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Background Prevention of triple-negative breast cancer (TNBC) is hampered by lack of knowledge about the drivers of tumorigenesis. Methods To identify molecular markers and their downstream networks that can potentially be targeted for TNBC prevention, we analyzed small RNA and RNA sequencing of a cell line model that represent early stages of TNBC development. We have identified direct gene targets of isomiRNA-140-3p and by using cell-based and in vivo model systems we have demonstrated the utility of targeting downstream pathways for prevention of TNBC. Results These analyses showed that 5’isomiRNA of miR-140-3p (miR-140-3p-1) and its novel direct gene targets, HMG-CoA reductase (HMGCR) and HMG-CoA synthase 1(HMGCS1), key enzymes in the cholesterol biosynthesis pathway, were deregulated in the normal-to-preneoplastic transition. Upregulation in the cholesterol pathway creates metabolic vulnerability that can be targeted. Consistent with this hypothesis, we found direct targeting of miR-140-3p-1 and its downstream pathway by fluvastatin to inhibit growth of these preneoplastic MCF10.AT1 cells. However, although, fluvastatin inhibited the growth of MCF10.AT1-derived xenografts, histological progression remained unchanged. The cholesterol pathway is highly regulated, and HMGCR enzymatic activity inhibition is known to trigger a feedback response leading to restoration of the pathway. Indeed, we found fluvastatin-induced HMGCR transcript levels to be directly correlated with the degree of histological progression of lesions, indicating that the extent of cholesterol pathway suppression directly correlates with abrogation of the tumorigenic process. To block the HMGCR feedback response to statins, we treated resistant preneoplastic cells with an activator of AMP-activated protein kinase (AMPK), a brake in the cholesterol feedback pathway. AMPK activation by aspirin and metformin effectively abrogated the statin-induced aberrant upregulation of HMGCR and sensitized these resistant cells to fluvastatin. Conclusions These results suggest the potential use of combined treatment with statin and aspirin for prevention of TNBC.

Background Neuroendocrine carcinoma (NEC) of the breast is a rare type of carcinoma that has not been well studied or characterized. Of the limited number of studies reported in the literature, most are case reports. A few small retrospective series studies have been reported. Methods We reviewed data on 142 cases of mammary NEC recorded in the surveillance, epidemiology, and end results (SEER) database during 2003–2009 and evaluated disease incidence and patient age, sex, and race/ethnicity; clinicopathologic characteristics; and survival in comparison to invasive mammary carcinoma, not otherwise specified. We also performed univariate and multivariate analyses to identify prognostic factors in this disease. Results Review of the 142 SEER cases revealed that NEC is an aggressive variant of invasive mammary carcinoma. It generally occurred in older women (>60 years); present with larger tumor size (>20 mm), higher histologic grade, and higher clinical stage; and result in shorter overall survival and disease-specific survival than invasive mammary carcinoma, not otherwise specified (IMC-NOS). Overall survival and disease-specific survival were shorter in NEC at each stage than in IMC-NOS of the same stage. Furthermore, when all NEC and IMC-NOS cases were pooled together, neuroendocrine differentiation itself was an adverse prognostic factor independent of other known prognostic factors, including age, tumor size, nodal status, histologic grade, estrogen/progesterone receptor status, and therapy. Conclusions NEC is a rare but aggressive type of mammary carcinoma. Novel therapeutic approaches should be explored for this uniquely clinical entity.

