High-risk and selected benign breast lesions diagnosed on core needle biopsy: Evidence for and against immediate surgical excision.

The vast majority of image-detected breast abnormalities are diagnosed by percutaneous core needle biopsy (CNB) in contemporary practice. For frankly malignant lesions diagnosed by CNB, the standard practice of excision and multimodality therapy have been well-defined. However, for high-risk and selected benign lesions diagnosed by CNB, there is less consensus on optimal patient management and the need for immediate surgical excision. Here we outline the arguments for and against the practice of routine surgical excision of commonly encountered high-risk and selected benign breast lesions diagnosed by CNB. The entities reviewed include atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, intraductal papillomas, and radial scars. The data in the peer-reviewed literature confirm the benefits of a patient-centered, multidisciplinary approach that moves away from the reflexive "yes" or "no" for routine excision for a given pathologic diagnosis.

Amyloid-ß precursor protein promotes cell proliferation and motility of advanced breast cancer.

BACKGROUND: Amyloid-ß precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease. Recently, the increased expression of APP in multiple types of cancers has been reported where it has significant correlation with the cancer cell proliferation. However, the function of APP in the pathogenesis of breast cancer has not previously been determined. In this study, we studied the pathological role of APP in breast cancer and revealed its potential mechanism. METHODS: The expression level of APP in multiple breast cancer cell lines was measured by Western blot analysis and the breast cancer tissue microarray was utilized to analyze the expression pattern of APP in human patient specimens. To interrogate the functional role of APP in cell growth and apoptosis, the effect of APP knockdown in MDA-MB-231 cells were analyzed. Specifically, multiple signal transduction pathways and functional alterations linked to cell survival and motility were examined in in vivo animal model as well as in vitro cell culture with the manipulation of APP expression. RESULTS: We found that the expression of APP is increased in mouse and human breast cancer cell lines, especially in the cell line possessing higher metastatic potential. Moreover, the analysis of human breast cancer tissues revealed a significant correlation between the level of APP and tumor development. Knockdown of APP (APP-kd) in breast cancer cells caused the retardation of cell growth in vitro and in vivo, with both the induction of p27(kip1) and caspase-3-mediated apoptosis. APP-kd cells also had higher sensitivity to treatment of chemotherapeutic agents, TRAIL and 5-FU. Such anti-tumorigenic effects shown in the APP-kd cells partially came from reduced pro-survival AKT activation in response to IGF-1, leading to activation of key signaling regulators for cell growth, survival, and pro-apoptotic events such as GSK3-ß and FOXO1. Notably, knock-down of APP in metastatic breast cancer cells limited cell migration and invasion ability upon stimulation of IGF-1. CONCLUSION: The present data strongly suggest that the increase of APP expression is causally linked to tumorigenicity as well as invasion of aggressive breast cancer and, therefore, the targeting of APP may be an effective therapy for breast cancer.

Solitary Fibrous Tumor of Breast and Axilla: Clinicopathological Profile of Five Tumors With Comparison of Risk Stratification Models.

Introduction: Solitary fibrous tumor (SFT) is a fibroblastic tumor with malignant potential that is underpinned by a recurrent inv12(q13q13)-derived NAB2::STAT6 fusion. Breast and axilla are uncommon locations for this entity. Methods: Records of two academic institutions were electronically searched for breast and axillary SFTs. Clinical and pathologic data were reviewed. Literature review for breast or axillary SFTs was performed. Present study and previously reported tumors were stratified using five SFT risk models: original and modified Demicco metastatic risk, Salas local recurrence risk, Salas metastatic risk, and Thompson local recurrence risk. Results: Five patients with breast or axillary SFT were identified. Median age was 49 years, and median follow-up (available for four patients) was 82 months. Three patients showed no evidence of disease, and one developed recurrence. Literature review identified 58 patients with breast or axillary SFT. Median age was 54 years, and median follow-up (available for 35 patients) was 24 months. Thirty-one patients showed no evidence of disease, three developed recurrence, and one developed metastasis. Original and modified Demicco models and Thompson model showed the highest sensitivity; original and modified Demicco models and Salas metastatic risk model demonstrated the highest specificity. Kaplan-Meier models were used to assess recurrence-free probability (RFP). Original and modified Demicco models predicted RFP when stratified by "low risk" and "moderate/intermediate and high risk" tumor, though sample size was small. Conclusions: While many SFTs of breast and axilla remain indolent, a subset may develop recurrence and rarely metastasize. The modified Demicco risk model demonstrated optimal performance characteristics.

