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.

Pearls and Pitfalls of Interpretation of Automated Breast US.

Dense breast tissue is an independent risk factor for breast cancer and reduces the sensitivity of mammography. Patients with dense breast tissue are more likely to present with interval cancers and higher-stage disease. Successful breast cancer screening outcomes rely on detection of early-stage breast cancers; therefore, several supplemental screening modalities have been developed to improve cancer detection in dense breast tissue. US is the most widely used supplemental screening modality worldwide and has been proven to demonstrate additional mammographically occult cancers that are predominantly invasive and node negative. According to the American College of Radiology, intermediate-risk women with dense breast tissue may benefit from adjunctive screening US due to the limitations of mammography. Several studies have demonstrated handheld US (HHUS) and automated breast US (AUS) to be comparable in the screening setting. The advantages of AUS over HHUS include lack of operator dependence and a formal training requirement, image reproducibility, and ability for temporal comparison. However, AUS exhibits unique features that can result in high false-positive rates and long interpretation times for new users. Familiarity with the common appearance of benign mammographic findings and artifacts, technical challenges, and unique AUS features is essential for fast, efficient, and accurate interpretation. The goals of this article are to (a) examine the role of AUS as a supplemental screening modality and (b) review the pearls and pitfalls of AUS interpretation. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Multidisciplinary Review of Intraductal Papilloma of the Breast can Identify Patients who may Omit Surgical Excision.

BACKGROUND: The purpose of this study was to define contemporary management recommendations regarding who would benefit from surgical excision of intraductal papilloma (IDP). METHODS: A prospective database from a single institution identified patients with IDP on percutaneous biopsy from February 2015 to September 2020. Categorical patient demographic, biopsy, and pathologic variables were analyzed using Fisher's exact test and continuous demographic and imaging variables using the Mann-Whitney U test. RESULTS: IDP was present in 416 biopsies, at a median age of 56 years. The median size was 0.9 cm, and the majority had greater than 50% of the target excised by biopsy. Surgical excision was performed for 124 of 416 biopsies (29.8%). Upgrade to malignancy was identified in 14 (11.3%): 8 to ductal carcinoma in situ (DCIS) and 6 to invasive cancer. Upgrade was significantly associated with concurrent ipsilateral breast cancer (p = 0.027), larger imaging size (p = 0.045), <50% excised with biopsy (p = 0.02), and atypia involving IDP (p = 0.045). Age, clinical presentation, and concurrent contralateral cancer were not significantly associated with upgrade. Lowest upgrade risk (0%) was in pure IDP ≤1 cm with >50% removed by biopsy. Of 401 biopsies that either did not upgrade or undergo excision, 7 (1.7%) developed subsequent breast cancer over a median follow-up of 23.5 months (interquartile range [IQR] 11,41), none at IDP site. CONCLUSIONS: After multidisciplinary review, the management of IDP can be stratified into low- and high-risk for upgrade groups using key criteria. Low-risk group may omit surgical excision, because those patients have 0% risk of upgrade over the limited short-term follow-up.

Does the Addition of Breast MRI Add Value to the Diagnostic Workup of Invasive Lobular Carcinoma?

BACKGROUND: Invasive lobular carcinoma (ILC) has unique histologic growth pattern. Few studies have focused on the value of breast magnetic resonance imaging (MRI) specifically for ILC. We hypothesized that MRI adds value to the diagnostic workup in ILC by better defining the extent of disease and identifying additional foci of malignancy, which can change the surgical plan. MATERIALS AND METHODS: This was a single-institution retrospective review of women diagnosed with ILC from 1/2012 to 7/2019 who underwent preoperative MRI. Patient, tumor characteristics, and initial surgical plan were reviewed. MRI had added value if ILC size correlated best to final pathologic size or if additional malignancy was identified. MRI was considered harmful if additional biopsies were benign or if the size was overestimated. RESULTS: ILC was identified in 166 breasts in 165 women. Original surgical plan was for lumpectomy in 86 (52%), mastectomy in 49 (30%), and undecided in 31 (18%). MRI changed the plan in 25 (19%) with 24 (96%) changing from lumpectomy to mastectomy. Additional biopsy was performed in 28% after MRI, the majority (n = 41, 72%) were benign or high risk and 16 (28%) identified additional malignancy. MRI was not a better size estimate than mammogram/ultrasound. Re-excision rate after lumpectomy was 6.8% (5/73). MRI added value in 48 (28.9%) and was harmful in 48 (28.9%). CONCLUSIONS: Using breast MRI in the diagnostic workup of ILC has both positive and negative implications on surgical treatment planning. A shared decision-making conversation is warranted before proceeding with MRI to maximize value and minimize harms associated with this diagnostic tool.

