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Triple-negative breast carcinomas constitute a wide spectrum of lesions, mostly being highly aggressive. Nevertheless, some special histologic subtypes can have low malignant potential. The purpose of the present paper is to review diagnostic criteria and prognostic parameters of breast neoplasms of special histotypes. Specifically, adenoid cystic carcinoma, adenomyoepithelioma, acinic cell carcinoma, mucoepidermoid carcinoma, tall cell carcinoma with reverse polarity, and secretory carcinoma will be discussed. For each tumour, definition and morphological and molecular features, together with prognostic parameters, will be presented. Paradigmatic cases will be illustrated.

BACKGROUND Breast cancer is the most common malignancy in females. Triple negative breast carcinomas (TNBC), one of the molecular subtypes of breast carcinoma, are not sensitive to hormonal therapy and are reported to have aggressive behaviour. The present study was done to evaluate the expression of Ki67 in triple negative breast cancer using immunohistochemistry (IHC) and correlate the Ki67 expression with other clinicopathological variables. METHODS Based on the IHC status (ER, PR, HER neu), 50 triple negative breast carcinoma cases were selected from January 2019 to June 2020 for a cross-sectional study in Department of Pathology, Government medical college Thrissur. Ki67 immunohistochemical staining was done on the tissue sections and the Ki67 score was correlated with clinicopathological variables. RESULTS Of the 50 cases, majority (74 % cases) had high Ki67 expression (score of more than 50 %). High Ki67 score was strongly associated with presence of lymphovascular emboli (LVE) (P value < 0.05). Even though most of the patients were above 50 years (72 %), no significant correlation was seen between age and Ki67 score. The association with tumour size, histopathological type, tumour grade and lymph node status were not statistically significant. CONCLUSIONS Ki67 expression was high in triple negative breast cancer with mean score of 62 %. High Ki67 score correlated with presence of LVE. High Ki67 would predict increased proliferation of breast cancer cells and could be considered as a prognostic marker. KEYWORDS TNBC- Triple Negative Breast Cancer, Ki 67 Score, Clinicopathological Variables

Supplemental Digital Content is available in the text., SP142 programmed cell death ligand 1 (PD-L1) status predicts response to atezolizumab in triple-negative breast carcinoma (TNBC). Prevalence of VENTANA PD-L1 (SP142) Assay positivity, concordance with the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay, and association with clinicopathologic features were assessed in 447 TNBCs. SP142 PD-L1 intraobserver and interobserver agreement was investigated in a subset of 60 TNBCs, with scores enriched around the 1% cutoff. The effect of a 1-hour training video on pretraining and posttraining scores was ascertained. At a 1% cutoff, 34.2% of tumors were SP142 PD-L1 positive. SP142 PD-L1 positivity was significantly associated with tumor-infiltrating lymphocytes (P

Objective: To determine the frequency of immunohistochemical expression of androgen receptor in triplenegative breast carcinoma. Study Design: Cross sectional study. Duration and Place of Study: This study included 30 cases confirmed as triple negative breast carcinoma atArmed Forces Institute of Pathology Rawalpindi, from Jan to Jul 2018. Methodology: Anti-androgen receptor antibody was applied and assessed. Positive expression was defined asgreater and equal to 10% nuclear immunostaining. SPSS-24 was used for analyzing data. Results: Out of 30 cases of triple negative breast carcinoma (TNBC), all patients were female. Patients’ agesranged between 21-72 years with a mean age of 46.35 years and a standard deviation of ± 13.4. Androgen receptor expression was positive in 8 cases (27%) of all triple negative breast carcinomas. Out of these androgen receptor (AR) triple negative breast carcinomas; all 8 cases were of histological subtype invasive ductal (mammary) carcinoma, non special type, 7 cases (23%) were of histological grade 3 and 1 was of histological grade 2. Conclusion: Androgen receptor expression is observed in 8 cases (27%) of triple negative breast carcinoma cases. Such patients can be selected as candidates for anti- androgen receptor targeted therapy.

Tumor immune microenvironment (TIME) is a significant prognostic parameter for triple negative breast carcinomas (TNBC) due to being a target for immunotherapeutic agents and its essential role during the cancer immunoediting process. In this study, CD8, FOXP3, CD163, PD-L1/SP142 and PD-L1/SP263 antibodies were examined in a sample of 51 TNBC cases. Patients who received neoadjuvant therapy were excluded. CD8, FOXP3 and CD163 antibodies were evaluated separately in intratumoral area (ITA) and tumor stroma (TS). PD-L1 status was also examined in tumor cells (TC) and immune cells (IC) using both SP142 and SP263 antibodies. In multivariate Cox regressions, the only antibody that was found to be significantly associated with survival was SP142. SP142-positivity in TC and IC was related to increased overall survival. Higher CD163 expression in ITA and SP263-positivity in IC were associated with younger age. Lymphatic/angioinvasion was more frequent in cases with negative/low CD8 and FOXP3 expressions. Moreover, metastatic axillary lymph node(s) was associated with negative/low FOXP3 expression in TS. CD8, FOXP3, CD163, SP142 and SP263 expressions were positively correlated with each other, except a mild discordance caused by CD163 in ITA. Although PD-L1 status with both SP142 and SP263 antibodies were concordant in the majority of cases, 33.3% and 13.7% of the cases showed SP142-negative/SP263-positive pattern in TC and IC respectively. In conclusion, we suggest that composition, density and localization of the immune cells and the check point molecules are important prognostic parameters in TNBC. Immunohistochemistry can be used as an accessible and less expensive tool to demonstrate TIME.

The Ki-67 index is a biomarker that indicates the proliferation of cancer cells and is considered an effective prognostic factor for breast cancer. However, a standard cut-off point has not yet been established for the Ki-67 index in triple negative breast carcinomas. Therefore, the objective of this retrospective study was to determine an optimal cut-off point to establish it as a more accurate prognostic factor in the triple negative molecular subtype. The immunohistochemical analysis of the Ki-67 index was performed in 98 patients with breast cancer. The survival study using the Kaplan-Meier method was used to analyze the factors related to overall survival. The cut-off points (20 and 25%) were selected from the univariate analysis because they had the highest Hazard ratio to perform the multivariate analysis. With statistical significance (p

Context: The immunohistochemical (IHC 4) biomarker profile is part of the standard histopathology report of all newly diagnosed and recurrent cases of carcinoma Breast. This profile is the basis for all neoadjuvant and adjuvant treatment planning in these cases. Aims: 1. To study the IHC4 biomarker profile of Carcinoma Breast cases at our Institute. 2. To study the correlation of the five types of molecular subgroups with various clinical and histological parameters. Settings and Design: 271 cases of carcinoma breast diagnosed and treated at our Institute, during the period 1st July 2017 till 30th June 2018. This is a prospective, observational study. Materials and Methods: All the cases of biopsy proven carcinoma Breast were subjected to immunohistochemical staining for four markers- ER, PR, Her 2, and Ki 67. Fo rmalin Fixed Paraffin Embedded tumor tissue was stained for 4 biomarkers and scored with appropriate method. (Interpretive Guide: ASCO - CAP Test Guidelines Recommendations 2013) Manual method of staining was employed, using commercially available reagents. The cases were classified into five molecular subtypes. Results: Triple negative breast carcinoma was the most frequent subgroup, followed by the luminal B and A types and the Her2 enriched cases were lowest in number. A few cases showed triple positive staining pattern. Conclusions: The IHC 4 biomarker findings in every case of carcinoma has a direct impact on the treatment decision making and also on risk stratification of the patients. Keywords: IHC 4, ER, PR, Her2, Ki67, Carcinoma breast.

Second primary malignancies (SPMs) are known to be associated with neuroendocrine tumors (NETs). The association necessitates a careful assessment of the dual-tracer positron emission tomography–computed tomography (PET-CT) imaging findings to identify these malignancies earlier. Such early diagnosis can provide incremental benefit for screening these SPMs apart from their known applications in the management of NETs. A case of incidentally detected metachronous triple-negative breast carcinoma on dual-tracer PET-CT imaging is presented using 18fluoro-2-deoxy-D-glucose (FDG) and 68Ga-DOTATATE that showed a high uptake on FDG but no uptake on somatostatin receptor-based imaging.

