HER2 Receptor Research Articles

Human Epidermal Growth Factor Receptor 2 Loss Following Treatment with Trastuzumab Deruxtecan in Patients with Metastatic Breast Cancer.

Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) which is HER2-positive (immunohistochemistry [IHC] score of 3+ or ISH positivity) or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2 overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 receptor status might change following T-DXd therapy. We retrospectively reviewed patients with MBC who received T-DXd at The University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC. We included 41 patients with MBC who received treatment with T-DXd, and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients (32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)) following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd. HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Re-evaluation of HER2 status post-T-DXd should be considered prior to certain alternate HER2-targeted therapies which require HER2 overexpression for efficacy.

Association of Proteasome Activity and Pool Heterogeneity with Markers Determining the Molecular Subtypes of Breast Cancer.

Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed. Breast cancer (BC) therapy depends on the subtype of the tumor, determined by the expression level of Ki67, HER-2, estrogen and progesterone receptors. Relationships between the presence of specific proteasome forms and proteins that determine the BC subtype remain unclear. Here, using gene expression data in 19,145 tumor samples from 144 datasets and tissues from 159 patients with different subtypes of BC, we investigated the association between the activity and expression of proteasomes and levels of BC subtype markers. Bioinformatic analysis of proteasome subunit (PSMB1-10) gene expression in BC was performed. Proteasome heterogeneity in BC cell lines was investigated by qPCR. By Western blotting, proteasome composition was assessed in cells and patient tissue lysates. Proteasome activities were studied using fluorogenic substrates. BC molecular subtypes were determined by immunohistochemistry. BC subtypes demonstrate differing proteasome subunit expression pattern and strong PSMB8-10 co-correlation in tumors. A significant increase in chymotrypsin- and caspase-like proteasome activities in BC compared to adjacent tissues was revealed. The subunit composition of proteasomes in tumor tissues of BC subtypes varied. Regression analysis demonstrated a positive correlation between proteasome activities and the expression of Ki67, estrogen receptors and progesterone receptors. BC subtypes demonstrate differences within the proteasome pool. Correlations between the proteasome activity, hormone receptors and Ki67 indicate possible mutual influence. Obtained results facilitate development of novel drug combinations for BC therapy.

HER2-Positive Breast Cancer Treatment and Resistance.

HER2-positive (+) breast cancer is an aggressive disease with poor prognosis, a narrative that changed drastically with the advent and approval of trastuzumab, the first humanized monoclonal antibody targeting HER2. In addition to another monoclonal antibody, more classes of HER2-targeted agents, including tyrosine kinase inhibitors, and antibody-drug conjugates were developed in the years that followed. While these potent therapies have substantially improved the outcome of patients with HER2+ breast cancer, resistance has prevailed as a clinical challenge ever since the arrival of targeted agents. Efforts to develop new treatment regimens to treat/overcome resistance is futile without a primary understanding of the mechanistic underpinnings of resistance. Resistance could be attributed to mechanisms that are either specific to the tumor epithelial cells or those that emerge through changes in the tumor microenvironment. Reactivation of the HER receptor layer due to incomplete blockade of the HER receptor layer or due to alterations in the HER receptors is one of the major mechanisms. In other instances, resistance may occur due to deregulations in key downstream signaling such as the PI3K/AKT or RAS/MEK/ERK pathways or due to the emergence of compensatory pathways such as ER, other RTKs, or metabolic pathways. Potent new targeted agents and approaches to target key actionable drivers of resistance have already been identified, many of which are in early clinical development or under preclinical evaluation. Ongoing and future translational research will continue to uncover additional therapeutic vulnerabilities, as well as new targeted agents and approaches to treat and/or overcome anti-HER2 treatment resistance.