Ipsilateral and Concurrent Breast Cancer and Atypical Ductal Hyperplasia: Does Atypia Also Need Surgical Excision?

BACKGROUND: Standard-of-care management of atypical ductal hyperplasia (ADH) is surgical excision. Multiple studies have identified features of ADH in patients at low risk for upgrade who may benefit from omission of surgical excision. Patients with an ipsilateral breast cancer have been excluded from studies investigating observation for the management of ADH. METHODS: This was a retrospective review of women with both a breast cancer and an ipsilateral separate site of ADH diagnosed on percutaneous biopsy, who underwent excision of both sites from 2008 to 2018. Radiographic and pathologic features of ADH and cancer were analyzed, including imaging size, biopsy modality, distance between sites, cancer subtype, grade, prognostic markers, ADH foci, and presence of necrosis or micropapillary features. Final pathology at the ADH site was used to determine upgrade. Multivariable logistic regression was performed to identify variables significantly associated with ADH upgrade to malignancy. RESULTS: Among 62 women meeting the inclusion criteria, 11 (17.7%) upgraded to malignancy [9 ductal carcinoma in situ (DCIS), 2 invasive cancer] at the site of ADH. Upgrade was significantly higher with ipsilateral DCIS (p = 0.03), ultrasound biopsy at the ADH site (p = 0.01), and ADH with necrosis (p = 0.04). The group at lowest risk for upgrade had stereotactic biopsy and ADH without necrosis (0% upgrade). CONCLUSION: The presence of breast cancer does not significantly increase the likelihood for upgrade at a separate site of ipsilateral concurrent ADH above contemporary reported upgrade rates of ADH alone (10-30%). When considering breast conservation for breast cancer, omitting excision of the site of ADH can be considered when low-risk features are present.

Supplemental Screening With Automated Breast Ultrasound in Women With Dense Breasts: Comparing Notification Methods and Screening Behaviors.

OBJECTIVE: Supplemental screening with ultrasound has been shown to detect additional breast malignancies in women with dense breast tissue and normal mammogram findings. The frequency of supplemental screening with automated breast ultrasound and the effect and type of breast tissue density notification on automated screening breast ultrasound utilization rates are unknown. MATERIALS AND METHODS: We examined normal mammogram results letters for patients with heterogeneously or extremely dense breast tissue between July 1, 2013, and June 30, 2014, by type of results letter, notification method, and sociodemographic characteristics. Logistic regression was used to examine the association between type of results letter and subsequent automated screening breast ultrasound. RESULTS: Among 3012 women with dense breast tissue and normal mammogram findings, 15% returned for supplemental automated screening breast ultrasound within 18 months of results letter notification. Compared with a similarly sized control group of women who did not undergo automated ultrasound, a significantly greater proportion of patients (86.9%) returned for breast ultrasound if they received a results letter indicating breast density in combination with a courtesy phone call (p < 0.001). Patients who received results letters with breast density notification including a statement that they may benefit from additional screening with automated breast ultrasound examination were 9.91 times (95% CI, 6.08-16.16) more likely to return for the examination than patients who did not receive breast density notification or mention of supplemental screening. CONCLUSION: Patient breast density notification and radiologists' recommendations for supplemental screening with breast ultrasound increase patient utilization of automated screening breast ultrasound examinations.

