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Introduction: The cytoskeletal protein ezrin is upregulated in many cancer types and is strongly associated with poor patient outcome. While the clinical and prognostic value of ezrin has been previously evaluated in breast cancer, most studies to date have been conducted in smaller cohorts (less than 500 cases) or have focused on specific disease characteristics. The current study is the largest of its kind to evaluate ezrin both at the protein and mRNA levels in early‐stage breast cancer patients using the Nottingham (n = 1094) and METABRIC (n = 1980) cohorts, respectively. Results: High expression of ezrin was significantly associated with larger tumour size (p = 0.027), higher tumour grade (p < 0.001), worse Nottingham Prognostic Index prognostic group (p = 0.011) and HER2‐positive status (p = 0.001). High ezrin expression was significantly associated with adverse survival of breast cancer patients (p < 0.001) and remained associated with survival in multivariate Cox‐regression analysis (p = 0.018, hazard ratio (HR) = 1.343, 95% confidence interval (CI) = 1.051–1.716) when potentially confounding factors were included. High ezrin expression was significantly associated with adverse survival of patients whose tumours were categorised as receptor (oestrogen receptor (ER), progesterone receptor (PgR) or HER2) positive (p < 0.001) in comparison to those categorised as triple‐negative breast cancer (p = 0.889). High expression of ezrin mRNA (VIL2) in the METABRIC cohort was also significantly associated with adverse survival of breast cancer patients (p < 0.001). Conclusion: Retrospective analyses show that ezrin is an independent prognostic marker, with higher expression associated with shortened survival in receptor‐positive (ER, PgR or HER2) patients. Ezrin expression is associated with more aggressive disease and may have clinical utility as a biomarker of patient prognosis in early‐stage breast cancer. [ABSTRACT FROM AUTHOR]

To determine the impact of definitive presurgical diagnosis on surgical margins in breast-conserving surgery (BCS) for primary carcinomas; clinicopathological features were also analyzed. This retrospective study included women who underwent BCS for primary carcinomas in 2016 and 2017. Definitive presurgical diagnosis was defined as having a presurgical core needle biopsy (CNB) and not being upstaged between biopsy and surgery. Biopsy data and imaging findings including breast density were retrieved. Inadequate surgical margins (IM) were defined per latest ASCO and ASTRO guidelines. Univariable and multivariable analyses were performed. 360 women (median age, 66) met inclusion criteria with 1 having 2 cancers. 82.5% (298/361) were invasive cancers while 17.5% (63/361) were ductal carcinoma in situ (DCIS). Most biopsies were US-guided (284/346, 82.0%), followed by mammographic (60/346, 17.3%), and MRI-guided (2/346, 0.6%). US and mammographic CNB yielded median samples of 2 and 4, respectively, with a 14G needle. 15 patients (4.2%) lacked presurgical CNB. The IM rate was 30.0%. In multivariable analysis, large invasive cancers (>20 mm), dense breasts, and DCIS were associated with IM (p = 0.029, p = 0.010, and p = 0.013, respectively). Most importantly, lack of definitive presurgical diagnosis was a risk factor for IM (OR, 2.35; 95% CI: 1.23–4.51, p = 0.010). In contrast, neither patient age (<50) nor aggressive features (e.g., LVI) were associated with IM. Lack of a definitive presurgical diagnosis was associated with a two-fold increase of IM in BCS; other risk factors were dense breasts, large invasive cancers, and DCIS. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen ( PSMA) has been found to be expressed in the tumor-associated neovasculature of multiple solid tumor types including breast cancers. However, thus far, the number of cases studied from some tumor types has been limited. In this study, we set out to assess PSMA expression in the tumor-associated vasculature associated with invasive breast carcinomas in a sizable cohort of patients. One hundred and six patients with AJCC stage 0- IV breast cancer were identified. Ninety-two of these patients had primary breast cancer [invasive breast carcinoma with or without co-existing ductal carcinoma in situ ( DCIS) (74) or DCIS alone (18)]. In addition, 14 patients with breast cancer metastases to the brain were identified. Immunohistochemical staining for PSMA and CD31 was performed on parallel representative tumor sections in each case. Tumor-associated vascular endothelial cell PSMA immunoreactivity was semi-quantitatively assessed based on two parameters: overall percent of endothelial positivity and staining intensity. PSMA expression for tumor-associated vascular endothelial cells was scored 0 if there was no detectable PSMA expression, 1 if PSMA staining was detectable in 5-50%, and 2 if PSMA expression was positive in >50% of microvessels. CD 31 staining was concurrently reviewed to confirm the presence of vasculature in each case. Tumor-associated vasculature was PSMA-positive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells. All but 2 cases (98%) showed absence of PSMA expression in normal breast tissue-associated vasculature. The 10-year overall survival was 88.7% (95% CI = 80.0%, 93.8%) in patients without brain metastases. When overall survival ( OS) was stratified based on PSMA score group, patients with PSMA scores of 0, 1, and 2 had 10-year OS of 95.8%, 96.0%, and 79.7%, respectively (p = 0.12). When PSMA scores of 0 and 1 were compared with 2, there was a statistically significant difference in OS (96.0% vs 79.7%, respectively, p = 0.05). Patients with a PSMA score of 2 had a significantly higher median tumor size compared with patients in the lower PSMA score groups (p = 0.04). Patients with higher nuclear grade were more likely to have a PSMA score of 2 compared with patients with lower nuclear grade (p < 0.0001). Patients with a PSMA score of 2 had a significantly higher median Ki-67 proliferation index compared with patients in the lower PSMA score groups (p < 0.0001). Patients with estrogen receptor ( ER)-negative tumors were more likely to have a PSMA score of 2 compared with patients with ER-positive tumors (p < 0.0001). Patients with progesterone receptor ( PR)-negative tumors were more likely to have a PSMA score of 2 compared with patients with PR-positive tumors (p = 0.03). No significant association was observed between PSMA score group status and lymph node involvement (p = 0.95). Too little variability was present in Human epidermal growth factor receptor-2 (Her2/neu) amplified tumors to correlate with PSMA score group status. To date, this is the first detailed assessment of PSMA expression in the tumor-associated vasculature of primary and metastatic breast carcinomas. Further studies are needed to evaluate whether PSMA has diagnostic and/or potential therapeutic value. [ABSTRACT FROM AUTHOR]

