recruited from the Family History Clinic at Belfast City Hospital. The proportion of women who receive information packs who progress to trial entry will be recorded, with target recruitment of twelve women to the trial. Participants will complete quality of life questionnaires, provide blood and urine samples and undergo baseline ultrasound-guided breast biopsy. Half of these women will receive a SERM (tamoxifen) for 3 months, whilst the other half receives oestrogen suppression therapy (goserelin and anastrazole), and then provide repeat questionnaires and samples (blood, urine and breast biopsy). Treatment groups will cross over for a further 3 months treatment, with a final set of questionnaires and samples taken. Compliance with treatment and adverse events will be monitored throughout the study. Eligibility Criteria Inclusion criteria: · Female · Age ≥18 years · Premenopausal · Known pathogenic BRCA1 mutation · Intact ovaries · No previous breast/ovarian/other carcinoma · No previous use of chemoprevention · Willingness to use non-hormonal methods of contraception Exclusion criteria: · BRCA1 mutation of uncertain significance · Contraindications to study drugs or breast biopsies · Pregnancy or breastfeeding · Inability to give informed consent · Patient awaiting risk reducing surgery Specific Aims The primary objective is to assess the feasibility of treatments by measuring successful recruitment rates and compliance. The secondary objective is to establish tolerability of interventions through quality of life measurements and adverse event occurrence. Exploratory objectives will assess the potential of treatments to reduce DNA damage through analysis of breast biopsies using comet assays and immunohistochemistry for 53BP1 and γH2AX (markers of DNA double-strand breaks). Oestrogen and metabolite levels will be measured in blood and urine samples using UPLC-MS/MS. Statistical Methods Not applicable due to nature and size of pilot study Present accrual: 1 participant Target accrual: 12 participants Contact information for people with specific interest in trial: aideen.campbell@qub.ac.uk or s.mcintosh@qub.ac.uk Citation Format: Campbell AM, Savage KI, McIntosh SA. Chemoprevention in BRCA1 mutation carriers (CIBRAC): A proof of concept clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-01-01.

Background: Image-guided percutaneous needle biopsy of the breast is a common procedure. In breast cancer patients (pts) undergoing core biopsies and surgical resection on the same day, the rate of tumor cell displacement along the needle track has been reported to be up to 50%. However, the clinical significance of this finding in triple negative breast cancer (TNBC) patients (pts) undergoing serial biopsies while receiving neoadjuvant chemotherapy (NACT) is unknown. Here we report the incidence of needle-track seeding (NTS) in a cohort of TNBC pts enrolled on a molecular triaging protocol involving serial biopsies of the index breast lesion. Methods: We reviewed the clinical records of 144 consecutive TNBC pts enrolled on a molecular triaging protocol at MD Anderson Cancer Center. Per protocol, all pts underwent a pre-treatment research biopsy and were initiated on anthracycline based NACT (AC). Pts with inadequate response to front-line NACT were encouraged to undergo additional biopsies of the index breast lesion prior to switching therapies. Serial breast ultrasound (US) was performed to monitor therapeutic response and incidental evidence of needle-track seeding noted on US was documented. Results: Clinicopathological characteristics of the pts are summarized in Table 1. 89% (128/144) of pts had a diagnostic breast biopsy done at another center prior to presenting at MDACC. To date, we have performed 209 US guided biopsies of index breast lesions in 144 pts. 92% (193/209) of these biopsies were done mainly for research purposes. 1.4% (2/144) of pts were found to have evidence of NTS on follow up US. The first pt had a T1N0 (1.9cm), grade 3, invasive ductal carcinoma (IDC) at diagnosis. She underwent a diagnostic biopsy followed by a research biopsy before initiating AC. She was found to have NTS as well as progression of disease (PD) on follow up US after 2 cycles of AC. The second pt had a T2N0 (3cm), grade 3 IDC at diagnosis. She underwent a diagnostic biopsy at another center, followed by a research biopsy before initiating AC. Like the first pt, she was found to have NTS and PD on follow up US after 2 cycles of AC. Both pts are currently on neoadjuvant clinical trials of novel agents. Conclusion: The rate of NTS detected on US in TNBC pts undergoing serial biopsies of index breast lesions while receiving NACT is low and further studies are needed to determine the impact of serial biopsies on long term outcomes in TNBC. Table 1: Patient CharacteristicsCharacteristicN=144Age - Median (years, interquartile range)55 (46-62)Tumor Size Mean (cm, standard deviation)3.4 (2.2)T1 – n(%)35 (24)T2 – n(%)89 (62)T3 – n(%)19 (13)T4 – n(%)1 (1)Clinical Nodal Status Negative – n(%)74 (51)Positive – n(%)70 (49)Grade 1 – n(%)1 (1)2 – n(%)17 (12)3 – n(%)124 (86)Unknown – n(%)2 (1)Histologic Subtype Invasive ductal carcinoma – n(%)121 (84)Invasive lobular carcinoma – n(%)2 (1)Mixed ductal and lobular carcinoma – n(%)3 (2)Metaplastic carcinoma – n(%)13 (9)Not specified – n(%)5 (3)Laterality Right – n(%)72 (50)Left – n(%)72 (50) Citation Format: Yam C, Santiago L, Candelaria RP, Adrada BE, Rauch GM, Hess KR, Litton JK, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran S, Helgason T, Huo L, Thompson AM, Gilcrease MZ, Symmans WF, Moulder SL, Yang W. Risk of needle-track seeding with serial ultrasound guided biopsies in triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-05.