The Impact of Closed-Loop Imaging on Actionable CT-Detected Breast Findings.

PURPOSE: Closed-loop imaging programs (CLIPs) are designed to ensure that patients receive appropriate follow-up, but a review of incidental CT-detected breast findings in the setting of CLIPs has not been performed. METHODS: A retrospective review was conducted of CT reports at a single academic institution from July 1, 2020, to January 31, 2022, to identify reports with recommendations for breast imaging follow-up. Medical records were reviewed to evaluate patient adherence to follow-up, CLIP intervention, subsequent BI-RADS assessment, and diagnosis. Adherence was defined as diagnostic breast imaging performed within 6 months of the CT recommendation. RESULTS: Follow-up recommendations for breast imaging were included in CT report impressions for 311 patients. Almost half of patients (47.3% [147 of 311]) underwent follow-up breast imaging within 6 months, yielding breast cancer diagnoses in 12.9% (19 of 147) and a biopsy-proven positive predictive value of 65.5% (19 of 29). Most patients who returned for follow-up within 6 months did so without CLIP intervention. The majority of CT report impressions in the follow-up group (85.0% [125 of 147]) contained specific recommendations for "diagnostic breast imaging." For patients who did not receive follow-up, the CLIP team tracked all cases and intervened in 19.1% (28 of 147). The most common intervention was a phone call and/or fax to the primary care provider. Outpatient CT examination setting and specific recommendation for diagnostic breast imaging were significantly associated with higher follow-up adherence (P < .0001). CONCLUSIONS: Actionable CT-detected breast findings require follow-up diagnostic breast imaging because of a relevant cancer detection rate of 12.9%. Although many patients return for breast imaging without intervention, almost half of patients did not receive follow-up and may account for a significant number of missed cancer diagnoses. Specific CT recommendation verbiage is associated with higher follow-up adherence, which can be addressed across settings even without CLIPs.

Atypia Involving Fibroadenomas: Outcomes and Upgrade Rates.

OBJECTIVE: Fibroadenomas (FAs) involved by atypia are rare. Consensus guidelines for management of FAs involved by atypia when diagnosed on image-guided biopsy do not exist because of limited data reporting surgical upgrade rates to ductal carcinoma in situ (DCIS) or invasive malignancy. Therefore, these lesions commonly undergo surgical excision. METHODS: This single-institution retrospective study identified cases of FAs involved by atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and/or lobular carcinoma in situ (LCIS) diagnosed on image-guided biopsy between January 2014 and April 2023 to determine upgrade rates. Cases with incidental atypia adjacent to but not involving FAs were excluded. RESULTS: Among 1736 FAs diagnosed on image-guided biopsy, 32 cases (1.8%) were FAs involved by atypia including 43.8% (14/32) ALH, 28.1% (9/32) ADH, 18.8% (6/32) LCIS, 6.3% (2/32) LCIS + ALH, and 3.1% (1/32) unspecified atypia. The most common imaging finding was a mass. Most cases, 81.3% (26/32), underwent subsequent surgical excisional biopsy. A single case of ADH involving and adjacent to an FA was upgraded to FA involved by low-grade DCIS on excision for an overall surgical upgrade rate of 3.8%. There were no cases upgraded to invasive malignancy. For those omitting surgical excision, there was no subsequent malignancy diagnosis at the FA biopsy site over a mean follow-up of 73 months. CONCLUSION: Cases of radiologic-pathologic concordant FAs involved by atypia have a low upgrade rate of 3.8% and should undergo multidisciplinary review. Larger multi-institutional analysis is needed to determine whether guidelines for excision of atypia should apply to atypia involving FAs.

Breast MRI assists in decision-making for surgical excision of atypical ductal hyperplasia.