Synthesis, Characterization, and In Vitro and In Silico Studies of Substituted‐Vanillin Hydrazones of Anthranilic Acid and Their Quinazolin‐4(3H)‐One Analogues as Anti Breast Cancer Agents

AbstractThis study synthesized a total of 18 new anthranilic acid hydrazones and quinazolin‐4(3H)‐one derivatives, evaluating their cytotoxicity against the MCF7 and HUVEC cell lines. The anticancer effects of these compounds and their interactions with estrogen receptor alpha (ERα) and HER2 through molecular docking and molecular dynamics simulations. Cytotoxicity assays revealed that most compounds exhibited higher selectivity for MCF7 cells compared to HUVEC cells, with compounds 12, 13, 14, 23, and 29 showing superior efficacy over the standard drug 5‐fluorouracil (5‐FU). Notably, compound 12 displayed the highest selectivity index (SI = 3.9) and an IC50 of 77.3 µM against MCF7 cells. Compounds 14 and 29 also demonstrated significant selectivity indices of 3.0 and 3.5, respectively, with IC50 values of 111.4 µM and 74.0 µM against MCF7 cells. Molecular docking studies identified compounds 14 and 29 as strong inhibitors of ERα and HER2, with stable interactions and favorable binding profiles in docking and MD analyses. Furthermore, ADME analysis indicated good drug like properties for most compounds, aligning with Lipinski's rule of five, supporting their potential as orally bioavailable drugs. This research highlights compounds 14, and 29 as promising candidates for targeted breast cancer therapy via inhibition of ERα and HER2

Comparison of [125I]I-labeled trastuzumab and pertuzumab for targeted Auger electron therapy of cancers overexpressing HER2 receptors

Objectives: The HER2 receptor is often overexpressed in various cancers, particularly in breast and ovarian cancers, and this overexpression significantly contributes to the growth and spread of these tumours. Trastuzumab (Herceptin) and pertuzumab (Perjeta) are widely used humanized monoclonal antibodies (mAbs) that have shown promise in treating patients with HER2-positive breast cancer. To enhance their effectiveness, mAbs have recently been combined with chemotherapeutic agents and radionuclides. The aim of our studies was to investigate the potential therapeutic use of trastuzumab and pertuzumab labelled with the Auger electron emitter - 125I. Methods: The radioimmunoconjugates synthesized using 125I and 131I were tested in various in vitro studies on SKOV-3 cells. These studies included tests for specificity, binding affinity, internalization, cytotoxicity (MTS assay), and confocal imaging. Results: The results confirmed that radioiodinated mAbs have high affinity and internalization properties in HER2+ cell line. In contrast to trastuzumab, significant localization of iodinated pertuzumab on the cell membrane was observed. MTS assay and spheroid studies demonstrated minor toxic effects from both radioconjugates, resulting from the combination of the mAbs' immunotoxic effect and the interaction of Auger electrons. However, [125I] I-pertuzumab exhibited higher cytotoxicity. Conclusions: Despite high internalization, both radiobioconjugates showed low cytotoxicity due to the lack of radionuclide localization in the cell nucleus. However, [125I] I-pertuzumab accumulated in the cell membrane, resulting in slightly higher cytotoxicity. To improve therapeutic efficacy, modifying [125I] I-trastuzumab and [125I] I-pertuzumab to transport them to the cell nucleus, e.g., using nuclear localization signal (NLS) peptides is crucial.

A Cost-Effective and Robust Cell-Based Bioassay Method for Evaluating the Bioactivity of Trastuzumab-like Antibodies.

Background/Objectives: Trastuzumab is an effective therapeutic intervention for treating HER2-positive breast cancers. The cost-effectiveness, global demand, and patent expiration of trastuzumab have led to the inflow of its biosimilars in the global market. With the rise of biosimilars in the biopharmaceutical market, it has become crucial to ensure that the biosimilar is at par with the original monoclonal antibody (mAb)in terms of efficacy, safety, and quality. Bioassay is one of the critical quality attributes (CQAs), hence developing a reliable and robust bioassay is essential for the evaluation of their biological activity and the harmonization of the quality of these biologics, supporting their safe and effective use in clinical practice. Methods: The present study aimed to develop a robust cell-based bioassay to assess the bioactivity of trastuzumab and its biosimilars for quality control testing. For this purpose, molecular characterization of different HER2-positive breast cancer cell lines of SKBR3, BT474, MDA-MD-453, MDA-MB-175, MCF-7, and MDA-MB-231 was performed to select a suitable cell line for the cell-based bioassay. Results: The SKBR3 cell line was found to express the HER2 receptors significantly higher in comparison to the other cell lines, and it was thereby selected for further bioassay optimization. The biological activity of trastuzumab was determined using the inhibition of proliferation (IOP) assay on the SKBR3, which was optimized based on the parameters of cell seeding density, drug dilution range, and incubation time, and it was further validated as per the compendial guidelines and found valid for the parameters of specificity, accuracy (% relative bias = 0.0067%), precision (repeatability: % GCV = 1.21%), linearity (R2 = 0.99), and range (50% to 200%). Additionally, the biological activity of different trastuzumab biosimilars was assessed using the validated IOP assay and compared to the HER2 binding assay performed by flow cytometry. The biological activity of different trastuzumab biosimilars was found to be comparable to the WHO primary reference standard of trastuzumab in terms of its relative potency using the IOP assay and binding assay by flow cytometry. Conclusions: Thus, an economic and robust cell-based bioassay method was successfully developed to assess the bioactivity of trastuzumab and its biosimilars.