The objective of this lecture is to review clinical management of women with the following histologic lesions associated with increased breast cancer risk: flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Women found to have one or more of these histologic findings in a benign breast biopsy have an increased risk of developing a future breast cancer. Published data will be reviewed that provides estimates of annual and longterm risk associated with these lesions. In addition, management of these lesions after core biopsy will be discussed, specifically the circumstances when surgical excision is recommended. Medical and surgical options for breast cancer risk reduction will be reviewed, as well as their appropriate clinical indications. Citation Format: Degnim AC. Clinical management of women with increased breast cancer risk based on histologic lesions [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES2-2.

Background: Fibroadenoma (FA) is a common benign breast lesion known to have a high incidence rate in younger women. There are controversial reports whether FA elevates the risk of developing breast cancers. In clinical practice, FA may be surgically removed due to multiple reasons making it complicated to study its impact on the development of breast cancers that have a higher incidence rate in older women. Fibroadenomatoid change (FAC), also known as fibroadenomatous hyperplasia, is an uncommon lesion with histologic features similar to that of FA but lacking well-defined borders and usually discovered incidentally on breast biopsy specimens. FAC is not surgically targeted. The Walter Reed Army Medical Center, through the Clinical Breast Care Project, has enrolled over 2000 subjects undergoing a biopsy; all the pathology was reviewed by a single pathologist. These subjects provide an opportunity to study the age-dependent pattern of FAC in different patient populations. Methods: Subjects were enrolled following IRB-approved protocols with data collected through two comprehensive questionnaires, a Core Questionnaire and a Pathology Checklist. A total of 1964 female subjects were identified for this study, including 1135 benign/atypical, 192 in situ, and 637 invasive cancer patients. Patients were divided into three age groups: =66 years. Chi-Square test in the SAS was used for statistical analysis. Results: As shown in the table, FA occurrence rate decreases significantly with increasing age in benign disease patients. FAC, on the other hand, shows a significantly higher occurrence rate in middle-aged patients with benign findings, and this trend is retained in the invasive or in situ cancer populations. FAC rate is also significantly higher in patients with cancer (invasive, or invasive and in situ combined) compared to benign patients in each age group with p-values ranging from 0.0001 to 0.019 (not shown). Discussion: Our preliminary results suggest that FAC occurs more often in middle-aged patients. It's significantly lower occurrence in patients with benign findings may be partially explained by the fact that breast cancer patients undergo more extensive surgeries, thus providing more breast tissue for pathologic evaluation. Otherwise, the increased FAC rate may suggest its role as a risk factor for cancer development. Since FAC may be considered a miniature FA that is not surgically targeted, it may be used as a window for the study of FA on its impact in cancer development. Further study needs to be performed to explain why FA and FAC have different age-dependent patterns and whether FA or FAC is a risk factor for breast cancer development. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-06.