BACKGROUND: Atypical ductal hyperplasia diagnosed on percutaneous breast biopsy typically undergoes surgical excision, upgrading to invasive breast cancer or ductal carcinoma in situ in 10% to 53%. In efforts to limit excision to those with highest upgrade risk, we sought to determine if breast magnetic resonance imaging has value in predicting upgrade. In this study, we will describe magnetic resonance imaging presentation of atypical ductal hyperplasia and assess magnetic resonance imaging accuracy in predicting upgrade. METHODS: All female patients ≥18 years with atypical ductal hyperplasia on percutaneous breast biopsy undergoing magnetic resonance imaging from 2008 to 2020 were included. Patient demographics, imaging presentation, magnetic resonance imaging enhancement kinetic curves, and pathology features were captured. Categorical variables were analyzed using Fisher exact to test for association between variables and upgrade. Continuous variables were analyzed using t tests. RESULTS: Magnetic resonance imaging was performed for 125 percutaneous breast biopsy with atypical ductal hyperplasia: 67 after and 58 before atypical ductal hyperplasia diagnosis. On magnetic resonance imaging, atypical ductal hyperplasia site had no enhancement in 45 (36%), nonmass enhancement in 50 (40%), and mass enhancement in 30 (24%). In total, 28% had atypical ductal hyperplasia diagnosed by magnetic resonance imaging-guided percutaneous breast biopsy. Surgical excision was performed for 96 (76.8%) and 15 (15.6%) upgraded (11 ductal carcinoma in situ, 4 invasive breast cancer). All 15 upgrades had enhancement. Any kinetic pattern enhancement was significantly associated with upgrade (P = .009) with upgrade most strongly associated with type III washout. The lowest risk for upgrade was pure atypical ductal hyperplasia and no magnetic resonance imaging enhancement (0%, n = 25). CONCLUSIONS: Active monitoring may be safely offered to women with pure atypical ductal hyperplasia on percutaneous breast biopsy when magnetic resonance imaging shows no enhancement. Any enhancement at atypical ductal hyperplasia site, particularly type III washout kinetics, should continue to undergo excision.

Safety of de-escalation of surgical intervention for atypical ductal hyperplasia on percutaneous biopsy: One size does not fit all.

BACKGROUND: Oncologic safety of active monitoring (AM) for atypical ductal hyperplasia (ADH) on core-needle biopsy (CNB) is not well defined. We sought to define oncologic outcomes for AM to manage ADH meeting institutional predefined low-risk criteria (LOW). METHODS: ADH was diagnosed on CNB from 10/2015-03/2020. LOW (pure ADH, size <1 cm, >50% removed by CNB, <3 foci, and no necrosis) patients were offered AM; all others were recommended for surgical excision. Oncologic outcomes were compared for AM and surgery. RESULTS: 111 were included, 21 (19%) meeting LOW. AM occurred in 18 (86%) while 3 elected for excision (with 0% upgrade). Of the 18 LOW in AM, 2 required additional CNB (none at ADH site): 0% were diagnosed with cancer over median 23 month follow-up. CONCLUSIONS: There were no missed cancers at ADH site during AM for LOW, confirming the oncologic safety of AM in this select group.

Use of Ultrasound and Ki-67 Proliferation Index to Predict Breast Cancer Tumor Response to Neoadjuvant Endocrine Therapy.