Objective Adenoid cystic carcinoma (ACC) of the breast is an uncommon salivary type of breast carcinoma. It is a triple negative breast carcinoma with a basal-like phenotype that behaves in an indolent manner. Herein, we aimed to document clinicopathologic findings and hormone receptor status of ACC in the breast diagnosed in our institution during an eleven-year period. Materials and methods Medical data of cases diagnosed as adenoid cystic carcinoma in the breast between January 2006 and December 2016 were retrospectively reviewed from hospital data base. Paraffin blocks of seven cases were retrieved from the archive of Pathology Department and androgen receptor (AR) immunohistochemistry was applied to each case. Results All of the cases diagnosed as ACC were females with a mean age 56.2. Solid growth pattern was present in two cases. P63 was constantly expressed in the whole group, and at least one additional myoepithelial marker (calponin, caldesmon, etc.) was co-expressed in tumors. While weak estrogen receptor expression was detected only in one patient, AR was strikingly expressed in majority (%85.7) of the tumors. Conclusion To our knowledge, our series is the first to report such high levels of AR expression. This new finding, in turn, suggests considering hormonal therapy as an option in the management of ACC of the breast.

Metastasis of tumour cell greatly contributes to the cause of mortality. Tumour-associated macrophage (TAM) and the intercellular adhesion molecule 1 (ICAM-1) were associated with metastases of breast carcinoma. However, the relationship between lymphatic vessel densities and invasion with TAM and ICAM-1 remained unclear. The aim of this study was to investigate the relationship of lymphovascular densities and invasions with patient’s clinicopathological data. The roles of TAM and ICAM-1 influencing lymphovascular invasions were also investigated. Haematoxylin and eosin (H&E) and immunohistochemical (IHC) staining on a consecutive section of 37 formalin fixed-paraffin embedded (FFPE) breast invasive carcinoma samples were carried out. The D2-40, CD34, CD163, and ICAM-1 antibodies were used to stain lymphatic vessel, blood vessel, TAM, and ICAM-1 receptor, respectively. The total lymphatic vessel density (LVD) was significantly reduced on increased tumor size (p=0.045). The increase of intra-tumoral LVD and lymphatic vessel invasion (LVI) was significantly associated with human epidermal growth factor receptor 2 (HER2) negative status (p=0.022 and p=0.05, respectively). The percentage of LVI was higher than blood vessel invasion (BVI) in 18.5%. Lymphovascular invasions detected in H&E were missed in 49.76% compared with those detected in IHC-stained tissues (206/410). ICAM-1 scores were significantly associated with non-triple negative breast cancer (non-TNBC) (p=0.008). ICAM-1 is significantly overexpressed on non-TNBC sample. Therefore, ICAM-1 might be clinically useful as a targeted molecule for non-TNBC patients. In histological reporting, in addition to H&E staining, IHC staining using D2-40 and CD34 should be considered to increase the accuracy of diagnosis.

Both systemic and intratumoral lipid metabolism have been recently reported to play pivotal roles in both tumor development and progression in various human malignancies including breast cancer. However, its details have remained largely unknown in breast cancer patients. Therefore, in this study, we focused on perilipin 2, which is involved in constituting the intracellular lipid composition. Perilipin 2 was first immunolocalized in 105 cases of breast cancer. The status of perilipin 2 immunoreactivity was significantly positively associated with histological grade, Ki-67 labeling index and HER2 status and negatively with estrogen receptor status of these patients. Subsequent in vitro study also revealed that its mRNA expression in triple negative breast carcinoma cells was higher than cells of other subtypes. We then examined the correlation between perilipin 2 immunoreactivity and intracellular lipid droplet evaluated by Oil-red O stating in 13 cases of breast carcinoma tissues. A significantly positive correlation was detected between the status of perilipin 2 and Oil-red O staining. These findings above did indicate that perilipin 2 could represent the status of intracellular lipid droplets in surgical pathology specimens of breast cancer and perilipin 2 was also associated with its more aggressive biological phenotypes.

Introduction Metaplastic breast carcinoma (MBC) is one of the rare special subtypes of breast carcinoma associated with poor prognostic features compared with invasive ductal carcinoma. Moreover, therapeutic options are limited in MBC owing to frequent triple-negative profiles of these tumors. Epidermal growth factor receptor (EGFR) is a proto-oncogene that is overexpressed in many human cancers, and is a potential therapeutic target. Therefore, in this study, we evaluated the expression of EGFR in MBC by immunohistochemistry, and its association with clinicopathological and prognostic parameters. Methods We conducted a retrospective observational study in the Department of Histopathology at Liaquat National Hospital and Medical College, Pakistan, over a period of seven years. A total of 61 cases with a histopathological diagnosis of MBC were included in the study. All slides were reviewed by histopathologists for diagnostic confirmation. Histopathological parameters, such as tumor size, grade, and nodal metastasis, were recorded. The representative tissue blocks were also retrieved and immunohistochemical studies were performed for cytokeratin 5/6 (CK5/6), Ki67, and EGFR. Results The mean age of the patients was 44.48 ± 13.01 years. The mean tumor size was 5.72 ± 2.72 cm, with most of the cases belonging to tumor (T)-stage T3. Axillary metastasis was present in 57.4% cases, and the perinodal extension was present in 11.5% cases. Most tumors were grade III (85.2%), with a mean Ki67 index of 39.67% ± 20.38%. Most of the cases were nonbasal (83.6%), owing to the absent CK5/6 expression. Tumor recurrence was noted in 14.8% cases, with a median follow-up of 43 (13-83) months and median disease-free survival of 36 (12-60) months. Positive EGFR expression was noted in 52.5% cases. A significant association of EGFR expression was noted with tumor grade, mean Ki67 index, axillary metastasis, and nodal (N)-stage. Cases with positive EGFR expression were found to have higher grade (grade III), with higher Ki67 index, higher frequency of axillary metastasis, and higher N-stage. Moreover, cases with positive EGFR expression had lower disease-free survival compared to cases with negative EGFR expression. Conclusion We found that a significant proportion of triple-negative MBC expressed EGFR. Moreover, EGFR overexpression was associated with poor pathological parameters and lower disease-free survival. Therefore, EGFR can be considered a potential prognostic biomarker and therapeutic target in triple-negative MBC; however, the correlation between gene amplification and protein overexpression is required to better uncover the role of EGFR as a therapeutic target.

Introduction Metaplastic breast carcinoma (MBC) is a special type of breast cancer that is most commonly triple-negative and has the worst outcome compared to other breast tumors. p53 is a tumor suppressor gene that is frequently mutated in many human cancers. The association of mutant p53 immunohistochemical expression with clinical and prognostic parameters has not been widely studied in triple-negative MBC. Therefore, in this study, we evaluated the expression patterns of p53 in triple-negative MBC and its association with clinical and prognostic parameters. Methods A retrospective observational study was conducted in the Department of Histopathology at Liaquat National Hospital and Medical College, Pakistan, for a duration of 11 years. A total of 101 cases of triple-negative MBCs were included in the study. p53 immunohistochemistry was performed on the representative tissue blocks. Cases with diffuse strong positive p53 expression were labeled mutant phenotype, while cases with weak patchy p53 expression were termed wild-type. Results The mean age of the patients was 48.33±11.47 years, and the mean tumor size was 3.98±2.07 cm. The mean Ki67 index was 48.98±22.97%. The median disease-free survival of the patients was 24 (three to 68) months, with a median follow-up of 37 (13 to 77) months. Most of the cases were tumor (T)-stage II (51.5%). Axillary metastasis was present in 36.6% of cases, with the perinodal extension in 16.8% of cases. Most cases were non-basal subtype (91.1%), and the majority of cases were grade III (85.1%). Recurrence was observed in 17.8% of cases. Among 101 cases, 52.5% cases showed mutant phenotype p53 expression. A significant association of p53 expression was noted with tumor grade, Ki67 index and disease-free survival. Cases with mutant phenotype p53 expression had a higher tumor grade, higher Ki67 index, and poorer disease-free survival than cases with wild-type p53 expression. Conclusion A substantial proportion of triple-negative MBC expressed diffuse strong expression (mutant phenotype) of p53 in our study, signifying a potential role of p53 as a therapeutic target in triple-negative MBC. Moreover, association of p53 with poor prognostic parameters, such as higher tumor grade and Ki67, and poor disease-free survival underscores the prognostic significance of p53 in triple-negative MBC.