OBJECTIVE: Vacuum-assisted breast biopsy (VABB) has replaced surgical biopsy for the assessment of mammographic abnormalities that are not evident clinically and or on ultrasound examination. The aim of this study was to determine the indications for, and accuracy of, vacuum-assisted breast biopsy (VABB) performed using digital breast tomosynthesis (DBT) guidance. (Hologic® Dimensions, Affirm guidance and Eviva handsets). MATERIALS AND METHODS: Design: Retrospective medical record and histopathologic review. Patients and method: We introduced DBT guided VABB in June 2014 having previously investigated such patients using the prone table technique. This is a review of the first 66 consecutive patients investigated using this technique up to April 2105. The following information was reviewed: Indication for VABB, (mammographic classification M1-5, type of abnormality – calcifications/mass/distortion), complications of the procedure itself, (failure to complete, infection, haematoma), the result of the multidisciplinary team (MDT) review of imaging/pathologic correlation and the outcome for the patient. RESULTS: In one case it proved impossible to locate the lesion and this patient has been excluded from further analysis. The mean age of the patients was 57 years (30-80years). VABB was proposed for patients with lesions initially reported as highly suspicious (M5) 4 patients (6%), suspicious (M4) in 18 patients (28%), intermediate (M3) in 37 patients (57%) or benign (M2) in 6 patients (9%). Mean size of the lesion was 13mm (range 3-100mm). Forty-four patients (68%) presented with micro calcifications, 14 (21%) with distortions in and 7 (11%) with masses. There were no complications (infection or haematoma) that required further management following the procedure. Review by the MDT agreed that all biopsies were adequate and removed representative tissue from the lesion (No B1s). Review showed that the histology was benign and consistent in 30 (46%) patients all of whom were discharged to routine screening. 19 (29%) cases were reported as B3 (ADH, flat atypia, LCIS or ALH) in whom all the calcifications had been removed in 13 (20%) and the patients discharged and 6 (9%) went to open biopsy for residual calcifications all of whom were benign on final analysis. There was one (1.5%) radial scar reported as B4 that went to open excision and proved benign. 15 (23%) proved malignant (B5a, B5b) and went on to definitive treatment (with one patient entered into the LORIS low risk DCIS trial). The procedure is quicker, more accurate (related to the higher resolution and larger window of the receptor plate) and involves less radiation exposure (often involving only one DBT exposure) when compared to performing the same procedure on the Hologic Platinum prone table. CONCLUSION: DBT-guided VABB is an accurate, convenient and safe procedure. Citation Format: Munir A, Moalla A, Williams HR, Thomas D, Huws AM, Holt SD. A review of 66 consecutive patients investigated for mammographic abnormalities by digital tomosynthesis guided vacuum assisted breast biopsy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-02-02.

Background: Breast cancer prevention is currently in a challenge due to the inability to identify high-risk women accurately only based on family history and pathologic evaluation of benign biopsy. Somatic molecular changes in clinically normal breasts have potential value for to improve the assessment of truly high-risk women. The identification of risk biomarkers in benign biopsy material will directly benefit the millions of women who undergo benign breast biopsy annually, adding precision to the risk implied by the histologic features of the benign biopsy. Therefore, we are pursuing robust biomarkers for breast cancer risk by sequencing pre-cancer benign biopsies, which may lead to discovery of genomic variation responsible for initiation and early progression of breast cancer. Methods: We are assembling a case-control set of benign breast biopsy matched by age, race, and duration of follow-up. The cases were the benign biopsies from women who subsequently developed breast cancer after at least one year, and the controls were the benign biopsy samples obtained from women who remain cancer free. 10-micron sections from formalin-fixed, paraffin-embedded tissue blocks are used for laser capture microdissection of selected epithelial areas and extraction of DNA. As a pilot experiment, we examined hotspot mutation in 4 cases and 4 control samples, using Ion AmpliSeq cancer hotspot panel consisting of 50 oncogenes/tumor suppressor and detecting 2855 hotspot mutation from COSMIC (Catalogue Of Somatic Mutations In Cancer). The average amplicon length was 154 (111-187) with average depth coverage of 1400x. SNP detection sensitivity was 98% for 5% variant frequency. Results: Among the 2855 hotspot mutation in 50 oncogenes/tumor suppressor detected, 153 mutation in 27 genes were identified in cases, and 62 mutations in 18 genes were found in controls. The most frequent mutanted gene was TP53 (71 mutation in cases, 24 mutation in controls). In 6 genes (CTNNB1, CDKN2A, ATM, KRAS, STK11 and SMARCB1), hotspot mutation was identified in at least two cases, but no hotspot mutation was identified in controls. Among the 4 cases, one cases had 95 hotspot mutation, much higher than the other 3 cases (5, 16, 37 mutation, respectively) and 4 controls (8, 11, 14, 29 mutation, respectively). This case progressed to triple negative (ER-, PR-, HER2-) breast cancer, a very aggressive subtype of cancer with poor prognosis. Conclusion: The pilot study of deep sequencing of breast benign biopsy suggested that the overall hotspot mutation frequency was higher in cases which progressed to malignant cancer compared to controls which did not progress to malignant cancer. Several genes were identified to be specifically associated with the progression. Citation Format: Jun Wang, Gang Feng, Nadereh Jafari, Ali Shidfar, David Ivanicic, Megan E. Sullivan, Seema A. Khan. Hotspot mutation in breast benign biopsy associated with subsequent progression to malignant breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-03.