BACKGROUND: Prediction of tumor shrinkage and pattern of treatment response following neoadjuvant endocrine therapy (NET) for estrogen receptor positive (ER+), Her2 negative (Her2-) breast cancers have had limited assessment. We examined if ultrasound (US) and Ki-67 could predict the pathologic response to treatment with NET and how the pattern of response may impact surgical planning. METHODS: A total of 103 postmenopausal women with ER+, HER2- breast cancer enrolled on the FELINE trial had Ki-67 obtained at baseline, day 14, and surgical pathology. A total of 70 patients had an US at baseline and at the end of treatment (EOT). A total of 48 patients had residual tumor bed cellularity (RTBC) assessed. The US response was defined as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). CR or PR on imaging and ≤70% residual tumor bed cellularity (RTBC) defined a contracted response pattern. RESULTS: A decrease in Ki-67 at day 14 was not predictive of EOT US response or RTBC. A contracted response pattern was identified in one patient with CR and in sixteen patients (33%) with PR on US. Although 26 patients (54%) had SD on imaging, 22 (85%) had RTBC ≤70%, suggesting a non-contracted response pattern of the tumor bed. The remaining four (15%) with SD and five with PD had no response. CONCLUSION: Ki-67 does not predict a change in tumor size or RTBC. NET does not uniformly result in a contracted response pattern of the tumor bed. Caution should be taken when using NET for the purpose of downstaging tumor size or converting borderline mastectomy/lumpectomy patients.

Incidental Breast Cancer on Chest CT: Is the Radiology Report Enough?

OBJECTIVE: To determine the frequency of incidental breast findings reported on chest CT for which breast imaging follow-up is recommended, the follow-up adherence rate, and the breast malignancy rate. The relationship between strength of recommendation verbiage and follow-up was also explored. METHODS: A retrospective review was conducted of chest CT reports from July 1, 2018, to June 30, 2019, to identify those with recommendation for breast imaging follow-up. Patients with recently diagnosed or prior history of breast malignancy were excluded. Medical records were reviewed to evaluate patient adherence to follow-up, subsequent BI-RADS assessment, and diagnosis (if tissue sampling performed). Adherence was defined as diagnostic breast imaging performed within 6 months of CT recommendation. Chi-square and Mann-Whitney U tests were used to determine statistical significance of categorical and continuous variables, respectively. RESULTS: A follow-up recommendation for breast imaging was included in chest CT reports of 210 patients; 23% (48/210) returned for follow-up breast imaging. All patients assessed as BI-RADS 4 or 5 underwent image-guided biopsy. Incidental breast cancer was diagnosed in 15% (7/48) of patients who underwent follow-up breast imaging as a result of a CT report recommendation and 78% (7/9) of patients undergoing biopsy. There was no significant difference in follow-up adherence when comparing report verbiage strength. CONCLUSION: It is imperative that incidental breast findings detected on chest CT undergo follow-up breast imaging to establish accurate and timely diagnosis of breast malignancy. Outreach to referring providers and patients may have greater impact on the diagnosis of previously unsuspected breast cancer.

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.

Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study.

Interventions that relieve vasomotor symptoms while reducing risk for breast cancer would likely improve uptake of chemoprevention for perimenopausal and postmenopausal women. We conducted a pilot study with 6 months of the tissue selective estrogen complex bazedoxifene (20 mg) and conjugated estrogen (0.45 mg; Duavee) to assess feasibility and effects on risk biomarkers for postmenopausal breast cancer. Risk biomarkers included fully automated mammographic volumetric density (Volpara), benign breast tissue Ki-67 (MIB-1 immunochemistry), and serum levels of progesterone, IGF-1, and IGFBP3, bioavailable estradiol and testosterone. Twenty-eight perimenopausal and postmenopausal women at increased risk for breast cancer were enrolled: 13 in cohort A with baseline Ki-67 < 1% and 15 in cohort B with baseline Ki-67 of 1% to 4%. All completed the study with > 85% drug adherence. Significant changes in biomarkers, uncorrected for multiple comparisons, were a decrease in mammographic fibroglandular volume (P = 0.043); decreases in serum progesterone, bioavailable testosterone, and IGF-1 (P < 0.01), an increase in serum bioavailable estradiol (P < 0.001), and for women from cohort B a reduction in Ki-67 (P = 0.017). An improvement in median hot flash score from 15 at baseline to 0 at 6 months, and menopause-specific quality-of-life total, vasomotor, and sexual domain scores were also observed (P < 0.001). Given the favorable effects on risk biomarkers and patient reported outcomes, a placebo-controlled phase IIB trial is warranted.

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.