Acinic cell carcinoma of the breast is a rare subtype of triple-negative breast cancer that recapitulates the appearance of tumors seen in salivary glands. We present the case of a 42-year-old woman with an irregular, nontender mass above the left nipple during routine obstetric appointment at 24 weeks gestation. She was subsequently diagnosed with triple-negative invasive ductal carcinoma of the left breast, Nottingham grade 3, via core needle biopsy. She was treated with neoadjuvant therapy (doxorubucin and cyclophosphamide) antenatally and paclitaxel in the postpartum period followed by left mastectomy with sentinel node biopsy. The carcinoma in the mastectomy specimen showed a spectrum of morphologic patterns with immunohistochemistry revealing strong positivity for alpha-1-antichymotrypsin, epithelial membrane antigen (EMA), lysozyme, and S100. The histomorphology paired with the immunoprofile led us to the diagnosis of acinic cell carcinoma. We retrospectively performed immunostains in the core biopsy specimen, which demonstrated GATA-3 and DOG-1 positivity. Next-generation sequencing of the postneoadjuvant specimen using a 70-gene panel revealed 2 single-nucleotide variant (SNV) mutations: tumor protein 53 (TP53) (c.747G>T) SNV mutation and rearranged during transfection (RET) (c.2899G>A) SNV mutation.

Objective: The aim of this study was to measure the expression of PD-L1, CD1a (a marker for immature dendritic cells), and CD83 (a marker for mature dendritic cells) and further examine the associations of PD-L1, CD83, and CD1a with overall survival (OS) in triple-negative breast carcinoma patients. Methods: PD-L1, CD1a, and CD83 expression in breast carcinoma tissues and CD83 expression in lymph node tissues were examined by immunohistochemistry and tissue microarray in 159 patients. Patients were classified into the low, medium, and high PD-L1, CD1a, and CD83 levels. Pearson χ2 test was used to analyze the correlations between PD-L1, CD1a, and CD83. The Kaplan-Meier method was used to calculate the OS. Multivariate analysis was used to identify determinants of 3- and 5-year OS. Results: 25.1, 25.8, and 49.1% of the patients had low, medium, and high PD-L1 levels, respectively. PD-L1 levels significantly correlated with CD1a (r = 0.30409, p < 0.001) and CD83 levels (r = 0.6146, p < 0.001) in breast carcinoma tissue, as well as CD83 levels (r = 0.17508, p = 0.027) in lymph node. The median OS was 83 months (range 12–106), and the 3- and 5-year OS rates were 94.97% (95% CI 91.57–98.37) and 86.79% (95% CI 81.53–92.06), respectively. Moreover, patients with high median CD1a levels had a significantly lower 5-year OS rate (75.6%) than those with low median CD1a levels (93.5%, p = 0.038). Conclusion: PD-L1, CD1a, and CD83 are variably expressed in triple-negative breast carcinoma tissues, and PD-L1 expression correlates with CD1a and CD83. Higher CD1a levels correlate with PD-L1 expression and predict worse OS in triple-negative breast carcinoma.

Secretory carcinoma of the breast (SBC) is a rare breast neoplasm. Most of the patients present at an early stage with a relatively indolent clinical course. Lymph node and distant metastasis are also very infrequent. The histomorphological features of the secretory breast carcinoma are quite characteristic. Predominantly three histological patterns, solid, microcystic, and tubular, have been noted with copious amounts of intra and extracellular secretory material. Most commonly, no positivity for estrogen receptor (ER), progesterone receptor (PR) and ERBB2(HER2/neu) is observed in SBCs. As SBC can occasionally be hormone receptor-positive, they should not be categorized in the triple-negative breast carcinoma (TNBC) group in general. A very characteristic genetic translocation t (12;15) has been noted in this rare tumor, resulting in a fusion between ETV6 and NTRK3 proteins. We present a case of a 60-year-old lady who presented with right breast lump of 1-month duration and was managed by lumpectomy and sentinel lymph node dissection. Axillary dissection was not performed because the sentinel lymph node biopsy was negative. Postoperative radiotherapy was given to the right breast with a boost to the tumor bed. No adjuvant chemotherapy was given No recurrence has been noted even after a year of the completion of treatment

Background High grade basal-like breast carcinomas are triple negative, express basal cytokeratins, and are known for the overall poor prognosis and aggressive behavior. HPV related multiphenotypic sino-nasal carcinoma has overlapping histology with basal-like breast carcinomas, but carry the defining feature of association with high risk HPV. Case presentation We present a case of a perimenopausal woman with a non-healing ulcerated lesion involving the nipple and breast following a trauma. Biopsy performed showed an HPV-positive basal-like carcinoma with squamous differentiation involving the breast, analogous to multiphenotypic carcinoma previously described in the sinonasal tract. Conclusion This is the first report of a case of a high- risk HPV related basal-like carcinoma with squamous differentiation, described in the literature. We highlight the morphology and immunophenotype of this lesion and its recognition when compared to other multiphenotypic lesions of the breast, and suggest that pathologists should consider HPV evaluation when encountering similar basal-like tumors involving the breast.

The Dako 28-8, Dako 22C3, and Ventana SP142 assays are among the approved programmed death ligand 1 (PD-L1) immunohistochemical companion/complementary diagnostics associated with cancer treatment. To address the concordance of these assays in triple-negative breast cancer (TNBC), we examined PD-L1 expression in 98 TNBC tumors and compared the positive rates using the three assays and three scoring methods: immune cell (IC), tumor cell (TC), and combined tumor cell and immune cell (TCIC) (an equivalent to combined positive score, or CPS). The positive rate for PD-L1 expression with a 1% cutoff was highest with 28-8, followed by the 22C3. These two assays demonstrated almost perfect or substantial agreement in all three scores. There was less agreement between SP142 and the other assays. Using the IC score or the TCIC score at a 1% cutoff (CPS 1), 4% of tumors were positive for PD-L1 with SP142 but negative with the other assays. Using SP142 with a 1% cutoff as a reference, the optimal cutoff for best agreement was at 1% for IC, 30% for TC, and 2% for TCIC (CPS 2) with the other two assays. A 2% cutoff for the 22C3 TCIC (CPS 2) yielded the best agreement with SP142 1% IC cutoff (kappa 0.65). Our study showed the lowest positive rate with SP142 among the three assays. However, the other two assays were not able to identify all tumors that would test positive with SP142 using IC or TCIC/CPS. It is unlikely to achieve high agreement between SP142 and the other two assays by changing the analytical cutoffs.

Background Androgen receptor (AR) expression is emerging as a prognostic biomarker in breast carcinoma (BCa). The study aimed to determine the prevalence of AR expression by immunohistochemical analysis among a cohort of Sri Lankan women with early BCa and to evaluate its association with clinicopathological features including immunohistochemical molecular subtype and early survival. Method We studied the clinical and pathological features and immunohistochemical profile of 141 women undergoing primary surgery for early BCa, followed by standard adjuvant therapy. AR status was assessed by immunohistochemistry in all cases. Overall survival (OS) and disease-free survival (DFS) was determined. The relationship between AR expression and clinical and pathological parameters and immunohistochemical molecular subtype was analyzed using Student T test and chi-square tests. Cox regression analysis was used to analyze the prognostic impact of AR expression. Results AR expression was seen in 40.8%(95%CI 33.10–49.07%) of the BCa study cohort. None of the clinical data studied showed a significant association with the AR status(p > 0.05). Ductal carcinoma in situ(p = 0.003), oestrogen receptor (ER) (p = 0.001) and progesterone receptor (PR) (p = 0.001) positivity and luminal IHC molecular subtype(p = 0.016) were significantly associated with AR-positive status. AR-negative status was significantly associated with tumour necrosis > 50%(p = 0.031), moderate to extensive lymphocytic infiltrate at the tumour margin(p = 0.025) and basal triple negative breast carcinoma(p = 0.016). The mean duration of patient follow-up was 46.70(95% CI 46.495–46.905) months (3.89 years). On univariate analysis, AR-positivity was associated with better OS among ER-positive tumours(p = 0.047), specifically in postmenopausal women (p = 0.030). In ER-negative tumours, AR positivity was associated with worse DFS (p = 0.036). On multivariate analysis, TNM stage and ER/AR status were predictive of survival. ER-positive/AR-positive (ER+/AR+) tumours demonstrated better OS than ER-positive/AR-negative (ER+/AR-) tumours(p = 0.015). ER-negative/AR-positive (ER−/AR+) tumours (p = 0.014) had a worse DFS than ER-negative/AR-negative (ER−/AR-) tumours. Conclusions AR prevalence obtained was low. AR positivity was associated with positivity for ER and PR. On multivariate analysis, apart from TNM stage only ER/AR status were predictive of OS and DFS, with concordant expression of ER/AR demonstrating a better, early survival.