The association between vascular endothelial growth factor expression in invasive breast cancer and survival varies with intrinsic subtypes and use of adjuvant systemic therapy: results from the Nurses' Health Study.

Vascular endothelial growth factor (VEGF) is important in breast carcinogenesis. However, whether the effect of VEGF expression on survival varies with intrinsic subtypes of breast cancer remains unclear and the prognostic significance of VEGF expression in breast cancer remains controversial. Using immunostaining of tissue microarray sections, VEGF expression was determined in 1,788 primary invasive breast cancers identified from the Nurses' Health Study cohort. Cox proportional hazards models were used to estimate hazard ratios (HR) of breast cancer-specific and overall mortality and distant recurrence, adjusted for epidemiological, clinicopathological, and related molecular factors, and year of diagnosis. Overall, 72.5% of breast cancers were positive for VEGF. VEGF expression was correlated with intrinsic subtypes (P < 0.0001), with higher frequency in luminal B, HER2, and basal-like types versus luminal A type. Although VEGF expression was not significantly related to worse survival when all cases were considered together, it was significantly associated with increased risks for breast cancer-specific mortality (BCSM) (HR = 1.41, 95% CI = 1.01, 1.97) and distant recurrence (HR = 1.49, 95% CI = 1.07, 2.07) among women with luminal A tumors. In 262 women untreated systemically, VEGF expression was significantly associated with BCSM (HR = 5.58, 95% CI = 1.17, 26.66). In 902 women receiving adjuvant hormonal therapy, VEGF expression did not significantly predict clinical outcomes. The VEGF-associated increased risk of BCSM is limited to luminal A tumors. VEGF expression is a prognostic but not predictive marker of hormonal response in non-metastatic invasive breast cancer.

Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models.

Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44-CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44-PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44-PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.See related commentary by Rodrigues and Vanharanta, p. 22.This article is highlighted in the In This Issue feature, p. 1.

The lncRNA BORG Drives Breast Cancer Metastasis and Disease Recurrence.

Long noncoding RNAs (lncRNAs) have emerged as potent regulators of breast cancer development and progression, including the metastatic spread of disease. Through in silico and biological analyses, we identified a novel lncRNA, BMP/OP-Responsive Gene (BORG), whose expression directly correlates with aggressive breast cancer phenotypes, as well as with metastatic competence and disease recurrence in multiple clinical cohorts. Mechanistically, BORG elicits the metastatic outgrowth of latent breast cancer cells by promoting the localization and transcriptional repressive activity of TRIM28, which binds BORG and induces substantial alterations in carcinoma proliferation and survival. Moreover, inhibiting BORG expression in metastatic breast cancer cells impedes their metastatic colonization of the lungs of mice, implying that BORG acts as a novel driver of the genetic and epigenetic alterations that underlie the acquisition of metastatic and recurrent phenotypes by breast cancer cells.

c-Abl inhibits breast cancer tumorigenesis through reactivation of p53-mediated p21 expression.

