Triple Negative Carcinoma Research Articles

Cell-of-Origin Targeted Drug Repurposing for Triple-Negative and Inflammatory Breast Carcinoma with HDAC and HSP90 Inhibitors Combined with Niclosamide.

We recently identified a cell-of-origin-specific mRNA signature associated with metastasis and poor outcome in triple-negative carcinoma (TNBC). This TNBC cell-of-origin signature is associated with the over-expression of histone deacetylases and zinc finger protein HDAC1, HDAC7, and ZNF92, respectively. Based on this signature, we discovered that the combination of three drugs (an HDAC inhibitor, an anti-helminthic Niclosamide, and an antibiotic Tanespimycin that inhibits HSP90) synergistically reduces the proliferation of the twelve tested TNBC cell lines. Additionally, we discovered that four out of five inflammatory breast carcinoma cell lines are sensitive to this combination. Significantly, the concentration of the drugs that are used in these experiments are within or below clinically achievable dose, and the synergistic activity only emerged when all three drugs were combined. Our results suggest that HDAC and HSP90 inhibitors combined with the tapeworm drug Niclosamide can achieve remarkably synergistic inhibition of TNBC and IBC. Since Niclosamide, HDAC, and HSP90 inhibitors were approved for clinical use for other cancer types, it may be possible to repurpose their combination for TNBC and IBC.

Tumor Microenvironment in Male Breast Carcinoma with Emphasis on Tumor Infiltrating Lymphocytes and PD-L1 Expression.

Male breast cancer (MBC) is rare and usually presents as a locally advanced disease. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with a better response to neoadjuvant chemotherapy and improved prognosis in all molecular subtypes of female breast cancer, but their role in MBC is less clear. We studied sTILs and the expression of programmed cell death ligand 1 (PD-L1) and pan-TRK in MBC. We retrospectively studied 113 cases of MBC surgically treated between 1988 and 2015. The tumors were evaluated for histological type and grade, stage, intrinsic subtype and sTILs. We performed immunohistochemistry for PD-L1 (clone SP142) and pan-TRK (clone EPR17341) on tissue microarrays. Pan-TRK positive cases were further analyzed by next-generation sequencing. The median age was 69 years (range 60-77). Invasive carcinoma of no special type was found in 94.7% of cases, of which 53.1% were grade 2. Estrogen receptor was positive in 92% of the tumors, progesterone receptor in 85.8%, androgen receptor in 70.8%; 4.4% were human epidermal growth factor receptor 2 (HER2)-positive, and 55.8% HER2-low. 40.7% of tumors were luminal A and 51.3% luminal B, 4.4% HER2-enriched and 3.5% triple negative carcinoma. sTILs density was <50% in 96.4% of the tumors, >50% in 3.6% of the tumors. PD-L1 immune cell score >1% was found in 7.1% of the tumors (all of luminal subtype). A weak focal cytoplasmic pan-TRK staining was present in 8.8% but without NTRK fusion. Neither sTILs nor PD-L1 had statistically significant outcomes. Our findings suggest that a subset of MBC patients harbors an immunological environment characterized by increased sTILs with PD-L1 expression. These patients may potentially benefit from immune checkpoint inhibitor therapy. Frequent HER2-low may offer novel anti-HER2 treatment options.

Tupichinol-E Reverse Epithelial to Mesenchymal Transition against ER Positive and Triple Negative Breast Cancer

Aim: To investigate the effects of Tupichinol E, an alkaloid present in Tupistra chinensis BAKER (Liliaceae) on the metastasis of Triple negative mammary carcinoma in-vitro, and elucidate the underlying mechanisms and Tupichinol E binding to EGFR stabilises the protein structure and is a pharmacologically active substance that can be used against cancer due to its potent activity. Methods: Growth of MCF-7 and MDA-MB-231 cells was assessed using MTT assay. Apoptosis and cell cycle of MCF-7 cells were evaluated with flow cytometry, and the related proteins were examined using Western blotting. Structurally similar EGFR inhibitors, their modes of binding and mechanism of actions are a new way to select lead compounds for better alternatives. Therefore molecular docking is done to find a potential anti-EGFR flavonoid. Results: Tupichinol E (35–280 μmol/L) inhibited the growth of MCF-7 cells in time- and dose-dependent manners (the IC50 values were 105±1.08 and 78.52±1.06 μmol/L, respectively, at 48 and 72 h). Treatment of MCF-7 cells with Tupichinol E (70–280 μmol/L) dose-dependently induced apoptosis of MCF-7 cells, accompanying activation of caspase 3. The cells treated with Tupichinol E (140 and 280 μmol/L) significantly increased the percentage of cells in G2/M phase with a reduction in the expression of cyclin B1. Osmertinib shows binding energy -107.23 kcal/mol with EGFR, while Tupichinol E shows binding energy -98.89 kcal/mol. Tupichinol E shows 1.5 times more binding affinity than Osmertinib. Conclusion: These results demonstrated that Tupichinol E is an effective antitumor compound in vitro and in-silico, and has the potential to be developed as a new anticancer drug.