【Background and Aim】 To date, fluorescence imaging has been used gradually for real time diagnosis in various clinical situations. Evaluation of margin on surgical specimens is essential to decide whether additional resection should be performed for breast cancer surgery. In the same context, rapid assessment of biopsy specimen is crucial because when they do not contain any part of the lesions, re-examination should be need. A fluorescence probe named γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) was rapidly activated by an enzyme, γ-glutamyltransferase (GGT). It was overexpressed in variety of cancers so promising for clinical use. The aim of this study is to examine the usefulness of the probe for breast cancer detection. 【Material and Methods】 We investigated the patients of breast cancer or benign disease who received examination consecutively from March 2015 to February 2016 in our hospital. The samples were obtained by core needle biopsy (CNB) or vacuum-assisted breast biopsy (VAB).We sprayed the probe on these samples immediately after examination and shoot images by CCD camera. To evaluate the fluorescence intensity along the time, we used a filtered CCD camera that could detect specifically gGlu-HMRG color (Discovery® INDEC Medical Systems Inc.). The images were automatically obtained every 30 seconds for 10 minutes after adding the probe on the specimens. The average value of the image in each region of interest (ROI) was analyzed using image analysis program Image J (https://imagej.nih.gov/ij/). We investigated the change of fluorescence intensity with the passage of time. We also compared the fluorescence intensity of malignant lesions with benign ones, and analyzed whether the fluorescence intensity could distinguish the malignant lesions from benign ones. 【Result】 We obtained 362 samples from96 tumors. Fifty-six tumors with 215 samples were benign, while 40 tumors with 147samples are malignant histologically. The fluorescence was immediately observed after sprayed the probe. The intensity had been increasing in proportion to time. The malignant specimens were rapidly increasing; in contrast, the benign ones were slowly. For example, when it took 60 seconds after spraying the probe that the intensity increase up to some level in malignant specimens, while benign one took 240 seconds up to the same level on average. Comparing the malignant lesions with benign ones after sprayed 120 seconds, the fluorescence intensity was higher in malignant specimens than benign ones (average fluorescence intensity; benign 0.9, malignant 2.3 p=0.0138). By ROC analysis whether the fluorescence intensity could distinguish the malignant lesions from benign, AUC, sensitivity and specificity was 0.63, 70% and 57%, respectively (cut off 0.2). 【Conclusion】 The probe was contributory to distinguish malignant and benign lesions and may be useful for the rapid diagnosis of CNB in practice. We are now trying to seek a more accurate probe to differentiate benign and malignant lesion as a next step. Citation Format: Takamaru T, Akashi ST, Kuwayama T, Sawada T, Hirota Y, Urano Y, Nakamura S. γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) is promising fluorescence probe for rapid diagnosis of breast cancer; - The feasibility study of real time imaging for breast cancer examination - [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-01-09.

Purpose: The Imagio® breast imaging system, a diagnostic opto-acoustic (OA) imaging device bearing the CE Mark, is in the U.S. FDA Premarket Approval process. OA provides both functional (relative oxygenation/de-oxygenation) and anatomic (angiogenesis) information that is co-registered and temporally interleaved in real time with gray-scale ultrasound that may improve distinction between benign and malignant masses. OA imaging pathology correlation was performed to elucidate the histologic features of OA features of breast cancers. Methods and Materials: A multicenter postmarket surveillance and clinical follow-up study was conducted in five Dutch sites in which 209 women with breast masses underwent OA prior to biopsy. Histopathology examination of the biopsies revealed 146 benign masses (mostly fibroadenomas) and 76 malignant masses (mostly invasive ductal carcinomas). For invasive ductal carcinomas, histologic grade and the features used to assess histologic grade (nuclear pleomorphism, tubule formation, and mitotic count) were assessed. For each mass, 5 pre-determined OA features, 3 internal features, and 2 external features were evaluated. The 3 internal scores (vessels, blush, and hemoglobin) and 2 external features (capsular boundary zone and peripheral boundary zone) were separately and collectively summed for testing relationships with traditional histopathology measures using a two-sided Jonckheere-Terpstra test of ordered outcomes. Distribution differences between benign and malignant masses were performed using a Wilcoxon Rank Sum test for each internal, external, and summed total internal, external, and total score. Results: The mean differences were significantly higher for malignant vs. benign for internal vessels (p=0.0009), internal blush (p=0.0085), external boundary zone (p Conclusion: OA feature summary scores appear to differentiate between benign vs. malignant and correspond to histologic grade and scoring components of histologic grade. The U.S. investigational PIONEER pivotal study (n=2,095) may further confirm these results. Citation Format: van de Vijver M, Lavin PT, Stavros AT. Breast biopsy histology relationships with opto-acoustic imaging of breast masses [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-03.