Immunotherapy with checkpoint inhibitors is well established as an effective treatment for non-small cell lung cancer and melanoma. The list of approved indications for treatment with PD-1/PD-L1 checkpoint inhibitors is growing rapidly as clinical trials continue to show their efficacy in patients with a wide range of solid tumours. Clinical trials have used a variety of PD-L1 immunohistochemical assays to evaluate PD-L1 expression on tumour cells, immune cells or both as a potential biomarker to predict response to immunotherapy. Requests to pathologists for PD-L1 testing to guide choice of therapy are rapidly becoming commonplace. Thus, pathologists need to be aware of the different PD-L1 assays, methods of evaluation in different tumour types and the impact of the results on therapeutic decisions. This review discusses the key practical issues relating to the implementation of PD-L1 testing for solid tumours in a pathology laboratory, including evidence for PD-L1 testing, different assay types, the potential interchangeability of PD-L1 antibody clones and staining platforms, scoring criteria for PD-L1, validation, quality assurance, and pitfalls in PD-L1 assessment. This review also explores PD-L1 IHC in solid tumours including non-small cell lung carcinoma, head and neck carcinoma, triple negative breast carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal carcinoma, colorectal carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The review aims to provide pathologists with a practical guide to the implementation and interpretation of PD-L1 testing by immunohistochemistry.

Triple negative breast carcinoma is a problematic subtype with poor outcomes. Many clinical trials are underway to find possible target to increase treatment options. Epidermal growth factor receptor (EGFR) has emerged as one such molecule which is over expressed in some of these patients and can be targeted by tyrosine kinase inhibitors. We describe a diagnostically challenging case of metastatic breast carcinoma, with extensive lung disease and poor Eastern Cooperative Oncology Group (ECOG) performance status, which expressed an uncommon EGFR mutation (Exon 21L861Q) and which benefitted from erlotinib following failure of all primary treatment modalities. The case uncovers the presence of these unusual mutations in breast carcinoma and highlights the importance of performing molecular analysis and the appropriate targeted therapy. This approach can be an important problem-solving tool, especially in cases where the patient is not fit for the other standard treatment options.

Objective To test the germline oncogenic mutations in BRCA1 and BRCA2 genes, associated with triple-negative breast cancer (TNBC) patients under study, by targeted sequencing of their DNA with next-generation sequencing (NGS) platform. Study design Cross-sectional observational study. Place and duration of study Histopathology Department, Armed Forces Institute of Pathology (AFIP) Rawalpindi, Pakistan from May to June 2020. Methodology Peripheral blood of 14 women (aged ≤60) with triple negative breast carcinoma (TNBC) was taken with the consent of performing germline genetic testing. Targeted NGS was performed for all coding regions and splicing sites of BRCA1 and BRCA2 genes, using AmpliSeq for Illumina BRCA Panel and Illumina MiSeq sequencer (placed at AFIP). Analysis and interpretation of the sequencing results have been done by using Illumina bioinformatics tools and external databases. Results Two hundred and fifty-four variants were detected in BRCA1 and BRCA2 genes, having variant quality score of 100 in all cases under study. As a result, two pathogenic variants and three variants of uncertain significance were interpreted in this germline pipeline. Cases with pathogenic variants had early onset breast cancer with age less than 35. Conclusion Germline variants in BRCA were detected in the known cases of TNBC, which will not only identify the most prevalent mutations in this region; but will also make them a candidate to receive targeted therapies, which was previously not possible without genetic testing. Moreover, this study further validates the importance of early BRCA genetic screening in young patients, who have positive family history of breast carcinoma. Key Words: Breast cancer, Triple negative, Next-generation sequencing, BRCA1, BRCA2.

Immunohistochemistry is an essential component of diagnostic breast pathology. The emergence of novel assays and applications is accompanied by new interpretation criteria and potential pitfalls. Immunohistochemistry assists in supporting breast origin for primary or metastatic carcinomas and identifying non-mammary metastases to the breast; however, no single immunostain is perfectly sensitive nor specific. GATA3 and Sox10 are particularly useful immunostains to identify triple negative breast carcinoma, which are often negative for other markers of mammary differentiation. Sox10 labeling is a major potential diagnostic pitfall, as Sox10 and S-100 label both triple negative breast carcinoma and metastatic melanoma; a pan-cytokeratin immunostain should always be included for this differential diagnosis. Novel immunohistochemistry serves as surrogates for the molecular alterations unique to several of special-type breast carcinomas, including the use of MYB in adenoid cystic carcinoma, pan-TRK in secretory carcinoma, and mutant IDH2 in tall cell carcinoma with reversed polarity (TCCRP). In addition, PD-L1 immunohistochemistry is an emerging, albeit imperfect, biomarker for breast cancer immunotherapy, with different assay parameters and scoring criteria in breast carcinoma compared to other tumor types. The expanding repertoire of novel immunohistochemistry provides additional diagnostic tools and biomarkers that improve diagnostic breast pathology and patient care.

The Ventana PD-L1 SP142 immunohistochemistry (IHC) assay is the FDA-approved companion diagnostic assay for atezolizumab therapy selection for patients with PD-L1-positive locally advanced or metastatic triple-negative breast carcinoma (TNBC). We aimed to elucidate clinical, pathologic, and molecular features associated with PD-L1 expression in TNBCs. Clinical, pathologic, and next-generation sequencing (NGS)-based molecular data for TNBCs tested with PD-L1 (SP142) IHC at our institution between 11/2018 and 12/2019 were retrieved and reviewed. PD-L1 positivity was defined as ≥1% IC staining. Patients with metastatic TNBC treated at first line with atezolizumab regimens were evaluated for treatment response and for time to treatment failure (TTF). Among 156 TNBCs, PD-L1 was positive in 47.4% of cases. Primary TNBCs were significantly more frequently PD-L1 positive, compared with recurrent/metastatic samples (p = 0.002). PD-L1-positive TNBCs had increased stromal IC, compared with PD-L1-negative samples (p

Folate Receptor Alpha (FRA) is a membrane protein expressed on the apical surface of epithelial cells. Its expression in increased in certain tumors, where it can serve as a target for therapy. Triple Negative Breast Carcinoma (TNBC) are a heterogeneous group of tumors, with limited therapy options and poor prognosis. We aimed to study the expression of FRA in TNBC. Tissue microarrays were prepared from archived paraffin blocks of 300 TNBC resection specimens. Staining for FRA immunohistochemistry was carried out using the clone 26B3.F2. Clinical and pathologic details of the patients were obtained from the electronic medical records. Chi square test was performed for correlation of clinicopathological features with FRA expression. Kaplan Meir and Cox Regression analysis were carried out to study the Disease Free Survival (DFS) and Overall Survival (OS). FRA showed positivity in 43% (129/300) of TNBCs in our study. In univariate analysis, TNBC expressing FRA had a significantly better OS compared to FRA negative tumors (p – 0.035). Also, FRA positive tumors showed a trend towards longer DFS, though this was not statistically significant. In multivariate analysis however, FRA expression did not emerge as a significant factor. To conclude, TNBCs in our study showed FRA expression and though this did not emerge as an important prognostic factor, it can represent a therapeutic target for future clinical trials.

Ethnopharmacological relevance Triple-negative breast cancer (TNBC) has a poorer prognosis than other subtypes due to its strong invasion and higher risk of distant metastasis. Traditional Chinese medicine (TCM) and natural medicine have the unique advantages of multitargets and small side-effects and may be used as long-term complementary and alternative therapies. Aim of the review: The present article summarizes the classical signaling pathways and potential targets by the action of TCM and natural medicine (including extracts, active constituents and formulas) on TNBC and provides evidence for its clinical efficacy. Methods The literature information was acquired from the scientific databases PubMed, Web of Science and CNKI from January 2010 to June 2020, and it was designed to elucidate the internal mechanism and role of TCM and natural medicine in the treatment of TNBC. The search key words included “Triple negative breast cancer” or “triple negative breast carcinoma”, “TNBC” and “traditional Chinese medicine” or “Chinese herbal medicine”, “medicinal plant”, “natural plant”, and “herb”. Results We described the antitumor activity of TCM and natural medicine in TNBC based on different signaling pathways. Plant medicine and herbal formulas regulated the related gene and protein expression via pathways such as PI3K/AKT/mTOR, MAPK and Wnt/β-catenin, which inhibit the growth, proliferation, migration, invasion and metastasis of TNBC cells. Conclusion The inhibitory effect of TCM and natural medicine on tumors was reflected in multiple levels and multiple pathways, providing reasonable evidence for new drug development. To make TCM and natural medicine widely and flexibly used in clinical practice, the efficacy, safety and mechanism of action need more in-depth experimental research.