The Current and Evolving Landscape of Breast Cancer Prediction and Prognosis

The biological behaviour of breast cancer is remarkably heterogeneous and it is essential to have tools which can provide the necessary risk stratification to plan clinical management. Breast cancer prediction and prognosis needs to be holistic, and account for multiple levels of organisation. The histological classification and grading of the tumour itself presents valuable predictive and prognostic information. Hormone receptor status remains a mainstay, but roles may emerge for assessment of the intrinsic molecular subtype, for a molecular subclassification of triple negative carcinomas, and for whole genome sequencing. The recent discovery that antibody drug conjugates are effective in patients with weak HER-2 protein expression has led to the definition of the HER-2 low group. There has been a proliferation in predictive and prognostic models, numbering over 900, but the majority are at high risk of bias and tend to perform less well when applied to populations beyond the development cohort. The Nottingham Prognostic Index is a notable exception. Of the molecular risk stratification tools currently available, Oncotype Dx is the most widely recommended and used, but the question as to which test is superior remains unanswerable with current data. There is growing interest in omics-based approaches from which a number of biomarkers are being developed. It is well established that the microenvironment of the tumour is key to the tumour’s behaviour. Some components contain and destroy the cancer, whereas others are co-opted by the tumour and aid in its progression; the current evidence is reviewed, including the current status of tumour infiltrating lymphocyte assessment and immune checkpoint inhibition in breast cancer. The use of the liquid biopsy to achieve early detection of tumours and to manage tumour evolution is receiving intense attention; approaches include circulating tumour cells and circulating tumour DNA. Specific assessment of tumour giant cells may also provide the ability to anticipate tumour evolution. The influence of the gut microbiome on breast cancer is an intriguing development which requires further intensive study. There is a paucity of biomarkers in the setting of hereditary breast cancer. The use of polygenic risk scores in this setting is an interesting development requiring further study. The greatest challenge of all is to pull from such complexity key decision nodes that are clear enough to guide treatment decisions without losing the depth and richness of the information that underlies them. Seeking and finding this balance has been and will continue to be the holy grail of all endeavours in this field.

Clinicopathological analysis of triple-negative carcinoma arising in breast microglandular adenosis

目的： 探讨起源于微腺体腺病的三阴性乳腺癌的临床病理学特征、免疫表型、发生机制和预后。 方法： 收集2012年11月及2021年10月温州医科大学附属萧山医院病理科2例起源于微腺体腺病的三阴性乳腺癌，观察组织学形态、临床病理特征，并结合国内外文献进行复习。 结果： 患者女性，年龄分别为55岁和34岁，因发现乳腺肿块就诊。镜下均可见典型微腺体腺病向非典型微腺体腺病和浸润性癌进展的连续形态变化，1例浸润性癌为产生基质的化生性癌，另1例为腺泡细胞癌和浸润性导管癌。浸润性癌免疫表型与微腺体腺病一致，S-100蛋白弥漫强阳性，雌激素受体、孕激素受体和HER2呈三阴性表达。例1行左乳全乳切除术，例2行保乳切除术，前哨淋巴结活检均无转移，随访4个月和9年无复发。 结论： 起源于微腺体腺病的癌多为三阴性乳腺癌，具有与微腺体腺病相同的免疫表型和基因突变谱，微腺体腺病可能是部分三阴性乳腺癌的前驱病变，存在向低/高级别三阴性乳腺癌进展的亚克隆。.

The Landscape of Tumor-Infiltrating Immune Cells in Feline Mammary Carcinoma: Pathological and Clinical Implications.

Feline mammary carcinoma (FMC) shares key molecular and clinicopathological features with human breast cancer. We have herein studied the inflammatory infiltrate of FMC in order to uncover potential therapeutic targets and prognostic markers. To this end, the expression of different markers (CD3, CD4, CD8, CD20, CD56, FoxP3, CD68 and CD163) was analyzed in total, stromal (s) and intratumoral (i) tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs), in 73 feline mammary carcinomas. The results revealed that higher percentages of sCD8+ TILs were associated with longer disease-free survival (p = 0.05) and overall survival (p = 0.021). Additionally, higher percentages of iCD4+ TILs correlated with positive lymph node status (p = 0.003), whereas CD163+ TAMs were associated with undifferentiated tumors (p = 0.013). In addition, sCD3+ (p = 0.033), sCD8+ (p = 0.044) and sCD68+ (p = 0.023) immune cells were enriched in triple negative normal-like carcinomas compared to other subtypes. Altogether, our results suggest that specific subsets of immune cells may play a major role in clinical outcome of cats with mammary carcinoma, resembling what has been reported in human breast cancer. These data further support the relevance of the feline model in breast cancer studies.