There is critical need for improved biomarker assessment platforms which integrate traditional pathological parameters (TNM stage, grade and ER/PR/HER2 status) with molecular profiling, to better define prognostic subgroups or systemic treatment response. One roadblock is the lack of semi-quantitative methods which reliably measure biomarker expression. Our study assesses reliability of automated immunohistochemistry (IHC) scoring compared to manual scoring of five selected biomarkers in a tissue microarray (TMA) of 63 human breast cancer cases, and correlates these markers with clinico-pathological data. TMA slides were scanned into an Ariol Imaging System, and histologic (H) scores (% positive tumor area x staining intensity 0-3) were calculated using trained algorithms. H scores for all five biomarkers concurred with pathologists' scores, based on Pearson correlation coefficients (0.80-0.90) for continuous data and Kappa statistics (0.55-0.92) for positive vs. negative stain. Using continuous data, significant association of pERK expression with absence of LVI (p = 0.005) and lymph node negativity (p = 0.002) was observed. p53 over-expression, characteristic of dysfunctional p53 in cancer, and Ki67 were associated with high grade (p = 0.032 and 0.0007, respectively). Cyclin D1 correlated inversely with ER/PR/HER2-ve (triple negative) tumors (p = 0.0002). Thus automated quantitation of immunostaining concurs with pathologists' scoring, and provides meaningful associations with clinico-pathological data. [ABSTRACT FROM AUTHOR]

Abnormal cell division leading to the gain or loss of entire chromosomes and consequent genetic instability is a hallmark of cancer. Centromere protein -A (CENPA) is a centromere-specific histone-H3-like variant gene involved in regulating chromosome segregation during cell division. CENPA is one of the genes included in some of the commercially available RNA based prognostic assays for breast cancer (BCa)—the 70 gene signature MammaPrint® and the five gene Molecular Grade Index (MGISM). Our aim was to assess the immunohistochemical (IHC) expression of CENPA in normal and malignant breast tissue. Clinically annotated triplicate core tissue microarrays of 63 invasive BCa and 20 normal breast samples were stained with a monoclonal antibody against CENPA and scored for percentage of visibly stained nuclei. Survival analyses with Kaplan-Meier (KM) estimate and Cox proportional hazards regression models were applied to assess the associations between CENPA expression and disease free survival (DFS). Average percentage of nuclei visibly stained with CENPA antibody was significantly higher (p = 0.02) in BCa than normal tissue. The 3-year DFS in tumors over-expressing CENPA (>50% stained nuclei) was 79% compared to 85% in low expression tumors (<50% stained nuclei). On multivariate analysis, IHC expression of CENPA showed weak association with DFS (HR > 60.07; p = 0.06) within our small cohort. To the best of our knowledge, this is the first published report evaluating the implications of increased IHC expression of CENPA in paraffin embedded breast tissue samples. Our finding that increased CENPA expression may be associated with shorter DFS in BCa supports its exploration as a potential prognostic biomarker. [ABSTRACT FROM AUTHOR]

The article discusses a study on the frequency of MAGI3-AKT3 fusion in 236 triple-negative breast cancers (TNBCs) represented in high-density microarrays. TNBC constitutes majority of breast carcinomas and notes that TNBC patients have poor response to conventional breast cancer therapies and experience poor survival. It confirms that MAGI3-AKT3 fusion is not a recurrent event in triple-negative breast cancer that should be acknowledged prior to evaluating targeted therapies in clinical trials.