Mouse-INtraDuctal (MIND): an in vivo model for studying the underlying mechanisms of DCIS malignancy.

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Similar to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression, while 17 (46%) samples injected into 107 xenografts remained non-invasive. Among the 20 samples that showed invasive progression, nine samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained non-invasive. Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and the extent of in vivo growth in xenografts predicted an invasive outcome. The Tempus XT assay was used on 16 patient DCIS formalin-fixed, paraffin-embedded sections including eight DCISs that showed invasive progression, five DCISs that remained non-invasive, and three DCISs that showed a mixed pattern in the xenografts. Analysis of the frequency of cancer-related pathogenic mutations among the groups showed no significant differences (KW: p > 0.05). There were also no differences in the frequency of high, moderate, or low severity mutations (KW; p > 0.05). These results suggest that genetic changes in the DCIS are not the primary driver for the development of invasive disease. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Radiologic and Pathologic Features Associated With Upgrade of Atypical Ductal Hyperplasia at Surgical Excision.

RATIONALE AND OBJECTIVES: To evaluate radiologic and pathologic features associated with upgrade of atypical ductal hyperplasia (ADH) to ductal carcinoma in situ or invasive breast cancer at surgical excision, in order to identify patients who may consider alternatives to excision. MATERIALS AND METHODS: This retrospective analysis examined patients who underwent surgical excision of biopsy-proven ADH at our institution. Imaging and pathology from biopsy were reviewed to determine radiologic (lesion size, radiologic abnormality, biopsy type, needle gauge, number of cores, percent of lesion removed) and pathologic features (histologic calcifications, presence of necrosis, micropapillary features, extent of ADH) associated with ADH upgrade. RESULTS: One hundred twenty four cases of percutaneous biopsy-proven ADH with subsequent excision were included. The overall upgrade rate was 17.7% (n = 22), with 17 cases to ductal carcinoma in situ and five to invasive cancer. Radiologic features associated with a lower upgrade rate were smaller lesion size (p = 0.032) and larger percent of lesion removed at biopsy (p = 0.047). Larger needle gauge at biopsy (p = 0.070), absence of necrosis (p = 0.051) and focal ADH (<3 foci, p = 0.12) were nearly associated with a lower rate of upgrade and were included for the purpose of multi parameter analyses. CONCLUSION: For women with ADH identified on percutaneous biopsy, the risk of upgrade may in part be determined by lesion size, percent of lesion removed at biopsy, presence of necrosis, and extent of ADH. Using a combination of these radiographic and pathologic features to stratify patients with biopsy-proven ADH may help identify women who could be considered for alternative treatment options.

Automated Breast Ultrasound Interpretation Times: A Reader Performance Study.

RATIONALE AND OBJECTIVES: This study aimed to determine the average time for breast radiologists of varied experience to interpret automated breast ultrasound (ABUS) examinations. MATERIALS AND METHODS: A reader performance study was conducted on female patients, with ACR BI-RADS 4 breast density classifications of C or D, who received both an ABUS screening examination and a digital mammogram from 2013 to 2014 at an academic institution. Three faculty breast radiologists with varied levels of ABUS experience (advanced, intermediate, novice) read all ABUS examinations, with interpretation times and final impressions (categorized as "normal" or "abnormal") recorded for each examination. RESULTS: Ninety-nine patients were included, with all readers demonstrating an average ABUS interpretation time of less than 3 minutes. Compared to the other two readers, the intermediate reader had a significantly longer mean interpretation time at 2.6 minutes (95% confidence interval 2.4-2.8; P < .001). In addition to having the shortest mean interpretation time, the novice reader also demonstrated reduced times in subsequent interpretations, with a significant decrease in interpretation times of 3.1 seconds (95% confidence interval 0.4-5.8) for every 10 ABUS examinations interpreted (P < .05). CONCLUSIONS: Overall, mean ABUS interpretation time by radiologists of all experience levels was short, at less than 3 minutes per examination, which should not deter radiologists from incorporating ABUS examinations into a busy clinical environment.

NEMO, a Transcriptional Target of Estrogen and Progesterone, Is Linked to Tumor Suppressor PML in Breast Cancer.

The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein promyelocytic leukemia (PML). E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the proinflammatory cytokine IL6. Mechanistic investigations indicated that IL6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene that harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation, and IL6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL6 secretion, increased phosphorylation of STAT3 on Ser727, and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical antitumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML. Cancer Res; 77(14); 3802-13. ©2017 AACR.

Microcalcifications of the breast: a mammographic-histologic correlation study using a newly designed Path/Rad Tissue Tray.

The introduction of screening mammography has brought about a greater knowledge of early breast cancer characteristics. These improvements have led to a reduction in size of suspicious lesions and a shift from surgical to image-guided core needle biopsies (CNBs). Establishing correlation between histologic and imaging findings is required for accurate diagnosis. Currently, there are no standardized multidisciplinary protocols for evaluating such lesions. We correlated histologic and radiologic findings in mammographically detectable calcified lesions in CNBs using specially designed Path/Rad Tissue Trays (patent pending, University of Kansas). Evidence of calcification was analyzed in 440 with and without the use of tissue trays. After mammographic identification of the lesion, CNBs are harvested, placed in tissue trays, and x-rayed to confirm sampling of the lesion. Images of CNBs with calcifications are marked by the radiologists and sent to the pathologist along with the biopsies. Trays with CNBs are then placed into cassettes and sent to the laboratory where they are embedded without disturbing orientation. Identification and localization of targeted microcalcifications were accomplished by radiologists and pathologists in 68 of 71 cases when using the tissue trays compared with 292 of 369 without tissue trays. Confirmation of microcalcifications was accomplished after deeper sectioning into tissue blocks from discordant cases. In conclusion, a systematic approach is recommended to standardize reporting of calcifications. The use of Path/Rad Tissue Trays has created a level of concordance between pathologists and radiologists that previously did no exist. It improved diagnostic reliability, encouraged communication between pathologists and radiologists, and minimized false diagnoses and/or delays in cancer diagnosis.

New techniques for mammography screening: advantages and limitations.

Screening mammography is the primary method used for the detection of breast cancer. Computer assisted detection (CAD) systems, magnetic resonance imaging of the breast, and breast lymphoscintigraphy with sentinel lymph node biopsy are three new imaging techniques developed to assist in the detection and evaluation of breast cancer and will be described and discussed.