Abstract CT176: A phase 1 open label, first in human trial to study safety and tolerability of NK-T cells combined with vvDD: An accelerated dose escalation in multiple tumor types

Abstract Introduction: BioEclipse Therapeutics has developed CRX100 an adoptive NK-T Cells therapy combined with vaccinia vvDD, an oncolytic virus. vvDD is a Western Reserve (WR) strain vaccinia virus (VACV) that has been further attenuated by the removal of the viral thymidine kinase and growth factor genes, and hence its replication and lytic activity is confined to tumor cells. In preclinical studies in immunocompetent mice the combined therapy eradicated tumor cells and initiated an adaptive immune response. Trial Design: Our ongoing phase 1 safety clinical trial (IND 19222 at Clinicaltrials.gov) began in January 2021 and includes planned treatment of approximately 24 patients with the potential for 2 doses each. With the dose of ex vivo activated autologous NK-T cells held constant (2-5 X 109), the dose of vvD is increased at 5 dose levels, 3X107, 1x108, 3x108, 1x109 and 3x109 pfu/dose. The first five doses are accelerated in cohorts of one patient and followed by a non-accelerated phase with a cohort of two patients and then 3 cohorts of three patients to determine the MTD, with an additional 8 patients then treated at the MTD. Dose limiting toxicities evaluated by a BOIN design will assist in the dose decision for phase 2. Inclusion and exclusion criteria: Patients will have tumor progression and have failed standard of care in the indications, triple negative breast cancer, gastric cancer, colorectal carcinoma, hepatocellular carcinoma, ovarian cancer or osteosarcoma. Results: To date, 4 patients have been treated, including 2 patients with ovarian cancer and 2 with CRC at 4 dose levels. No dose limiting toxicities have been observed. The most common AE is mild fever at 6-12 hours after infusion. Two CRC patients treated at a vvDD dose of 3x107 and 1x109 experienced disease progression. Patient 101-005 with ovarian cancer received two separate infusions 3 months apart each at a dose of 1x108 PFU vvDD combined with 2-5 X 109 ex-vivo activated autologous NKT. Tumor assessment after the first dose showed stable disease (+17.2%) by iRECIST. The CA125 serum biomarker increased temporarily about 3 weeks after infusion. The second ovarian patient (101-007) treated with 3x108 vvDD combined with 2-5 X 109 ex-vivo activated autologous NKT had unconfirmed progression (+21%). There was a slight increase and then a decrease of the CA-125 from 303 to 268. The patient developed new ascites 4 weeks after infusion and required a paracentesis. The ascites did not recur after the paracentesis. Conclusion: Thus far in escalation, all doses of the therapy have been safe and well-tolerated. Two patients with ovarian cancer treated with the adoptive NKT cell therapy combined with an oncolytic virus demonstrated changes in CA-125 potentially consistent with immune inflammation. Peripheral blood obtained at 3 and 6 month will be analyzed to assess specific immune responses. Dose escalation and enrollment continue for this study. Citation Format: Oliver Dorigo, Pamela Reilly Contag, Justin Moser, Sandip Pravin Patel, Mark W. Frohlich. A phase 1 open label, first in human trial to study safety and tolerability of NK-T cells combined with vvDD: An accelerated dose escalation in multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT176.

Abstract 1861: Trophoblast cell surface antigen 2 (TROP2) expression in human tumors: A tissue microarray study on 18,563 tumors