Current methods of breast cancer detection are often confounded by imaging limitations, such as lesion size, benign breast tissue, and dense breasts. These limitations result in unnecessary biopsies due to false positive findings based on imaging. Despite the increased ability to detect early breast cancer, the over-use of biopsy remains an issue. There is a critical need for new approaches to breast cancer detection that improve diagnostic accuracy when clinical assessment is challenging. Provista Diagnostics has developed Videssa® Breast - a blood-based proteomic test that measures serum protein biomarkers (SPBs) and tumor-associated autoantibodies (TAAbs). Patient biochemical data is combined with clinical data to generate a diagnostic score that correlates with either the absence or presence of breast cancer (Grades I through III). The ability of Videssa® breast to detect cancer (Invasive Breast Cancer and Ductal Carcinoma in situ) was evaluated using prospective, multi-center clinical trials. The Provista-001 study enrolled 351 women ages 25-49 and included a follow-up visit at 6 months with an additional blood draw. Eligible patients included women assessed as ACR BIRADS® 3 or 4 on imaging with no history of breast cancer or prior breast biopsy. Serum samples from the initial visit and 6 month follow-up visit of Provista-001 were analyzed using Videssa® Breast to determine if diagnostic results for benign subjects were similar over the course of the study. Samples were analyzed for SPBs and TAAbs in order to determine whether analyte levels and diagnostic scores change over a 6-month period in patients diagnosed with a benign breast condition. Linear regression data for analytes shows overall high fidelity between the initial visit and follow-up. In addition, samples that were TAAb-positive for a given target at the initial visit tended to remain positive at follow-up. Sample background, deriving from unidentified immunological factors, can confound the analytical output when measuring TAAbs in serum. Interestingly, sample background was highly reproducible between both visits, suggesting that these values are related to inherent patient-specific factors. Overall, these data demonstrate high analytical reproducibility for in expression of independent Videssa® Breast biomarkers in patients diagnosed with a benign breast condition over the course of six months. Data for 236 women were compared between visits and demonstrated greater than 80% concordance in diagnostic status. The ability of Videssa® breast to provide consistent diagnostic results over 6 months further supports use of the test as an adjunct to imaging for the early detection of breast cancer and provides physicians with an additional tool that can be used to inform the decision to biopsy or increase vigilance through active monitoring. Citation Format: Benson KL, Henderson MC, Silver M, Gordon K, Borman S, Letsios E, Tran Q, Mulpuri R, Reese DE. A liquid biopsy test for breast cancer detection provides consistent diagnostic results in patients over six months [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-01-07.

Background: Current breast cancer screening guidelines call for annual mammography for asymptomatic women age 45 to 54 and once every two years for women age 55 and older. Women with suspicious screening mammograms are recommended for a diagnostic mammogram and may also undergo MRI or ultrasound. Ultimately, suspicious findings unresolved by imaging typically result in the recommendation of a breast biopsy. Approximately 10% of suspicious diagnostic mammograms are recommended for breast biopsies and 67% to 95% of these biopsies yield negative results. With the goal of reducing the number of patients with benign pathology undergoing invasive biopsies, we conducted a screen for serum protein biomarkers and identified a novel panel for the non-invasive detection of breast cancer. Methods: Serum samples were collected at two sites from women with suspicious diagnostic mammogram findings (primarily BI-RADS category 4) undergoing biopsy for the evaluation of a potential malignancy. Serum samples from 100-patients (50 benign pathology and 50 malignant pathology) were evaluated on the SOMAscan Assay 1.3k, which measures levels of 1,310 different protein analytes. Statistical screening methodologies, such as individual t-tests with control for false discovery, were used to identify markers with the potential to distinguish benign from malignant pathology. The candidate markers were further studied and combined using generalized linear modeling to develop three potential diagnostic models. K-fold cross validation was used to guard against over fitting of the models. Results: A 15-marker model resulted in an AUC of 0.92 with a sensitivity of 90% and specificity of 76%. Two 6-marker models (with 4 markers in common) each resulted in AUC of 0.85, yielding a sensitivity of 90% with a specificity of 56% or 64%. Conclusions: This study reveals a novel panel of serum protein biomarkers that may allow for the non-invasive and sensitive detection of breast cancer in BI-RADS category 4 patients. A multicenter study is underway to further refine and validate this panel in a larger set of prospectively collected patient samples. Citation Format: Chapman KB, Copeland K, Kidd J, Qiu L, Sheibani N, Tam O, Friedman L, Korn R, Fiorica J, Lourenco A, Suthers S, Hesterberg L. Development of a panel of serum-based protein biomarkers for the non-invasive detection of breast cancer in BI-RADS category 4 patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-03-05.