Despite success in preclinical animal models, most cancer prevention drugs fail to show efficacy in clinical trials. One potential reason could be that study end points in animal models are not sufficiently robust. Preclinical efficacy studies often use tumor development, as measured by palpation, as an endpoint. A comprehensive study design that includes more rigorous measures by histologic assessment of all the mammary glands is less common. We hypothesized that the efficacy of drug treatment may vary based on the approach to tumor assessment. SV40C3TAg mice that spontaneously develop TNBC-like tumors were used to assess the efficacy of drugs for breast cancer prevention. Histological grading was performed using a 5-point scale. Animals were treated with fluvastatin and/or aspirin for 16 weeks and the experiment was concluded at 22 weeks, and all the mammary glands removed for histologic assessment. Grossly palpable mammary glands (> 3 mm) and /or histologic grade 4–5 was considered tumor bearing and treatment non-responder. 112 mammary glands from 40 mice were assessed. A high concordance (> 90%) was noted between palpably enlarged glands and the finding of grade 4–5 lesions. Conversely, among 74 non-palpably enlarged mammary glands, more than 66% were histologically high-grade and would have been wrongly classified as tumor-free based on gross tumor measurement. In drug efficacy studies, significant differences were noted in the rate of treatment response based on the method of tumor assessment, with a 22% response rate noted using the histological grading system and a 65% response rate using gross palpation. These analyses suggest that there is poor concordance between the gross tumor measurements and histological tumor assessment in a mouse model of breast cancer. Thus, gross tumor measurement alone is insufficient for determining chemopreventive efficacy in preclinical animal models.

Annexin A1 (ANXA1) is an anti-inflammatory protein reported to play a role in cell proliferation and apoptosis, and to be deregulated in breast cancer. The exact role of annexin A1 in the biology of breast cancer remains unclear. We hypothesized that the annexin A1 plays an oncogenic role in basal subtype of breast cancer by modulating key growth pathway(s). By mining the Cancer Genome Atlas (TCGA)-Breast Cancer dataset and manipulating annexin A1 levels in breast cancer cell lines, we studied the role of annexin A1 in breast cancer and underlying signaling pathways. Our in-silico analysis of TCGA-breast cancer dataset demonstrated that annexin A1 mRNA expression is higher in basal subtype compared to luminal and HER2 subtypes. Within the basal subtype, patients show significantly poorer overall survival associated with higher expression of annexin A1. In both TCGA patient samples and cell lines, annexin A1 levels were significantly higher in basal-like breast cancer than luminal and Her2/neu-positive breast cancer. Stable annexin A1 knockdown in TNBC cell lines suppressed the mTOR-S6 pathway likely through activation of AMPK but had no impact on the MAPK, c-Met, and EGFR pathways. In a cell migration assay, annexin A1-depleted TNBC cells showed delayed migration as compared to wild-type cells, which could be responsible for poor patient prognosis in basal like breast cancers that are known to express higher annexin A1. Our data suggest that annexin A1 is prognostic only in patients with basal like breast cancer. This appears to be in part due to the role of annexin A1 in activating mTOR-pS6 pathway.

Background Our goal was to analyze clinicopathologic features of patients with atypical ductal hyperplasia (ADH) diagnosed on directional vacuum-assisted biopsy (DVAB) targeting microcalcifications to identify factors predicting the presence of carcinoma. Materials and Methods We retrospectively evaluated the clinical, mammographic, and histologic features of 140 patients with DVAB-diagnosed ADH who underwent either segmental excision (86.4%) or mammographic follow-up (≥2 years; 13.6%). Cases with mass lesions or ipsilateral cancer were excluded. Results In 16 cases, carcinoma was found on excision. All cases without excision showed no new abnormalities on mammographic follow-up. Only the amount of calcifications removed (≤95%) significantly correlated with the rate of upgrade of ADH to carcinoma ( P  = .037). Significant histologic predictors of upgrade to carcinoma included number of terminal duct-lobular units (TDLU; >2) involved ( P  = .0306), presence of significant cytologic atypia suspicious for intermediate or high-grade carcinoma ( P  < .0001), and necrosis ( P  = .0006). Among ADH cases without significant atypia and/or necrosis, the extent of ADH (≤2 vs. >2 TDLU involved) was not a significant predictor of carcinoma ( P  = 1.0000). Conclusions ADH associated with calcifications in the absence of a mass lesion can be categorized into different risk groups using a multidisciplinary approach with correlation of histologic and mammographic findings. ADH lesions with significant cytologic atypia and/or necrosis are most likely to be associated with carcinoma and should be excised. ADH without these features, regardless of extent of involvement, and with >95% removal of the targeted calcifications, is associated with a minimal risk (<3%) of carcinoma and may undergo mammographic follow-up only.

DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability. DNA damage causes activation of the DNA damage response (DDR) that is an important cellular mechanism for maintaining genomic integrity in the face of genotoxic stress. While the cellular response to genotoxic stress has been extensively studied in cancer models, less is known about the cellular response to oncogenic stress in the premalignant context. In the present study, by using breast tissues samples from women at different risk levels for invasive breast cancer (normal, proliferative breast disease and ductal carcinoma in situ) we found that DNA damage is inversely correlated with risk of invasive breast cancer. Similarly, in MCF10A based in vitro model system where we recapitulated high DNA damage conditions as seen in patient samples by stably cloning in cyclin E, we found that high levels of oncogene induced DNA damage, by triggering inhibition of a major proliferative pathway (AKT), inhibits cell growth and causes cells to die through autophagy. These data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized 'normal-like' breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis.

AimsSecretory carcinoma of breast (SCB) typically harbours ETV6-NTRK3 gene fusion. Pan-Trk immunohistochemistry analysis (IHC) has been shown to be sensitive for SCB diagnosis. However, weak focal pan-Trk nuclear staining was previously found in 10% of non-secretory breast carcinomas. To further examine pan-Trk IHC specificity, we evaluated pan-Trk staining in various breast carcinoma subtypes.MethodsThe study cohort consisted of 346 invasive breast carcinomas (IBCs), including 8 SCBs and 48 triple-negative histological mimickers (36 metaplastic carcinomas, including 12 matrix-producing carcinomas; 5 adenoid cystic carcinomas; 5 apocrine carcinomas; 2 acinic cell carcinomas), 101 triple-negative IBCs of no special type, 101 estrogen receptor (ER)-positive/HER2-negative IBCs and 88 HER2-positive IBCs. Six salivary gland secretory carcinomas were also included. Pan-Trk IHC was performed on tumours using a rabbit monoclonal pan-Trk antibody. Any nuclear staining in the invasive carcinoma cells was considered positive.ResultsAll 14 secretory carcinomas from breast and salivary gland exhibited moderate to strong pan-Trk nuclear staining. In contrast, no pan-Trk nuclear staining was identified in any of the 338 non-secretory IBCs. Focal cytoplasmic pan-Trk staining was observed in nine non-secretory IBCs (2.7%), and was considered nonspecific and negative.ConclusionsOur results indicate that pan-Trk nuclear staining is highly specific for SCB. In low-grade to intermediate-grade IBCs that share histological features with SCB, adding pan-Trk to a routing panel of estrogen receptor/progesterone receptor/HER2 is highly diagnostic. Our results also support using pan-Trk IHC to differentiate SCB from its triple-negative histological mimickers, such as adenoid cystic carcinoma, matrix-producing carcinoma, apocrine carcinoma and acinic cell carcinoma.

Pseudoangiomatous stromal hyperplasia tumors are rare. In this retrospective study, we evaluated the clinical, radiologic, and pathologic features of pseudoangiomatous stromal hyperplasia tumors and compared histologic findings of pseudoangiomatous stromal hyperplasia tumors with clinical outcome. We identified 26 patients (mean age, 47 years) with pseudoangiomatous stromal hyperplasia tumors who had been diagnosed at our institution. Sixteen patients (62%) were premenopausal, and 13 (50%) had a history of oral contraceptive or hormone replacement therapy use. Ten patients (38%) presented with a palpable mass; in the other patients, the tumors were detected by mammography (where it usually appeared as a hyperdense mass with irregular margins) or sonography (where it usually appeared as a hypoechoic mass). Lesions were a mean of 4.2 cm at the largest dimension (range, 0.8–11 cm). Histologically, pseudoangiomatous stromal hyperplasia was classified as simple in 18 patients (69%) and fascicular/proliferative in eight patients (31%). In one patient (4%), an invasive ductal carcinoma was present within the pseudoangiomatous stromal hyperplasia tumor. We found associated benign epithelial lesions in eight patients (31%) and/or gynecomastia-like changes in 17 patients (65%). The presence of gynecomastia-like changes was significantly associated with intralobular location of pseudoangiomatous stromal hyperplasia (P=0.00085, by Fisher’s exact test). Follow-up data were available for 15 patients (mean±s.d., ≤27±17 months). No additional pathology or substantial changes in existing lesions were found on imaging. All pseudoangiomatous stromal hyperplasia tumors diagnosed by core needle biopsy but not subsequently excised remained clinically and radiologically stable; therefore, offering the option of close clinical surveillance instead of surgery in patients with pseudoangiomatous stromal hyperplasia tumors diagnosed by core needle biopsy in selected patients.