INTRODUCTION: The present histologic and immunohistochemical prognostic markers of breast carcinoma do not effectively identify the subset of patients with poor prognosis. Y-Box binding protein 1 (YB1) is a novel biomarker which may identify and aid in targeted personalized therapy for such patients. MATERIALS AND METHODS: The study was conducted on histopathology specimens of 74 patients of breast carcinoma who had undergone modified radical mastectomy. YB1 immunohistochemistry (IHC) was performed on manual tissue microarray blocks (each having 15 cores). The YB1 expression was quantified in terms of “immunoreactive score” which was correlated with clinical parameters, hormone receptor status, and Her2neu overexpression by IHC. The Her2neu status of the equivocal cases was further evaluated by fluorescent in situ hybridization (FISH). RESULTS: YB1 was positive in 36/74 (48.6%) cases. On IHC and analysis by FISH, 25/74 (34%) cases had Her2neu overexpression. Estrogen receptor (ER) and progesterone receptor (PR) positivity was found in 42% and 36.5% cases, respectively. YB1 immunopositivity was negatively correlated with ER and PR expression, but showed a significant positive correlation with Her2neu expression. No correlation was found with other clinical parameters, tumor stage, and grade, except lymph node involvement, which showed a positive association with YB1 expression. Triple-negative breast carcinoma constituted 25.6% of the total cases, out of which 73.6% were YB1 positive. CONCLUSION: This study found that YB1 has an association with Her2neu expression. It may in future provide a therapeutic target in Her2neu overexpressing tumors.

Introduction Recently, Burstein et al identified 4 stable molecular subtypes of triple negative breast cancer (TNBC) by mRNA profiling: luminal androgen receptor (LAR), mesenchymal (MES), basal-like immune-activated (BLIA), and basal-like immune-suppressive (BLIS) types. The purpose of this study was to assess the feasibility of immunohistochemistry (IHC) surrogate panel in classifying the TNBC molecular subtypes using a large cohort of TNBC retrieved from a single institution. Materials and Methods IHC for androgen receptor [AR], claudin-3, E-cadherin, cytokeratin 5/6 [CK5/6], epidermal growth factor receptor [EGFR], indoleamine 2,3-dioxygenase 1 [IDO1], and Forkhead box C1 [FOXC1] were performed using the tissue microarray constructed from 200 TNBC samples. Results The 200 TNBCs were classified as LAR (AR+, n = 22; 11.0%), MES (claudin 3– and/or E-cadherin–, n = 23; 11.5%), basal-like (CK5/6+ and/or EGFR+, n = 85; 42.5%), mixed (n = 60; 30%), and unclassifiable type (n = 10; 5%). LAR type was associated with older patient age, apocrine histologic features, low density of stromal tumor-infiltrating lymphocytes (TIL), and low Ki-67 labeling index. MES type was associated with tumor cell discohesiveness and metaplastic features. Basal-like type was associated with younger patient age, high histologic grade, high stromal TIL density, and high Ki-67 labeling index. Basal-like TNBCs were further classified as BLIA (IDO1+ and FOXC1−, n = 27) or BLIS type (IDO1- and FOXC1+, n = 11). BLIS type was associated with large tumor size and low stromal TIL density, which had the worst prognostic outcome among 4 subtypes. Conclusion The IHC surrogate panel may define TNBC subtypes with distinct clinicopathologic characteristics and prognostic significance.

Highlights • Adenoid cystic carcinoma (ACC) of the breast is a rare type of primary breast cancer accounting for less than 0.1% of all primary breast cancers. • Unlike other triple negative breast cancers that are associated with poor prognosis, ACC has an overall excellent prognosis. • Mammographically, these tumors may appear as asymmetric densities or irregular masses. Sonographically, they appear as well-defined, irregular, heterogeneous, or hypoechoic masses. Nonetheless, the radiographic findings are non-specific and can be misdiagnosed as benign lesions. Subsequently, it could be challenging for a radiologist to make the correct diagnosis of carcinoma without histologic confirmation. • Due to the rarity of the tumor and large variations in the patterns of practice, guidelines for treatment have not been established. Because of these distinct clinicopathologic features that set it apart from the other triple negative breast cancers, an understanding of ACC of the breast is essential for surgical pathologists, breast surgeons, and oncologists., Introduction Adenoid cystic carcinoma of the breast (breast-ACC) is a rare tumor with a favorable prognosis, despite its triple-negative status and special type of basal-like tumor for which scant population-based descriptive data exist. We sought to provide new population-based information on breast-ACC in India. Due to the paucity of the number of cases, the natural history of the disease is not fully understood. This study was undertaken to examine the clinico-pathological characteristics of the disease and to evaluate the outcome of surgical intervention in a tertiary referral care centre. Materials and methods A retrospective analysis of all patients diagnosed and treated for ACC Breast in our hospital over the past 10 years was carried out (2005–2015). A database of the characteristics of these patients was developed. In all, 14 patients were identified. The investigations performed included routine blood investigations, chest X-ray, bone scan and either an ultrasound or a CT scan. Results During the time period of 10 years, of 2347 with breast malignancy admitted to our department, only 14 were diagnosed as having ACC (3.15%). All patients were women (100%). The patients had a median age of 60.7 years (range 37–81). The most common symptom was lump in the breast. Two patients (14.2%) presented with nipple and skin retraction and two patients (14.2%) were asymptomatic with the diagnosis made by an incidental finding on routine examination. The CT and/or magnetic resonance imaging (MRI) showed the typical features of carcinoma breast. All the 14 patients were taken up for surgery. Nine patients underwent Modified radical mastectomy and five patients underwent Breast conservation surgery. Axillary lymph node dissection was carried out in seven patients and sentinel lymph node biopsy in the remaining. Tumor cells had a characteristic histologic pattern of ACC of the breast. Perineural invasion was present in six cases. Discussion ACC of the breast is a very rare malignancy, accounting for less than 0.1% of all breast neoplasms. It affects the left and right breasts equally and tumors arise irrespective of the breast quadrants. However, in about 50 percent of patients, lesions are found in subareolar region. Pain or tenderness described in the minority of cases has not been correlated with histologically-confirmed perineural invasion. ACC is categorized as a basal-like subtype of breast carcinoma. Most cases are macroscopically well-circumscribed. Occasionally, pink, tan, or gray microcysts are evident. A tumor typically consists of a dual-cell population of luminal and myoepithelial-basal cells which may be arranged in one or more of three architectural patterns: tubular-trabecular, cribriform, and solid-basaloid. There is no consensus on the optimal management for patients with ACC of the breast. Based on its indolent clinical course and favorable outcome, ACC of the breast is generally cured by breast-conserving surgery, such as wide excision or quadrantectomy with or without radiotherapy. Conclusion Breast-ACC among women is characterized by ER-negative/PR-negative expression, rare regional lymph node involvement, a favorable prognosis with excellent survival, and absence of associated cancers. These findings reinforce the importance of tailored treatments for breast-ACC and the apparent heterogeneity of basal-like breast cancers.

Purpose Dysregulation of miRNA profile has been associated with a broad spectrum of cellular processes underlying progression of various human malignancies. Increasing evidence suggests that specific microRNA clusters might be of clinical utility, especially in triple-negative breast carcinoma (TNBC), devoid of both predictive markers and potential therapeutic targets. Here we provide a comprehensive review of the existing data on microRNAs in TNBC, their molecular targets, a putative role in invasive progression with a particular emphasis on the epithelial-to-mesenchymal transition (EMT) and acquisition of stem-cell properties (CSC), regarded both as prerequisites for metastasis, and significance for therapy. Methods PubMed and Medline databases were systematically searched for the relevant literature. 121 articles have been selected and thoroughly analysed. Results Several miRNAs associated with EMT/CSC and invasion were identified as significantly (1) upregulated: miR-10b, miR-21, miR-29, miR-9, miR-221/222, miR-373 or (2) downregulated: miR-145, miR-199a-5p, miR-200 family, miR-203, miR-205 in TNBC. Dysregulation of miR-10b, miR-21, miR-29, miR-145, miR-200 family, miR-203, miR-221/222 was reported of prognostic value in TNBC patients. Conclusion Available data suggest that specific microRNA clusters might play an important role in biology of TNBC, understanding of which should assist disease prognostication and therapy.