Breast Imaging Reporting and Data System (BI-RADS) is a standard system used by clinicians to describe mammogram findings and sort the results into categories numbered 0 through 6; this makes accurately communicating about these test results and following up after the tests much easier. For example, the BI-RADS 4 score is given to lesions that carry a risk of malignancy between 2 and 95% such that a majority (69 to 95%) of BI-RADS 4 lesions are biopsied. Our goal is to create a better risk estimate score to stratify patients by developing a more accurate threshold for biopsy. To accomplish this goal, we defined the personal risk factors, relevant descriptors in the mammography and pathology findings for every patient with BI-RADS 3, 4, or 5 risk score. Clinical data were sourced from the Methodist Environment for Translational and Outcomes Research (METEOR) data warehouse at the Houston Methodist Hospital. METEOR data warehouse contains 135,280 unique patient mammogram reports dating from January 1, 2006 to May 30, 2015. Manual abstraction from this large number of free text reports is not feasible due to the constraints on time and labor costs, and risk of human-error during manual extraction. We developed a natural language processing (NLP) tool called Methodist hOspital Text Teaser (MOTTE) to extract defined clinical parameters and derive the desired meaning from the volumes of free text reports automatically. MOTTE is a rule-based software tool programmed in Java, Structured Query Language (SQL) and an open source machine learning toolkit, OpenNLP. MOTTE combines regular expressions and algorithms to identify where in the dictionary keywords and phrases related to a concept are found. Mammography findings from January 2006 to May 2015 were extracted including breast density as well as the presence of mass, calcifications, architectural distortion, asymmetric density, and calcification characteristics. A total of 717 patients with BI-RADS 5 mammograms who underwent breast biopsy within 3 months of the abnormal mammogram report date were identified using MOTTE, which also extracted personal history, family history, and subtype information (ER, PR, and HER2 status) of those patients. Clinical data including age, race, height, weight, and body mass index (BMI) were extracted from the METEOR data warehouse for those 717 patients. The extracted data were verified and validated with 99% accuracy by assessing a random 10% of records against a gold standard of manual chart review, which was completed by the clinical coauthors. MOTTE surpasses the manual method in terms of consistency, time, cost, and data preparation. Our ongoing study is to apply the MOTTE to extract distinct characteristics of BI-RADS 4 scored patients. The finding would help to refine biopsy recommendations and create a predictive model to drive evidence-based biopsy decision-making in breast cancer care. Citation Format: Puppala M, He TC, Ogunti R, Wong STC. Use of natural language processing on mammography and pathology findings to supplement BI-RADS to improve clinical decision making in breast cancer care [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-03-08.

Objective - High rates of screening mammography have been reported among Hispanic women in the U.S. However, a potential harm of screening is a false positive result with recall breast imaging or biopsy. Our objective was to identify factors associated with false positive results on screening mammography among a predominantly Hispanic population in New York City. Methods - We enrolled women receiving mammography at Columbia University Medical Center in New York, NY. They completed a questionnaire on breast cancer risk factors and gave consent to access their medical records for breast imaging and biopsy reports for the past 15 years. Breast cancer risk was assessed using the Gail model and eligibility for BRCA genetic testing was determined using a family history screener. High breast density was defined qualitatively as heterogeneously or extremely dense. Recall breast imaging was based upon a BIRADS score of 0, 3, 4, 5, or 6 on the screening mammogram. False positive breast biopsies were any biopsies that did not yield breast cancer. Results - From November 2014 to May 2015, 1325 women were enrolled: median age 58 years (range, 29-89); white/black/Hispanic/other (%): 10/10/76/4; 25% met high-risk criteria for breast cancer; 31% had high breast density; 71% were undergoing annual mammography; 53% had at least one recall breast imaging and 6% had at least one false positive breast biopsy. In multivariable analysis, high breast cancer risk, high breast density, and more frequent screening mammograms were associated with recall breast imaging and biopsy. Conclusions - Based upon our results, a potential strategy to reduce the false positive rates on screening mammography is to target women at high risk for breast cancer or with high breast density for screening with breast tomosynthesis, which has less false positives than digital mammography. Additionally, we may adopt less frequent breast cancer screening in average risk women to further reduce the harms of screening. Factors associated with Recall Breast Imaging and False Positive BiopsyVariableOR (95% CI)P-valueAnnual Mammograms vs. Every 2+ Years2.42 (1.88, 3.13) Citation Format: William Ueng, Julia McGuinness, Katherine Infante, Meghna S. Trivedi, Hae Seung Yi, Raven David, Alejandro Vanegas, Jennifer Vargas, Rossy Sandoval, Rita Kukafka, Katherine D. Crew. Factors associated with false positive results on screening mammography in a population of predominantly Hispanic women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1790.