Purpose The recent findings from the DESTINY-Breast04 trial highlighted the clinical importance of distinguishing between HER2 immunohistochemistry (IHC) scores 0 and 1 + in metastatic breast cancer (BC). However, pathologist interpretation of HER2 IHC scoring is subjective, and standardized methodology is needed. We evaluated the consistency of HER2 IHC scoring among pathologists and the accuracy of digital image analysis (DIA) in interpreting HER2 IHC staining in cases of HER2-low BC. Methods Fifty whole-slide biopsies of BC with HER2 IHC staining were evaluated, comprising 25 cases originally reported as IHC score 0 and 25 as 1 +. These slides were digitally scanned. Six pathologists with breast expertise independently reviewed and scored the scanned images, and DIA was applied. Agreement among pathologists and concordance between pathologist scores and DIA results were statistically analyzed using Kendall coefficient of concordance ( W ) tests. Results Substantial agreement among at least five of the six pathologists was found for 18 of the score 0 cases (72%) and 15 of the score 1 + cases (60%), indicating excellent interobserver agreement ( W  = 0.828). DIA scores were highly concordant with pathologist scores in 96% of cases (47/49), indicating excellent concordance ( W  = 0.959). Conclusion Although breast subspecialty pathologists were relatively consistent in evaluating BC with HER2 IHC scores of 0 and 1 +, DIA may be a reliable supplementary tool to enhance the standardization and quantification of HER2 IHC assessment, especially in challenging cases where results may be ambiguous (i.e., scores 0–1 +). These findings hold promise for improving the accuracy and consistency of HER2 testing.

PurposeHER2 overexpression and gene amplification are routinely tested by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. In addition, HER2 mRNA expression is also tested by the Oncotype DX assay. Discordance between laboratories among the different assays remains a problem. To improve the routine HER2 reporting, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) updated their guidelines in 2018. Our study will compare concordance of HER2 status by IHC and FISH using ASCO/CAP 2013 and 2018 guidelines with Oncotype DX.MethodsWe retrospectively reviewed 657 estrogen receptor positive primary breast cancer cases with available Oncotype DX tests between 2011 and 2018. Medical records were reviewed for HER2 results by IHC, FISH, and Oncotype DX. The HER2 results by different assays and between 2013 and 2018 guidelines were compared.ResultsOf the 657 cases, 280 were tested by IHC, FISH, and Oncotype DX. HER2-equivocal cases by IHC 2013 guidelines were all negative (67/67, 100%) by FISH 2018 guidelines and by Oncotype DX. HER2-equivocal cases by FISH 2013 guidelines were all negative (16/16, 100%) by FISH 2018 guidelines, while 15/16 (93.8%) negative and 1/16 (6.2%) equivocal by Oncotype DX. The HER2-equivocal and HER2-negative groups were similar in age, gender, histology, grade, and Ki67 score.ConclusionsHER2 concordance was highest between Oncotype DX (99.6%) and FISH per 2018 guidelines. This suggests that the ASCO/CAP 2018 guidelines improved the accurate stratification of HER2-equivocal cases.