Abstract Trophoblast cell surface antigen 2 (TROP2) is the target of sacituzumab govitecan (SG), an antibody-drug conjugate that was recently approved for previously treated triple negative breast cancer and urothelial carcinomas. To comprehensively determine TROP2 expression in normal and neoplastic tissues, a tissue microarray containing 18,563 samples from 150 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. TROP2 positivity was found in most normal epithelial cell types and in 109 of 150 tumor categories, including 92 of 95 epithelial tumor categories. Particularly high rates of TROP2 positivity and highest expression levels were seen in squamous cell carcinomas of various origins and various categories of urothelial, breast, prostate, pancreatic, and ovarian cancers (>95% positive). High TROP2 expression was linked to advanced stage (p=0.0069) and nodal metastasis (p<0.0001) in colorectal cancer as well as to nodal metastasis in gastric adenocarcinoma (p=0.0246) and papillary thyroid cancer (p=0.0013). Low TROP2 expression was linked to advanced stage in urothelial carcinoma (p<0.0001), high pT (p=0.0024) and high grade (p<0.0001) in breast cancer, as well as with high grade (p=0.0005) and pT stage (p=0.0009) in papillary renal cell carcinomas. Associations between TROP2 expression and clinicopathological features were not found in clear cell renal cell carcinomas, high grade serous ovarian carcinomas, pancreatic adenocarcinomas and in endometroid endometrium carcinomas. In summary, TROP2 is abundantly expressed in a broad range of epithelial neoplasms. Both TROP2 upregulation and downregulation can be associated with cancer progression in a tumor type dependent manner. As anti-TROP2 cancer drugs have demonstrated efficiency and induce tolerable side effects they may be applicable to a broad range of tumor entities in the future. Citation Format: David Dum, Claudia Hube-Magg, Ronald Simon, Elena Bady, Tim Mandelkow, Niclas C. Blessin, Maximilian Lennartz, Guido Sauter, Sarah Minner, Andreas M. Luebke. Trophoblast cell surface antigen 2 (TROP2) expression in human tumors: A tissue microarray study on 18,563 tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1861.

MYB RNA In Situ Hybridization Is a Useful Diagnostic Tool to Distinguish Breast Adenoid Cystic Carcinoma From Other Triple-negative Breast Carcinomas.

Breast adenoid cystic carcinoma (AdCC) has overlapping features with basal-like triple-negative breast carcinoma (TNBC), yet carries a more favorable prognosis, and accurate diagnosis is critical. Like salivary gland AdCC, breast AdCC demonstrates recurrent alterations in the MYB gene. Novel chromogenic RNA in situ hybridization (ISH) for MYB has emerged as sensitive and specific for salivary gland AdCC. Here, we evaluate MYB RNA ISH in invasive ductal carcinomas (IDCs) including basal-like TNBC, and in the histologic mimics ductal carcinoma in situ (DCIS) and collagenous spherulosis. MYB RNA ISH was also performed on previously constructed tissue microarrays containing 78 evaluable IDC, including 30 basal-like TNBC (EGFR+ and/or CK5/6+), 19 luminal A (ER+/HER-2-), 12 HER-2+ (ER-/HER-2+), 11 non-basal-like TNBC, and 6 luminal B (ER+/HER-2+). MYB RNA ISH overexpression was seen in 100% (n=18/18) of primary breast AdCC and 10% (n=8/78) of IDC (P<0.0001). MYB RNA ISH was overexpressed in 37% (n=7/19) of luminal A and 8% (n=1/12) of HER-2+ IDC, and in no cases of TNBC or luminal B IDC. The majority (67%, n=8/12) of DCIS and all (n=7) cases of collagenous spherulosis demonstrated overexpression of MYB RNA. MYB gene rearrangement was detected in 67% (n=4/6) evaluable AdCC. Although MYB RNA ISH overexpression cannot be used to distinguish between cribriform DCIS or collagenous spherulosis and AdCC, MYB RNA ISH is absent in basal-like TNBC and rare in ER+ or HER-2+ IDC. MYB RNA ISH could be a useful, sensitive, and rapid diagnostic adjunct in the workup of a triple-negative carcinoma in the breast.

Особливості експресії СОХ-2 в різних молекулярних підтипах інвазивного протокового раку грудної залози