We previously reported that constitutive c-Abl activity (CST-Abl) abrogates the tumorigenicity of triple-negative breast cancer cells through the combined actions of two cellular events: downregulated matrix metalloproteinase (MMP) and upregulated p21Waf1/Cip1 expression. We now find decreased c-Abl expression to be significantly associated with diminished relapse-fee survival in breast cancer patients, particularly those exhibiting invasive and basal phenotypes. Moreover, CST-Abl expression enabled 4T1 cells to persist innocuously in the mammary glands of mice, doing so by exhausting their supply of cancer stem cells. Restoring MMP-9 expression and activity in CST-Abl-expressing 4T1 cells failed to rescue their malignant phenotypes; however, rendering these same cells deficient in p21 expression not only delayed their acquisition of senescent phenotypes, but also partially restored their tumorigenicity in mice. Although 4T1 cells lacked detectable expression of p53, those engineered to express CST-Abl exhibited robust production and secretion of TGF-ß1 that engendered the reactivated expression of p53. Mechanistically, TGF-ß-mediated p53 expression transpired through the combined actions of Smad1/5/8 and Smad2, leading to the dramatic upregulation of p21 and its stimulation of TNBC senescence. Collectively, we identified a novel c-Abl:p53:p21 signaling axis that functions as a powerful suppressor of mammary tumorigenesis and metastatic progression.

Comparison of Oncotype DX Recurrence Score by Histologic Types of Breast Carcinoma.

CONTEXT: Oncotype DX (ODX) is a widely used commercial assay that estimates the risk of distant recurrence and may predict the benefit of chemotherapy in a subset of breast cancers. Some studies have shown the ability to predict Oncotype DX recurrence score (ODXRS), based on routinely reported pathologic features; however, there are limited data correlating specific histologic type of breast cancer to ODXRS. OBJECTIVE: To compare ODXRS to specific histologic types of breast cancer. DESIGN: One hundred eighty-four cases were sent for ODXRS testing and the results were compared with histologic type and grade. RESULTS: The highest average ODXRS was seen in invasive ductal carcinoma with micropapillary features (29) followed by invasive ductal carcinoma not otherwise specified (mean = 19.4, SD = 11.6), invasive mucinous carcinoma (mean = 17.2, SD = 5.9), invasive lobular carcinoma (mean = 15.7, SD = 7.2), mixed ductal and lobular carcinoma (mean = 14.1, SD = 7.7), tubular carcinoma (10.0), and mixed ductal and mucinous carcinoma (mean = 8.0, SD = 4.2). Most tumors that had a high ODXRS were grade 3 invasive ductal carcinoma, representing 13 of a total of 20 cases (65%). Interestingly, 3 of the 4 cases of pure invasive mucinous carcinoma had an intermediate ODXRS. CONCLUSIONS: Although the numbers are small, our findings raise further awareness of the significance between histologic type and grade, and RS in breast cancer. In some special histologic types of breast cancer, particularly those considered to follow either an excellent or poor clinical course by histology alone, it is unclear whether the ODXRS results are as meaningful as in carcinomas of no special type. Further investigation with higher numbers and outcome data is needed.

Touch preparations for the intraoperative evaluation of sentinel lymph nodes after neoadjuvant therapy have high false-negative rates in patients with breast cancer.

CONTEXT: The use of a touch preparation for intraoperative sentinel lymph node diagnosis has become a preferred method of many pathologists because of its reported high sensitivity and rapid turnaround time. However, after neoadjuvant chemotherapy many lymph nodes have significant treatment-related changes that may affect the diagnostic accuracy of the intraoperative evaluation. OBJECTIVE: To determine the accuracy of touch preparation for the intraoperative diagnosis of metastatic breast carcinoma in the neoadjuvant setting. DESIGN: We reviewed retrospectively the results of intraoperative evaluations for 148 different sentinel lymph nodes from 63 patients who had undergone neoadjuvant chemotherapy for invasive breast cancer at our institution. The intraoperative touch preparation results were compared with the final pathology reports in conjunction with relevant clinical data. RESULTS: Use of touch preparation for the evaluation of sentinel lymph nodes intraoperatively after neoadjuvant therapy was associated with a low sensitivity of 38.6% (95% confidence interval [CI], 24.4-54.5) but high specificity of 100% (95% CI, 96.5-100). There was no difference in sensitivity rates between cytopathologists and noncytopathologists in this cohort (P = .40). Patients with invasive lobular carcinoma and those who had a clinically positive axilla before the initiation of neoadjuvant therapy were the most likely to have a false-negative result at surgery. CONCLUSIONS: Intraoperative touch preparations should not be used alone for the evaluation of sentinel lymph nodes in the setting of neoadjuvant therapy for breast cancer because of low overall sensitivity.