Xingxing Chen,1,2,* Fan Xia,1,2,* Jurui Luo,1,2,* Jinli Ma,1,2 Zhaozhi Yang,1,2 Li Zhang,1,2 Yan Feng,1,2 Zhimin Shao,2,3 Xiaoli Yu,1,2 Xiaomao Guo1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 3Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China *These authors contributed equally to this work Background: This study investigated the effect of postmastectomy radiotherapy (PMRT) in patients with stage II–III triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC) and modified radical mastectomy (MRM).Patients and methods: A total of 104 women with stage II–III TNBC who received NAC and MRM at our institution between January 2000 and July 2007 were identified. Patients were divided into 2 groups (PMRT and non-PMRT) for statistical analysis.Results: The median follow-up time was 64months (range 12–123months). The 5year cumulative locoregional recurrence (LRR) and disease recurrence (DR) rates were 26.5% and 49.6%, respectively. Despite their more adverse prognostic features, patients with PMRT had lower 5year cumulative LRR and DR rates than those without PMRT (LRR: 18.3% vs 52.2%, respectively, p=0.0005; DR: 45% vs 69.1%, p=0.0334, respectively). On multivariate analysis of the entire study cohort, forgoing PMRT was significantly associated with developing LRR and DR. Subset analysis revealed that PMRT significantly reduced the 5year LRR rate in patients with pre-chemotherapy clinical stages IIA (8.3% vs 46.2%, p=0.019) and IIIA (16% vs 66.7%, p=0.003). PMRT also significantly reduced the 5year DR rate in patients with pre-chemotherapy clinical stage IIA (24.5% vs 69.3%, p=0.0151) and ≥IIIB (70.8% vs 100%, p=0.0481).Conclusion: In our cohort of patients with TNBC treated with NAC and MRM, PMRT significantly improved locoregional control and disease-free survival in the entire cohort as well as in patients with stage IIA disease. Our results may help in tailoring adjuvant treatment decisions for these particular patient populations. Keywords: triple-negative breast carcinoma, neoadjuvant chemotherapy, surgery, adjuvant radiation therapy, locoregional recurrence, disease recurrence

Background The characterization of poorly differentiated neoplasms in fine-needle aspiration (FNA) and small biopsy specimens usually requires immunohistochemistry (IHC) with a panel of markers. Because of an increasing need to preserve limited diagnostic material for tumor genotyping and a mounting demand for cost containment, the authors investigated the usefulness of dual-color IHC with antibodies directed against broad-spectrum keratins and SOX10, a neuroectodermal transcription factor consistently expressed in melanoma, in the workup of epithelioid malignant neoplasms. Methods A total of 107 cases of FNA cell blocks (49 cases) and small biopsies (58 cases) were selected, including 34 melanomas, 31 epithelioid/pleomorphic sarcomas, and 42 carcinomas. IHC was performed on all specimens using a peroxidase-based brown chromogen for SOX10 and an alkaline phosphatase-based red chromogen for keratins AE1/AE3. The presence or absence of staining in lesional cells was scored. Results The majority of tumors demonstrated 1 of 3 distinct patterns: 1) malignant melanomas with nuclear SOX10 (sensitivity of 94% and specificity of 95%); 2) epithelioid/pleomorphic sarcomas negative for both SOX10 and AE1/AE3 (sensitivity of 84% and specificity of 88%); and 3) carcinomas with cytoplasmic AE1/AE3 (sensitivity of 76% and specificity of 98%). In addition, a fourth pattern with cytoplasmic AE1/AE3 and nuclear SOX10 was observed in a subset of carcinomas, most notably triple-negative breast cancers. Conclusions SOX10/keratin dual-color IHC appears to be an effective, sensitive, and specific test to distinguish between melanoma, sarcoma, and carcinoma. This approach can identify melanoma, prioritize additional studies, and limit the number of markers needed to workup an epithelioid malignant neoplasm, thereby potentially reducing costs and preserving valuable tissue for ancillary studies with which to guide therapy. Cancer Cytopathol 2018;126:179-89. © 2018 American Cancer Society.

Germline mutations in BRCA genes have been shown to predispose patients to breast cancer. Studies have suggested that p53 alteration is a necessary step in tumorigenesis in BRCA carriers. Our previous study showed p53 alteration in morphologically normal/benign breast luminal cells in sporadic breast cancer patients, the so-called breast p53 signature. Here, we studied p53 status in 66 BRCA1/2 carriers' breasts: 29 patients with breast carcinoma (2 patients with bilateral breast carcinomas) and 37 without. Seven of the 12 (58%) triple-negative breast carcinomas in BRCA carriers were positive for p53 alteration (immunohistochemical stain and/or sequencing), the same frequency as in sporadic triple-negative breast carcinomas. Focal p53 positivity in adjacent normal/benign luminal cells was identified in 4 of the 7 cases with p53-positive carcinomas but not in breasts with p53-negative carcinomas, indicating that p53 positivity in normal/benign breast luminal cells is not a random event. Furthermore, in BRCA carriers' prophylactic mastectomies, 12 of the 94 (12.77%) breasts had focal p53 positivity in normal/benign luminal cells, with 2 cases in bilateral breasts, significantly higher than in previously studied mammoplasty specimens (0%). Our study suggests that germline BRCA gene mutations could result in genomic instability and an elevated gene mutation rate (such as the p53 gene) in breast luminal cells compared with the general population, predisposing BRCA carriers to develop p53-positive/triple-negative breast carcinomas.

Vascular endothelial growth factor A (VEGF-A) is considered one of the most important factors in tumor angiogenesis, and consequently, a number of therapeutics have been developed to inhibit VEGF signaling. Therapeutic strategies to target brain malignancies, both primary brain tumors, particularly in pediatric patients, and metastases, are lacking, but targeting angiogenesis may be a promising approach. Multiparametric MRI was used to investigate the response of orthotopic SF188 luc pediatric glioblastoma xenografts to small molecule pan-VEGFR inhibitor cediranib and the effects of both cediranib and cross-reactive human/mouse anti-VEGF-A antibody B20-4.1.1 in intracranial MDA-MB-231 LM2–4 breast cancer xenografts over 48 hours. All therapeutic regimens resulted in significant tumor growth delay. In cediranib-treated SF188 luc tumors, this was associated with lower K trans (compound biomarker of perfusion and vascular permeability) than in vehicle-treated controls. Cediranib also induced significant reductions in both K trans and apparent diffusion coefficient (ADC) in MDA-MB-231 LM2–4 tumors associated with decreased histologically assessed perfusion. B20-4.1.1 treatment resulted in decreased K trans , but in the absence of a change in perfusion; a non-significant reduction in vascular permeability, assessed by Evans blue extravasation, was observed in treated tumors. The imaging responses of intracranial MDA-MB-231 LM2–4 tumors to VEGF/VEGFR pathway inhibitors with differing mechanisms of action are subtly different. We show that VEGF pathway blockade resulted in tumor growth retardation and inhibition of tumor vasculature in preclinical models of pediatric glioblastoma and breast cancer brain metastases, suggesting that multiparametric MRI can provide a powerful adjunct to accelerate the development of antiangiogenic therapies for use in these patient populations.