Purpose MRI has great potential in the imaging of response to neoadjuvant chemotherapy in primary breast cancer. The aim of this study was to ascertain whether changes in lesion heterogeneity, as measured using texture analysis (TA),are linked with pathological response to treatment in primary breast cancer, according to lesion immunophenotype. Materials & Methods Sixty-one consecutive patients with biopsy-proven primary breast cancer underwent anthracycline-based NAC with baseline (pre-NAC) and interim (post 3-cycles NAC) MRI examinations performed on a 32-channel 3.0T MRI scanner (Siemens Trio; Erlangen) using a 7-channel breast biopsy coil. T2-weighted images (voxel size: 1.1x1.1x1.1mm3) were used for texture analysis, which was executed using MaZda software (University of Lodz; Poland). Slices were matched between imaging time-points and regions of interest manually placed to encompass the lesion. Where multiple lesions were present, only the index lesion was used. Lesion heterogeneity was assessed using the entropy feature, as derived from the co-occurrence matrix, and percentage changes between baseline and interim examinations calculated. Final pathologic response of the surgical resections was assessed using the Residual Cancer Burden (RCB) index, as calculated from tumor bed dimensions, residual cellularity and axillary node burden. Good responders (GR) were classified as those attaining a pCR or RCB-I score, while RCB-II and RCB-III lesions were considered poor responders (PR). Cancers were subdivided into estrogen-receptor positive (ER+), HER2 amplified (HER2+) and triple negative (TN) groups. Changes in lesion heterogeneity in relation to RCB response category and tumor subtype were compared using Mann Whitney U tests with significance at p ≤0.05 level. Results Patients who ultimately achieved a good pathological response demonstrated significantly greater reduction in lesion heterogeneity at TA between baseline and interim (pCR: 20.0%, RCB-I: 10.6%) than those who had a poor response (RCB-II: 6.8%, RCB-III: 3.4%) (p RCB response categories in each tumor subtype was as follows: ER+: GR- 4 patients, PR- 13; HER2+: GR- 7, PR- 13; TNBC: GR- 7, PR- 17. There were statistically significant differences in the degree of reduction of lesion heterogeneity between good responders and poor responders for the ER+ (p=0.010; Mann-Whitney U) and TNBC patients (p Conclusion Changes in lesion heterogeneity between baseline and interim MRI examinations, as measured using TA on T2-weighted images, correlate with pathologic response to NAC treatment in primary breast cancer using the RCB score. Larger reductions in lesion heterogeneity between baseline and interim examinations predict for a good response to treatment especially in ER+ and TNBC. Further evaluation of TA as a predictor of RCB score, with increased numbers in tumor subgroups, is required in a clinical trial setting. Citation Format: Waugh SA, Purdie CA, Evans AJ, Lerski RA, McGhee H, Vinnicombe SJ, Thompson AM. Response to neoadjuvant chemotherapy assessed by magnetic resonance imaging (MRI) texture analysis compared with residual cancer burden (RCB) and tumor subtype in primary breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-10.