Tumor microenvironmental signaling elicits epithelial-mesenchymal plasticity through cooperation with transforming genetic events.

Epithelial-to-mesenchymal transition (EMT) facilitates the escape of epithelial cancer cells from the primary tumor site, which is a key event early in metastasis. Here, we explore how extrinsic, tumor microenvironmental cytokines cooperate with intrinsic, genetic changes to promote EMT in human mammary epithelial cells (HMECs). Viral transduction of transforming genetic events into HMECs routinely generated two distinct cell populations. One population retained epithelial characteristics, while an emergent population spontaneously acquired a mesenchymal morphology and properties associated with cancer stem cells (CSCs). Interestingly, the spontaneous mesenchymal/CSCs were unable to differentiate and lacked epithelial-mesenchymal plasticity. In contrast, exposure of the transformed HMECs retaining epithelial characteristics to exogenous transforming growth factor-ß (TGF-ß) generated a mesenchymal/CSC population with remarkable plasticity. The TGF-ß-induced mesenchymal/CSC population was dependent on the continued presence of TGF-ß. Removal of TGF-ß or pharmacologic or genetic inhibition of TGF-ß/SMAD signaling led to the reversion of mesenchymal/CSC to epithelial/non-CSC. Our results demonstrate that targeting exogenous cytokine signaling disrupts epithelial-mesenchymal plasticity and may be an effective strategy to inhibit the emergence of circulating tumor cells. The model of epithelial-mesenchymal plasticity we describe here can be used to identify novel tumor microenvironmental factors and downstream signaling that cooperate with intrinsic genetic changes to drive metastasis. Understanding the interaction between extrinsic and intrinsic factors that regulate epithelial-mesenchymal plasticity will allow the development of new therapies that target tumor microenvironmental signals to reduce metastasis.

Stereotactic core biopsy: Comparison of 11 gauge with 8 gauge vacuum assisted breast biopsy.

PURPOSE: The compare the performance and ability to obtain a correct diagnosis on needle biopsy between 11 gauge and 8 gauge vacuum assisted biopsy devices. MATERIALS AND METHODS: Hospital records of all consecutive stereotactic core biopsies performed over five years were retrospectively reviewed in compliance Health Insurance Portability and Accountability Act (HIPPA) policy and with approval from the hospital institutional review board (IRB). Pathology from core biopsy was compared with surgical pathology and/or imaging follow-up. A histological underestimation was defined if the surgical excision yielded a higher grade on pathology which changed management. RESULTS: 828 needle core biopsies (47.5%, 393/828 with 11 gauge and 52.5%, 435/828 with 8 gauge) yielded 471 benign, 153 high risk and 204 malignant lesions. 30/193 (15.5%) 11 gauge lesions and 16/185 (8.6%) 8 gauge lesions demonstrated higher grade pathology on surgical excision. The difference in the rates of the number of correct diagnoses on core needle biopsy between 11 gauge (363/393, 92.4%) and 8 gauge (419/435, 96.3%) based on either surgical or clinical/imaging follow up and the difference in the number of discordant benign core biopsies between 11 (17/217, 7.8%) and 8 gauge (4/254, 1.6%) necessitating a surgical biopsy was significant (P=0.013; P=0.001). Although there were more underestimations with the 11 gauge (25/193, 13.0%) than 8 gauge (15/185, 8.1%) needle, this was not significant. CONCLUSION: Our study demonstrates improved performance and increased diagnostic ability of 8 gauge needle over 11 gauge in obtaining a correct diagnosis on needle biopsy.