We aimed to describe our experience with metaplastic breast carcinoma (MBC), evaluate its clinical outcome compared with triple-negative breast cancer (TNBC), and provide a through and comprehensive review of the literature to date.We reviewed MBC cases (n = 46) from our institution. The following variables were recorded: tumor histologic subtype, Nottingham grade, tumor size, lymph node status, Tumor, Node, Metastases stage, biomarkers profile, patient's age and race, therapy modality (chemotherapy and radiation), and survival (disease-free survival [DFS] and overall survival [OS]). The clinical and pathological data for TNBC (n = 508) cases were extracted from the breast cancer database. To compare the survival between MBC and TNBC, a subgroup of MBC cases (n = 40) were matched with TNBC cases (n = 40) on the basis of known prognostic confounders.There were 17 of 46 (37%) cases with mesenchymal differentiation, 12 (26.1%) squamous cell carcinoma, 14 (30.4%) spindle cell carcinoma, and 3 (6.5%) mixed type. MBC presented at a more advanced stage than TNBC (P = .014) and was more likely to recur (34% vs. 15.5%; P = .004). More MBC patients died from disease than TNBC (29% vs. 16%; P = .05). In the multivariate analysis, MBC had approximately twice the risk of local recurrence than TNBC (95% confidence interval, 1.01-3.83; P = .05). MBC patients had worse DFS and OS than the matched TNBC patients (P .001 and P = .033, respectively). A review of the literature comparing MBC versus TNBC is presented.Our results suggest that MBC is clinically more aggressive than TNBC. Further studies might help delineate the differences between these 2 entities.

Objective The aim of this study was to investigate the clinicopathological characteristic of adenoid cystic carcinoma (ACC). Materials and methods The clininopathological features, along with relapse free survival(RFS) and overall survival(OS) of 36 patients with ACC were retrospectively investigated and compared with those of 108 grade 1 invasive ductal carcinoma not-otherwise-specified (G1-IDC-NOS) patients. Results Most cases of ACC were ER, PR and HER-2 negative which was classified as triple-negative subtype. Five cases were concomitant with other pathological types of cancer. Axillary lymph node dissection(ALND) was performed in 31 patients and 2 of them with lymph nodes metastasis. Two patients died of lung metastases at 46 and 116 months after the surgery respectively. Compared with G1-IDC-NOS, ACC showed lower Ki-67 index, less lymph nodes metastasis, lower P53 expression, and higher proportion in location of upper outer quadrant of breast. There was no difference of OS and RFS between ACC and G1-IDC-NOS. Conclusions ACC of the breast was a rare disease with a good prognosis although most of them were classified as triple-negative subtype. And the value of axillary node dissection and adjuvant therapy needs to be further investigated.

This chapter deals mainly with core biopsy diagnosis of malignant neoplasms (B5 lesions). These include various types of carcinomas as well as sarcomas, lymphomas and metastatic lesions to the breast. A detailed description of most common and uncommon carcinomas of the breast is given as well as how hormone receptor status and HER2 amplification are assessed. Other features that have to be included in the report are detailed including the presence or absence of DCIS elements, necrosis, elastosis, calcification and tumour infiltrating lymphocytes (TILs). The molecular classification of breast carcinoma is also dealt with.

Triple negative breast cancers have the highest relapse risk and the least favourable prognosis of all breast cancer subtypes, leading to an escalation of chemotherapy, substantially during recent years. Secretory carcinoma of the breast is a rare triple negative neoplasm, first described in children but more often presenting in adults. We report a case of a 70-years-old woman, initially diagnosed on the biopsy with a triple negative infiltrating Not Otherwise Specified (NOS) carcinoma of the breast, before it was later correctly identified as a secretory carcinoma, notably because of an abundant intra and extracellular secretory material. This new diagnosis, confirmed by fluorescence in-situ hybridization analysis showing ETS variant 6 (ETV6) gene rearrangement, allowed the de-escalation of chemotherapy therapy. Four years later, the patient is free of recurrences.

BackgroundTriple-negative breast carcinoma (TNBC) patients do not benefit from hormone- or human epidermal growth factor receptor 2- (HER2-) targeted therapies. Accurate testing is pivotal for these patients.MethodsTNBC cases that were retested at our institution during a 3-year period were evaluated for concordance rates in estrogen (ER) and progesterone (PR) receptor and HER2 results.ResultsWe found 19 (22%) discrepancies (13 major/6 minor) among 86 cases. Minor discrepancies were in HER2 changes by immunohistochemistry, and all cases were demonstrated to be negative by and dual in situ hybridization. All major discrepancies were in ER/PR expression changes. In only 2 cases the treatment changed based on repeated results and/or patient history.ConclusionsDiscrepancies in prognostic/predictive testing continue to be frequent despite rigorous regulations. However, since for the majority of patients in our setting, the treatment plan did not change, reflex retesting for TNBC has been deemed unnecessary in our institution.

EHD2 is a mechanotransducing ATPase localized in caveolae invaginations at the plasma membrane. EHD2 has recently been associated with several human cancers, however the significance of EHD2 transcript levels in cancer prognosis remains debated. Breast cancer is the most commonly occurring cancer in women and prognosis is variable depending on the subtypes. Triple negative breast cancer (TNBC) often has a poor therapeutic response. The aim of this study was to assess the prognostic significance of EHD2 transcripts and protein expression levels in breast carcinomas. We found that low EHD2 levels were associated with enhanced proliferation, migration and invasion of TNBC cells. EHD2 expression was significantly reduced in TNBC tissues and the loss of EHD2 led to higher expression of the pro-tumoral cytokine IL-8. In apparent contradiction with in vitro data, multivariate analysis of two independent cohorts of breast cancer patients revealed that low EHD2 was in fact associated with good prognosis in the highly proliferative TNBC subtype. Accordingly, TNBC low EHD2 expressers were found to benefit the most from chemotherapy when compared to all subtypes of breast cancers. Our study validates EHD2 expression level as an independent prognostic factor of metastasis-free survival and as a new predictive marker of chemotherapy efficacy in TNBC patients.

GATA-binding protein 3 (GATA3) is a diagnostically useful immunohistochemical marker of breast cancer. Because of its strong association with estrogen receptor expression, GATA3 has markedly reduced sensitivity in triple-negative breast cancer (TNBC). We constructed a tissue microarray using a large series of TNBCs and evaluated GATA3 expression by TNBC subtype as defined by surrogate immunohistochemical markers. A total of 205 TNBCs were classified into cancers of the molecular apocrine type (n=23, 11.2%), claudin-low type (n=21, 10.2%), basal-like type (n=91, 44.4%), mixed type (n=62, 30.2%), and null type (n=8, 3.9%). The GATA3 scores (staining intensity × proportion) were categorized as negative (0), focally positive (1-10), or positive (11-300). GATA3 staining was negative in 153 cancers (74.6%), focally positive in 11 (5.4%), and positive in 41 (20.0%). The rate of focal positivity or positivity for GATA3 was significantly higher in the molecular apocrine type (73.9%, 17/23) than in other types of TNBCs (P=.001). The mean GATA3 score of molecular apocrine-type TNBC was significantly higher than that of the other types (P=.001) and differed significantly between androgen receptor (AR)-positive and AR-negative TNBCs (P

Background Folate receptor alpha (FRA) overexpression by immunohistochemistry (IHC) has been shown to various degrees in histologic specimens from breast ductal carcinoma (DC), serous carcinoma of Mullerian origin (SCM), and primary lung adenocarcinoma (ADC) among others. Antifolate therapies have recently shown usefulness in FRA overexpressing malignancies. We assessed the feasibility for detecting FRA overexpression by IHC in cytologic cell blocks (CB) from the aforementioned carcinomas. Method Cases of breast DC, SCM and lung ADC were included. The CB were immunostained with FRA employing mAb 26B.3.F2 (Biocare Medical, Concord, CA). FRA staining was scored qualitatively, by intensity, and staining area. Results 4/20 (20%) triple negative breast cancer (TNBC), 27/29 (93%) SCM, and 20/22 (91%) lung ADC showed positive FRA immunoreactivity. All ER/PR positive (n = 5) and Her2-neu positive (n = 5) DC were negative with FRA IHC. Conclusions FRA expression can be detected with a higher degree of confidence in SCM (93%) and lung ADC (91%) in CB, and to a lesser degree in TNBC. Our data also shows that FRA expression by IHC was more frequently associated with TNBC (20%) when compared with ER/PR positive or Her2neu positive breast cancers. FRA overexpression detected by IHC in CB is highly concordant with the published results of surgical specimens from SCM and lung ADC and less so from TNBC. Hence, IHC FRA analysis can be performed in the CB preparation with a high degree of confidence in SCM and lung ADC. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