The purpose of the study was to determine the role of COX-2 in the development and progression of molecular subtypes of invasive ductal breast cancer by comparing COX-2 expression level between different clinical and pathological prognostic parameters. Materials and methods. We studied 193 cases of invasive ductal breast cancer using comprehensive morphological, including immunohistochemical methods. General histological processing of samples was performed according to standard methods. Immunohistochemical studies for COX-2, ER, PR, c-erbB2, Ki-67 were performed according to the manufacturer's protocol with the control of samples. The grade of malignancy was determined according to the modified scheme of P. Scarff, H. Bloom and W. Richardson. COX-2 expression level was quantified using the Histoscore counting system in 86 cases. Immunoreactive index was defined as the product of positive cells and color intensity with a value from 0 to 12. The distribution of tumors with weak or strong expression of COX-2 was determined at the level of limit 6. Comparison of COX-2 expression at different clinical and pathological parameters was evaluated using the criterion Pearson χ2. For all types of analysis, differences were considered significant at p &lt;0.05. Results and discussion. Immunohistochemical studies showed overexpression of COX-2 tumor cells in 53.49 [42.95-63.87] % of cases of invasive ductal breast cancer, mainly in premenopausal patients. Increased expression of COX-2 was determined in tumors with metastases to regional lymph nodes (53.66 66 [38.46-68.52] % - 63.64 (34.52-88.13] %), large size (73, 81 (59.63-85.82] % - 85.71 [52.74-99.97] %), running clinical stage (65.12 [54.78-74.78] %), with a low degree of differentiation G3 (80.95 [61.88-94.45] %), negative ER status and overexpression of HER-2/neu. Overexpression of COX-2 prevailed in patients under the age of 50 years (69.23 [54.04-82.54] %), in patients with triple-negative carcinoma phenotype (75.00 [54.26-91.01] %) and HER-2/neu + phenotype of invasive ductal breast cancer (73.68 [52.19-90.47] %). Conclusion. Overexpression of COX-2 has been associated with adverse prognosis factors such as young age, metastatic lymph node involvement, large tumor size, G3 poorly differentiation (high grade), negative ER status and HER-2/neu overexpression, and has been associated with an increased risk of recurrence of the disease, progression of the tumor process, increased risk of death. Overexpression of COX-2 may be a sign of an aggressive phenotype with metastatic potential, depend on hormonal status and be useful as a prognostic biomarker of invasive ductal breast cancer

Clinical case of torpid course of metastatic triple negative breast cancer

Background. Breast cancer is the most common cancer and the leading cause of cancer death in women worldwide. The presence of an unfavorable molecular biological subtype significantly worsens the prognosis, making it necessary to individualize treatment strategy for each patient.The aim of the study was to demonstrate the achievement of long-term remission in the treatment of metastatic triple-negative breast cancer. Case description. A 42-year-old patient presented to Ryazan Oncologic Dispensary in October 2006 with complaints of lump in her left breast. She was diagnosed with stage cT2N0M0 triple-negative carcinoma of the left breast. She underwent radical mastectomy for left breast cancer (October, 2006). Disease progression (metastases to lungs and mediastinal lymph nodes) occurred in June 2009. The patient received 6 courses of polychemotherapy according to the FAC regimen with a favorable response. In February 2011, the patient was found to have metastatic lesion in the brain, which was surgically removed in March, 2011. She received metronome chemotherapy. Recurrence of brain metastasis occurred 6 months after chemotherapy. The patient received external beam radiation therapy, which resulted in tumor regression, and metronomic chemotherapy was continued with a positive effect. The patient was followed up for 6 years with no evidence of disease progression. In July 2019, the follow-up examination revealed stage cT2N0M0 triple-negative cancer in the right breast. The patient underwent radical mastectomy for the right breast and 8 courses of adjuvant polychemotherapy (4 courses of AC + 4 courses of paclitaxel). The patient is alive with no signs of disease progression.Conclusion. This clinical case demonstrated personalized approach to the treatment of patients with triple-negative breast cancer. Fifteen years had passed since the detection of the primary tumor. During this time, the disease progressed three times, and breast cancer was diagnosed on the opposite side. Combined modality treatment including chemotherapy, surgery and radiotherapy allowed satisfactory results to be achieved. The patient is still alive with no signs of disease progression.

Abstract P1-03-01: Heterogeneity between core needle biopsy and primary tumor tissue in early breast cancer patients: Comparison of intrinsic subtypes after different treatment regimes