Current and future immunotherapy for breast cancer.

Substantial therapeutic advancement has been made in the field of immunotherapy in breast cancer. The immune checkpoint inhibitor pembrolizumab in combination with chemotherapy received FDA approval for both PD-L1 positive metastatic and early-stage triple-negative breast cancer, while ongoing clinical trials seek to expand the current treatment landscape for immune checkpoint inhibitors in hormone receptor positive and HER2 positive breast cancer. Antibody drug conjugates are FDA approved for triple negative and HER2+ disease, and are being studied in combination with immune checkpoint inhibitors. Vaccines and bispecific antibodies are areas of active research. Studies of cellular therapies such as tumor infiltrating lymphocytes, chimeric antigen receptor-T cells and T cell receptor engineered cells are promising and ongoing. This review provides an update of recent major clinical trials of immunotherapy in breast cancer and discusses future directions in the treatment of breast cancer.

Mastectomy, HER2 Receptor Positivity, NPI, Late Stage and Luminal B-Type Tumor as Poor Prognostic Factors in Geriatric Patients with Breast Cancer.

Background/Objectives: This study aims to explore the risk factors associated with poor survival outcomes in geriatric female patients with breast cancer. Methods: This study utilized data from the METABRIC database to evaluate the risk factors associated with poor survival outcomes among geriatric breast cancer patients. A total of 2909 female patients, 766 of whom were geriatric, were included in the study. The effects of the type of surgery; breast cancer types; cellularity; Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status; molecular class; axillary lymph nodes; Nottingham prognostic index (NPI); status of receiving systemic chemotherapy (SCT), hormone therapy (HT), and radiotherapy (RT); tumor size and tumor on overall survival (OS); and progression-free status (PFS) of geriatric patients were investigated. Additionally, the disease-specific survival of geriatric patients was compared with other patients. Results: HER2 receptor positivity, advanced-stage tumors (T3-T4), a high NPI, and Luminal B subtypes were significant predictors of worse outcomes. Conversely, Luminal A tumors, associated with favorable hormonal responsiveness, demonstrated the best progression-free survival (PFS). HER2-positive patients exhibited a poorer PFS compared to their HER2-negative counterparts, underscoring the need for careful management of aggressive subtypes in older adults. Additionally, patients undergoing mastectomy were less likely to receive adjuvant therapies, contributing to inferior outcomes compared to breast-conserving surgery (BCS). Conclusions: Mastectomy, HER2 positivity, high NPI, advanced stages, and Luminal B tumors are significant prognostic factors in geriatric breast cancer patients.

Transmembrane Amino Acid Transporters in Shaping the Metabolic Profile of Breast Cancer Cell Lines: The Focus on Molecular Biological Subtype.