Background: Triple-negative breast cancer constitutes approximately 12%-17% of all breast cancer cases, and >33% of patients develop distant metastases. Systemic cytotoxic chemotherapy is the primary treatment for patients with metastatic triple-negative breast cancer; however, the role of first-line platinum-based chemotherapy in these patients remains controversial. This meta-analysis evaluated the efficacy and safety of platinum-based first-line chemotherapy for patients with metastatic triple-negative breast cancer. Methods: We systematically searched the PubMed, Embase, Cochrane, and Clinical Trials registry databases up to June 1, 2020 to identify randomized controlled trials that investigated platinum-based vs. first-line platinum-free chemotherapy in patients with metastatic triple-negative breast cancer. We used fixed and random effects models to calculate pooled hazard ratios and odds ratios with 95% confidence intervals for progression-free and overall survival, objective response rates, and grade 3 and 4 adverse events. Results: Four randomized controlled trials ( N = 590 patients) were included. Platinum-based chemotherapy significantly increased the objective response rates from 43.1% to 62.7% (odds ratio 2.34, 95% confidence interval 1.66-3.28, P < 0.001). Three randomized controlled trials ( N = 414 patients) reported survival outcomes. Patients administered platinum-based regimens showed significantly longer progression-free survival (hazard ratio 0.55, 95% confidence interval 0.37-0.82, P = 0.004) and a nonsignificant trend toward improved overall survival (hazard ratio 0.76, 95% confidence interval 0.57-1.00, P = 0.05). Only 2 studies reported the rates of grade 3 and 4 adverse events; grade 3-4 thrombocytopenia was more commonly associated with platinum-based chemotherapy (odds ratio 7.54, 95% confidence interval 1.37-41.60, P = 0.02) and grade 3-4 fatigue with platinum-free chemotherapy (odds ratio 0.23, 95% confidence interval 0.08-0.68, P = 0.008). Conclusions: First-line platinum-based chemotherapy was associated with significantly increased objective response rates, longer progression-free survival, and a nonsignificant trend toward improved overall survival in patients with metastatic triple-negative breast cancer at the high risk of grade 3-4 thrombocytopenia.

Background Cancer surgery remains the most effective single treatment modality for curing patients with solid tumors. However, only half of all cancer patients undergo curative resection. Of those, a significant number will eventually relapse from occult metastases. Administration of therapy prior to surgery, known as neoadjuvant therapy, has revolutionized cancer surgery. It not only decreases overall tumor burden, rendering previously inoperable disease operable, but also improves survival by providing systemic disease control in patients at high risk of having microscopic distant metastases at the time of surgery. While traditional neoadjuvant therapy using conventional chemotherapy and radiation therapy has improved patient outcomes across a spectrum of solid tumors, the potential of neoadjuvant immunotherapy is currently unknown. Various immune modulating agents have achieved significant clinical success in the management of metastatic and treatment resistant cancers, yet their utility in the neoadjuvant setting remains unclear. In theory, neoadjuvant immunotherapy is particularly interesting because it utilizes the primary tumor as a rich source of antigens for T cell priming. As a result, it may be successful in eliciting an immune response where adjuvant immunotherapy treatment has failed. Here we designed a preclinical study utilizing neoadjuvant immunotherapy and demonstrate the efficacy of employing immune stimulating agents synergistically with surgical resection. Methods We used two different murine models of solid tumors – a metastatic triple negative breast carcinoma and a colorectal carcinoma to compare neoadjuvant immunotherapy, resection alone, or immunotherapy alone treatments on local and systemic disease control, and survival. We found that neoadjuvant immunotherapy offered the best survival as well as the best locoregional and metastatic disease control when compared to the other groups. In fact, in the highly aggressive and spontaneously metastatic breast carcinoma model the neoadjuvant treatment group was the only group in which a long-term surviving cohort of mice was cured. When these long-term survivors were rechallenged with the same tumor, they were immune, confirming that the treatment successfully conferred immunological memory. When exposed to a new tumor type, however, they remained susceptible, confirming the specificity of this immunologic memory. Disease control was found to be T cell dependent as depletion of either both CD4+ and CD8+, or CD8+ only T cells resulted in loss of therapeutic benefit in mice treated with neoadjuvant immunotherapy. Conclusion We found that neoadjuvant immunotherapy successfully initiated cell mediated antitumor activity both locally and systemically at an anatomically distant disease site. This resulted in improved survival in the neoadjuvant group when compared to groups receiving resection alone or immunotherapy alone. As increased options to incorporate immunotherapy in the clinic become available to clinicians, this study explores the timely and clinically important question of how immunotherapy may optimally be combined with surgical resection. The results of the study are readily translatable and may be utilized to inform establishment of neoadjuvant immunotherapy regimens for patients with early stage and locally advanced solid tumors. Citation Format: Wan Xing Hong, Idit Sagiv-Barfi, Debra Czerwinski, Ronald Levy. Neoadjuvant immunotherapy for solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5568.

Purpose Triple-negative breast carcinoma (TNBC) is accompanied with high risk of metastasis and recurrence. The present study aimed to explore the clinicopathological and prognostic roles of putative tumor-related genes in patients with TNBC. Methods Thirty pairs of frozen-thawed tumors were used to select reliable indicators via real-time quantitative polymerase chain reaction (RT-qPCR). Then, 150 pathology specimens were used to evaluate the expression of proteins in TNBC through immunohistochemistry. In addition, Kaplan-Meier curves and Cox regression analysis were also performed to analyze the overall survival and disease-free survival. Results RT-qPCR results indicated that among all the proteins analyzed using fresh-frozen TNBC samples, the expression levels of only Survivin and zinc finger of the cerebellum 1 (ZIC1) were obviously different from those in the corresponding normal tissues. Survivin and ZIC1 expression had opposite effects on the clinicopathological diagnosis and prognostic assessment in TNBC patients. Further, there was a negative correlation between Survivin and ZIC1 expression. In addition, the "Survivin-positive ZIC1-negative group" was associated with histologic grade, lymph node metastasis, and TNM staging (p < 0.001) and this was also an independent factor for evaluating the prognosis of TNBC in patients. Conclusion In summary, the expression levels of Survivin and ZIC1 in TNBC are different from those in normal tissues and are negatively correlated mutually. The combined detection of Survivin and ZIC1 expression levels could allow better comprehensive diagnosis and prognostic evaluation for TNBC patients.

OBJECTIVE To determine association of p53 overexpression with hormone receptor status in breast carcinoma. STUDY DESIGN Descriptive cross-sectional study. PLACE AND DURATION OF STUDY Department of Pathology in collaboration with Department of Oncology, King Edward Medical University, Lahore, from January 2017 to January 2018. METHODOLOGY All adult female patients coming to Department of Oncology with reports of breast cancer biopsy and receptor status were included. Their age, type of surgery, grade of cancer, stage of cancer, and hormone receptor status were noted from records. P53 immunomarker was applied on tumor containing tissue blocks. Pearson Chi-square test was run for strength of association between the variables using SPSS V. 22. RESULTS Mean age of 91 patients at diagnosis was 48 years ±12.49. Fifty-five (60.4%) patients had ER positive tumors, 36 (39.6%) were ER negative, 53 (58.2%) had PR positive status, and 38 (41.8%) were negative. Same number was seen in HER2 neu staining. Out of 91 cases, 31 (34.1%) were p53 positive and 60 (65.9%) were negative. Out of 55 (60.4%) ER positive cases, 11 (12.1%) were positive for p53 and 44 (48.4%) were p53 negative (p

Objectives To evaluate the morphokinetic, pharmacokinetic, and diffusion characteristics of triple-negative breast cancers on magnetic resonance (MR) imaging and to analyze whether there is a relation between these parameters and the time to progression. Material and methods This was a retrospective observational study of a consecutive series of 100 patients with histologically confirmed triple-negative breast cancer studied at our center between January 2005 and December 2010. We reviewed the findings on MR locoregional extension studies, the histological findings, and the follow-up of patients until August 2014. Results The most common MR findings for these tumors were a rounded mass (47.3%), well-defined borders (53.7%), ring enhancement (46.2%), type 3 curves (50.5%), hyperintensity within the tumor on T2-weighted sequences, high ADC values (1.04 × 10 −3 mm 2 /s), and increased capillary permeability (Kep) (0.94 min −1 ). No significant association was observed between the morphokinetic or pharmacokinetic characteristics and the time to progression. The in situ component in the surgical specimens was high, although its expression was low. During follow-up, 25% of patients had metastases, with a predilection for the visceral organs, and survival was low. Conclusion Tumors with the triple-negative phenotype mostly presented in MR as rounded tumors with well-defined borders and ring enhancement. We found no significant association between the morphokinetic or pharmacokinetic characteristics and the time to progression.