Abstract Background: All initial therapeutic decisions in early breast cancer are commonly based on the expression profiles of estrogen (ER), progesterone (PR) and the human epidermal growth factor 2 (HER2) receptors. However, breast cancer is a very heterogeneous disease, and receptor changes were manifold reported during progression. Only little data is known about receptor changes after upfront therapy. Here, we compared receptor expression profiles between core needle biopsy (CNB) tissue and primary tumor tissue after different treatment regimes. Methods: In a German single center study, we retrospectively analyzed 248 breast cancer patients during primary treatment regime between 2014 and 2020. Patients had either neoadjuvant chemotherapy, neoadjuvant endocrine therapy or no upfront therapy. Tumor material was obtained by core needle biopsy (CNB) at primary diagnosis and during primary oncological surgery of the axilla and breast. Analysis of histological subtype, grading, Ki67 index and expression profiling of ER, PR, HER2, was performed using formalin-fixed, paraffin-embedded (FFPE) specimens. Immunohistochemical examination was performed according to the ASCO/CAP guidelines using the Ventana-platform. Tumors were grouped into different intrinsic subtypes according to the international St. Gallen classification in either Luminal A, Luminal B, HER2-enriched or triple negative. 35 patients were excluded because the intrinsic subtype was not specified in the CNB and final postoperative specimen, therefore 213 patients were included in the primary analysis. Results: In the primary analysis (n=213), median age was 53 years (IQR 43 - 64). Based on the initial CNB receptor profile 105 (49%) patients had a Luminal A carcinoma, 46 (22%) patients had a Luminal B HER2 negative carcinoma, 22 (10%) patients had a Luminal B HER2 positive carcinoma, 6 (3%) patients had a HER2 enriched carcinoma and 33 (16%) patients had a triple negative carcinoma. In the primary analysis 84 (39%) patients had neoadjuvant chemotherapy, 48 (23%) patients had neoadjuvant endocrine therapy and 81 (38%) patients had no upfront therapy. Overall, 77 (36%) patients had an intrinsic subtype change between CNB and definitive surgical treatment, 139 (64 %) patients had no subtype change. There were 44 (52%) changes after neoadjuvant chemotherapy, 17 (35%) changes after neoadjuvant endocrine therapy and 16 (20%) subtype changes after no upfront therapy (p&amp;lt;0.0001 for the effect of neoadjuvant chemotherapy). ER receptor status changed in 5 (6%) patients after neoadjuvant chemotherapy, 6 (13%) changes were observed after neoadjuvant endocrine therapy and 2 (2%) ER changes occurred after no upfront therapy. Concerning the PR receptor there were 23 (27%) receptor changes after neoadjuvant chemotherapy, 17 (35%) changes after neoadjuvant endocrine therapy and 9 (11%) changes after no upfront therapy (p&amp;lt;0.0001 for the effect of neoadjuvant endocrine therapy). Regarding the HER2 receptor, there were 18 (21%) receptor status changes after neoadjuvant chemotherapy, 2 (4%) changes after neoadjuvant endocrine therapy and 2 (2%) subtype changes after no upfront therapy (p=0.0001 for the effect of neoadjuvant chemotherapy).Neoadjuvant chemotherapy led significantly more often to a decrease of HER2 expression, compared to neoadjuvant endocrine therapy or no upfront therapy. Conclusions: Our results imply the high frequency of intrinsic subtype changes after neoadjuvant therapy. Subtype changes should be taken into account for an optimal and individual treatment. Further research needs to be conducted to investigate whether an individual treatment decision based on the receptor profile after primary treatment might improve clinical outcome of breast cancer patients. Citation Format: Laura Weydandt, Anne Kreklau, Ivonne Nel, Lars-Christian Horn, Bahriye Aktas. Heterogeneity between core needle biopsy and primary tumor tissue in early breast cancer patients: Comparison of intrinsic subtypes after different treatment regimes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-03-01.

A systemic review on triple negative breast cancer

Triple negative carcinoma (TNBC) is outlined as cancer cells that don’t have steroid or progestin receptors and additionally absence of HER2 macromolecule (. i.e., The cells negative on all 3 tests). These cancers tend to be additional common in ladies younger than age forty, World Health Organization black or BRCA one mutation. The pathologic process potential in TNBC is comparable to it of alternative carcinoma subtypes, however these tumors ar related to a shorter median time to relapse and death. One necessary goal is so the identification of prognostic factors and markers to dependably choose high and low risk subsets of patients aim. TNBC for various treatment approaches of subtypes with differential responsiveness to specific agents. These review focuses on the history of medical specialty and treatment of TNBC.

SRY-box transcription factor 10 is a highly specific biomarker of basal-like breast cancer.

Basal-like breast cancer is an aggressive molecular subtype associated with younger age and early relapse. Most cases lack expression of oestrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, limiting targeted therapeutic options. Basal-like breast cancer is defined by the expression of genes in the outer/basally located epithelial layer of mammary glands, including those encoding cytokeratin (CK) 5 and CK14, and epidermal growth factor receptor (EGFR). SRY-box transcription factor 10 (SOX10), for which there is a readily available immunohistochemical stain, is expressed in a subset of breast cancers, particularly triple-negative carcinomas. In this study, we sought to: (i) assess the association between SOX10 expression and intrinsic molecular subtypes as defined by Prediction Analysis of Microarray 50 (PAM50) gene expression; and (ii) compare the performance of SOX10 with that of other surrogate markers of the basal-like subtype, including CK5, EGFR, nestin, and inositol polyphosphate 4-phosphatase type II (INPP4B). SOX10 immunostaining was performed on tissue microarrays constructed from a contemporary series enriched for ER-negative and weakly ER-positive cancers that had also undergone PAM50 gene profiling. A total of 211 cases were informative for both SOX10 immunohistochemistry and PAM50 subtype, including 103 basal-like cancers. Staining for SOX10 was positive in 73 of 103 basal-like cancers and in only two of 108 cancers of other subtypes (P < 0.001), resulting in a sensitivity of 70.9% and a specificity of 98.1%. SOX10 was more specific than the other tested basal markers, and the results were independent of ER status. SOX10 is a moderately sensitive, but highly specific, immunohistochemical biomarker for the basal-like intrinsic subtype of breast cancer, which, unlike other commonly used immunohistochemical biomarkers, is independent of hormone receptor status.