Background Women with positive screening mammograms but negative at assessment (false-positive) are referred back to routine screening assuming that they have an average risk of breast cancer. However in a long-term follow-up of women with false-positive screening mammography we found that these women had in fact an excess risk of breast cancer later in life; RR=1.67(von Euler-Chelpin et al, JNCI 2012). This finding has later been supported by Castells et al.(Cancer Epidemiol, 2013). Furthermore, we studied the breast cancer cases in false-positive women and found that 26% of the cases were misclassified and were in fact true positives. However, even correction for misclassification, the false-positive women in our study remained at an excess breast cancer risk. At the same time, it was clear that, in the later periods of our study, when more modern techniques were used, the rate of misclassification decreased (von Euler-Chelpin et al, Cancer Epidemiol., 2014). Over time there have been changes both in the imaging and biopsy techniques. We used data from an organised screening programme in Denmark. Since its start in 1991, needle biopsies have been performed on all palpable solid lesions and on all uncertain, suspicious or malignant findings. In the very beginning fine needle aspiration cytology (FNAC) was used, later to be replaced by needle core biopsies in the majority of cases. Since 2002, suspicious micro-calcifications and impalpable mammographic findings not found by ultrasound have been examined using stereotactic needle core biopsy and later with vacuum-assisted breast biopsy as a replacement for surgical biopsy. To have a needle breast biopsy taken is a psychological burden on the woman. To minimize the harms and maximize the benefits is at the core of developing medical care. We therefore mapped the use of needle biopsies over time in a long-standing, organised screening programme. Method: We used data from the population-based screening mammography program in Copenhagen, Denmark. The programme has a database including personal records on demographic data, date of invitation, data of screening, and test results,1998-2013. Data from the Mammography Register were linked to the Danish Pathology Register (for biopsy procedures). Results: A total of 208 500 screens were included in the study. The rate of recall for assessment ranged between 1.7-3.2% of screened women with a mean of 2.4. The false-positive rate ranged between 1.0-2.5% with a mean of 1.6%. In 1998, 56% of all recalled women had a biopsy taken, which by 2013 had risen to 74% (using two-year smoothing). In proportion of all screens, the biopsy rate was 1.9% in 1998/99 which then fell to 0.7% in 2005/06 and the rose again 2.0% in 2012/13. In 1998, 59% of the biopsies were fine-needle aspiration cytology (FNAC) which by 2013 was only used in 11% of the cases, and replaced by core biopsies, ultrasound or stereotactic guided. Conclusion While the recall rate, as well as the false-positive rate, has been fairly stable during the study period the use of needle core biopsies has had a u-shaped development and has intensified in the later years. Citation Format: von Euler-Chelpin M, Vejborg I, Lænkholm A-V, Guleria S, Peterkin A, Lynge E. When needles are needed. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-02-11.

Introduction: Mammographic density (MD) is a strong breast cancer risk factor; however, the majority of women with high MD have neither a prevalent tumor nor will they develop one in immediate follow-up. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is another strong breast cancer risk predictor. However, it is uncertain how correlated microvessel density (MVD), a histological marker of vascularity, is with MD and if it adds information for disease detection. We therefore investigated relationships between MVD, area and volume measures of MD, and biopsy diagnosis among 218 women referred for image-guided vacuum-assisted breast biopsies. Methods: MVD was determined by counting CD31 (endothelial marker) positive vessels in whole sections of breast biopsies in three areas containing five 40X high power fields. Average MVD per area was calculated and then transformed based on a Box-Cox analysis to approximate a normal distribution. MD volume was quantified using single X-ray absorptiometry (SXA) in digital mammograms and MD area was quantified on the same image using thresholding methods. We used linear regression to evaluate associations between MVD (as the outcome) and MD measures (area and volume) adjusted for age and body mass index (BMI) in the overall population and stratified by biopsy diagnosis: cases (in situ or invasive carcinoma, n = 44) vs. non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between MVD and biopsy diagnosis (cases vs. non-cases) in models adjusted for age, BMI, and MD measures. Results: MVD was inversely associated with absolute dense area and absolute dense volume in the overall sample (area p = 0.01, volume p = 0.11) and among non-cases (area p = 0.009, volume p = 0.007). In age-, BMI-, and dense area- or dense volume- adjusted logistic regression models, MVD was significantly associated with risk of in situ/invasive disease independent of absolute dense area (OR = 1.16, 95% CI = 1.04, 1.28) and independent of absolute dense volume (OR = 1.16, 95% CI = 1.05-1.29). Conclusion: Our histopathologic analysis suggests that tissue vascularity, as reflected by MVD, may predict breast cancer risk independently of MD, thus providing theoretical support for the potential utility in breast cancer detection of imaging methods that reflect vascularity, such as contrast-enhanced MRI. Citation Format: Ashley S. Felix, Petra Lenz, Ruth M. Pfeiffer, Stephen M. Hewitt, Jennifer Morris, Deesha Patel, Berta Geller, Pamela M. Vacek, Donald L. Weaver, Rachael E. Chicoine, John Shepherd, Amir P. Mahmoudzadeh, Jeff Wang, Bo Fan, Sally Herschorn, Jason Johnson, Louise A. Brinton, Mark E. Sherman, Gretchen L. Gierach. Relationships between mammographic density, microvessel density, and breast biopsy diagnosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2768. doi:10.1158/1538-7445.AM2015-2768