The neural crest transcription factor SOX 10 is preferentially expressed in triple negative breast carcinomas

Introduction: The expression of SOX 10 by immunohistochemistry has been documented in benign breast myoepithelial cells and in ductal carcinomas classified by the molecular subtype defined by immunohistochemistry. Material and methods: Material and methods: 77 cases of infiltrating ductal carcinomas of the mammary gland with Sox 10 reactivity were analyzed and subdivided by immunohistochemistry into the different molecular subtypes. The IHC panel used to define molecular subtypes included Estrogen Receptors (ER), Progesterone Receptors (PR), Her 2, cytokeratin(CK) 5/6, Epidermal Growth Factor Receptor (EGFR). Results: In our study we demonstrated in 31 cases (44.25%) of 77 infiltrating ductal carcinomas SOX 10 immunoreactivity, which was only observed in basal and undifferentiated subtype triple negative carcinomas. Conclusion: The expression of Sox 10 in triple negative infiltrating ductal carcinomas supports the concept that these neoplasms show myoepithelial differentiation

Triple-negative apocrine carcinoma as a rare cause of a breast lump in a Syrian female: a case report and review of the literature

BackgroundApocrine carcinoma is a rare tumor that constitutes < 4% of all breast malignancies, characterized by the proliferation of large atypical cells with strictly defined borders, abundant eosinophilic cytoplasm, large nuclei, and prominent nucleoli in more than 90% of tumor cells. Triple-negative apocrine carcinoma is a rare molecular subtype that constitutes less than 1% of triple-negative breast cancers and is characterized by negative expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor, with positive expression of androgen receptor.Case presentationWe report a case of a 45-year-old Syrian female who presented to our hospital due to a painless palpable mass in her left breast. Following physical and radiological examinations, an excisional biopsy was performed. Microscopic examination of the specimen followed by immunohistochemical staining revealed the diagnosis of a triple-negative apocrine carcinoma.ConclusionTriple-negative apocrine carcinoma is an extremely rare neoplasm that must be considered in the differential diagnoses of breast lesions through detailed clinical, histological, and immunohistochemical correlations. In our manuscript, we aimed to present the first case report of a Syrian female who was diagnosed with a triple-negative apocrine carcinoma, aiming to highlight the importance of detailed clinical, histological and immunohistochemical correlations with a detailed review of diagnostic criteria, molecular characteristics, and treatment recommendations.

Pancreatic Metastasis from Breast Cancer: A Clinicopathological Study of Four Cases by Fine Needle Aspiration

Abstract Introduction/Objective Pancreatic metastases are rare, and the most common neoplasms are carcinomas from the kidney, lung, and breast. Methods/Case Report We present four cases of breast ductal carcinoma in patients with metastases to the pancreas diagnosed by endoscopic ultrasound guided fine needle aspiration (EUS-FNA). The four female patients ranged from 37 to 64 years in age. Three patients had breast cancer histories, ranging from 1 to 21 years. The patient without cancer history was found to have breast mass also. Two patients had triple negative breast ductal carcinoma. The breast cancer biomarkers on the other two patients showed ER+, PR-, Her2 3+, and ER-, PR-, Her2 3+, respectively. Two patients had histories of metastatic breast cancer involving bone, liver and brain. All patients presented with symptoms associated with pancreatic mass. By imaging, solitary pancreatic head masses were found in three patients, ranging from 2.4 to 3.7 cm. One patient had two pancreatic masses (head, 2.6 cm; body, 2.9 cm). EUS-FNAs targeting the pancreatic head masses were performed on the four patients. Cell blocks were available for all except one (due to limited cells), which had subsequent histology diagnosis. Results (if a Case Study enter NA) FNAs demonstrated loosely cohesive tumor cells with enlarged, hyperchromatic nuclei, occasional prominent nucleoli, and occasional intracytoplasmic vacuoles, morphologically and immunohistochemically (CK7 +, GCDFP-15 focally +, CA19.9 -, biomarkers similar to primary tumors) consistent with breast primary. Follow-up revealed three patients expired one month, 2.5 years, and 5 years post-diagnosis, respectively. One patient without prior cancer history has been stable for 7 years. Conclusion Our study demonstrates the clinicopathological features of four cases of breast ductal carcinoma metastasized to the pancreas. We emphasize the important role of EUS-FNA for diagnoses of pancreas metastases. The finding of two of four cases with triple negative biomarkers may raise the importance of close follow-up in these patients for pancreatic metastasis.

Impact of Epithelial-Mesenchymal Transition on the Immune Landscape in Breast Cancer.

Simple SummaryThe process of epithelial–mesenchymal transition (EMT) is thought to influence breast cancer tumor progression by affecting both tumor cells and the tumor microenvironment (TME). We aimed to study the impact of EMT-related markers on a breast cancer cohort and specifically analyze the involvement of Snail, Twist, ZEB1, N-cadherin, Vimentin, GRHL2, E-cadherin, and EpCAM and their respective outcome on both immune infiltration of the TME and clinicopathological features. The inflammatory infiltrate was more often associated with poorly differentiated carcinomas including triple-negative breast cancer (TNBC). The altered pattern of protein expression of epithelial markers markedly influenced the magnitude of the inflammatory infiltrate found in the TME. Overall, our data highlight the potential beneficial association of the EMT signature with the immune inflammatory response. This may open new avenues for rational decision making in the clinical use of immunotherapy in subsets of breast cancer patients, specifically TNBC.The impact of epithelial–mesenchymal transition (EMT) signature on the immune infiltrate present in the breast cancer tumor microenvironment (TME) is still poorly understood. Since there is mounting interest in the use of immunotherapy for the treatment of subsets of breast cancer patients, it is of major importance to understand the fundamental tumor characteristics which dictate the inter-tumor heterogeneity in immune landscapes. We aimed to assess the impact of EMT-related markers on the nature and magnitude of the inflammatory infiltrate present in breast cancer TME and their association with the clinicopathological parameters. Tissue microarrays were constructed from 144 formalin-fixed paraffin-embedded invasive breast cancer tumor samples. The protein expression patterns of Snail, Twist, ZEB1, N-cadherin, Vimentin, GRHL2, E-cadherin, and EpCAM were examined by immunohistochemistry (IHC). The inflammatory infiltrate in the TME was assessed semi-quantitatively on hematoxylin and eosin (H&E)-stained whole sections and was characterized using IHC. The inflammatory infiltrate was more intense in poorly differentiated carcinomas and triple-negative carcinomas in which the expression of E-cadherin and GRHL2 was reduced, while EpCAM was overexpressed. Most EMT-related markers correlated with plasma cell infiltration of the TME. Taken together, our findings reveal that the EMT signature might impact the immune response in the TME.

Prevalence and Molecular Profile of Breast Carcinoma Using Immunohistochemistry Markers in Mexican Women.

BackgroundIn Mexico, breast cancer is the leading cause of death by malignant tumors in women aged 20 and older. The World Health Organization estimates that 69% of deaths caused by breast cancer occur in developing countries. Little is known about the prevalence of breast carcinoma in Mexico and its molecular subclassification.MethodsThis retrospective cross-sectional study included patients who underwent a mastectomy (single, radical or lumpectomy) or a breast tumor biopsy (core-needle or excisional) from January 2002 to December 2018. The primary purpose of the study was to determine the prevalence and molecular profile of breast in comprehensive cancer center in Mexico and compare our results with those published in the US. This study was approved by our scientific and bioethical committee.ResultsThe final analysis included 379 patients. The youngest patient was 23 years old and the oldest patient was 89; the mean age at diagnosis was 54.63 years. Patients of 40 years old or younger accounted for 48 of the cases (12.66%) and those older than 40 accounted for 331 of the cases (87.33%). The molecular subclassification showed luminal A subtype in 139 cases (36.67%), luminal B subtype in 143 cases (37.73%), human epidermal growth factor receptor 2-positive carcinomas in 32 cases (8.44%) and triple-negative carcinomas in 65 cases (17.15%). Diabetes mellitus was present in 43 patients (11.34%), hypertension in 78 patients (20.58%), obesity in 82 patients (21.63%) and 66 patients reported being treated with exogenous hormone therapy (17.41%).ConclusionsBreast carcinoma occurs at an earlier age in Mexican women compared to women in the US. Hormone-positive tumors were found to be more prevalent in older patients, while high-grade tumors were more frequently identified in younger patients.

Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma.

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial–mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.