Amino acid metabolism in breast cancer cells is unique for each molecular biological subtype of breast cancer. In this review, the features of breast cancer cell metabolism are considered in terms of changes in the amino acid composition due to the activity of transmembrane amino acid transporters. In addition to the main signaling pathway PI3K/Akt/mTOR, the activity of the oncogene c-Myc, HIF, p53, GATA2, NF-kB and MAT2A have a direct effect on the amino acid metabolism of cancer cells, their growth and proliferation, as well as the maintenance of homeostatic equilibrium. A distinctive feature of luminal subtypes of breast cancer from TNBC is the ability to perform gluconeogenesis. Breast cancers with a positive expression of the HER2 receptor, in contrast to TNBC and luminal A subtype, have a distinctive active synthesis and consumption of fatty acids. It is interesting to note that amino acid transporters exhibit their activity depending on the pH level inside the cell. In the most aggressive forms of breast cancer or with the gradual progression of the disease, pH will also change, which will directly affect the metabolism of amino acids. Using the cell lines presented in this review, we can trace the characteristic features inherent in each of the molecular biological subtypes of breast cancer and develop the most optimal therapeutic targets.

A systems biology-based study to assess the effects of TNF-alpha ± apigenin in triple-negative breast cancer cell line

Triple-negative breast cancer (TNBC) is a type of breast cancer that lacks estrogen, progesterone, and HER2 receptors. Various treatment methods are available for breast cancer, but therapies with minimal toxic side effects are particularly important. This study computationally investigates the impact of apigenin, a compound used in traditional Chinese medicine, on the TNBC cell line. The GSE120550 dataset was retrieved from the NCBI-GEO database. BRB-ArrayTools were used for pre- and post-processing to identify significantly differentially expressed genes. Additionally, the DAVID web server was utilized to analyze three main components:"biological process," "cellular component," and "molecular function," along with the KEGG signaling pathway. Finally, a Venn diagram was employed to thoroughly investigate the number of shared genes among 15 groups derived from 6 compared sample sets. The primary analysis of 6 pairs of samples revealed significant differentially expressed genes (DEGs), which were prioritized using the TOPPgene web server. These identified genes, playing key roles in inhibiting the progression of BC, are involved in various signaling pathways. Protein-protein interaction network analysis highlighted the biomarkers associated with the inhibitory effects of apigenin across the 15 sets derived from the 6 sample pairs. The findings of this study confirm the inhibitory effects of apigenin, with no toxic side effects, on patients with TNBC. This natural compound holds promise for future therapeutics and novel drug designs.

Prognostic Significance of Immunohistochemical Expression of Cyclin D1 and β-Catenin in Invasive Ductal Carcinoma (IDC)

Introduction: Invasive ductal carcinoma (IDC) is the most prevalent subtype of breast cancer, distinguished by diverse clinical manifestations and molecular heterogeneity. Prognostic outcomes are influenced by multiple factors, including the patient’s age at diagnosis, tumor size, histological grade, disease stage, lymph node metastasis (LNM), and hormone receptor status (ER, PR, HER2). This research has highlighted the potential of emerging molecular biomarkers such as Cyclin D1 and β-Catenin in enhancing prognostic precision. Methodology: This retrospective, cross-sectional study analyzed the medical records of female patients diagnosed with IDC. Tumor size, grade, and stage were examined alongside lymph node involvement to assess the extent of disease dissemination. Immunohistochemistry (IHC) was employed to determine the expression of ER, PR, and HER2 receptors. Additionally, emerging biomarkers such as Cyclin D1 and β-Catenin were evaluated to explore their prognostic value. A total of 150 tumor samples were collected from multiple cancer treatment facilities across Rawalpindi, Punjab, Pakistan. Findings and Discussion: The mean age at diagnosis was 50.6 years, with the majority of patients (68%) between 36 and 55 years. Tumor analysis revealed that 76.7% of lesions were <30 mm in size, and 46.7% were classified as grade II. LNM was detected in 39.3% of patients, indicating significant metastatic potential. Regarding receptor expression, 45.5% of tumors were ER-positive, 42.9% PR-positive, and 54.8% HER2-positive, aligning with global incidence trends. The investigation of molecular markers showed Cyclin D1 overexpression in 60% of cases, predominantly in ER-positive tumors, suggesting better endocrine therapy responsiveness. β-Catenin was detected in 33.3% of samples and correlated with aggressive tumor phenotypes, emphasizing its potential role in identifying high-risk patients. These molecular markers align with globally research. Conclusion: This study emphasizes the significance of early detection and comprehensive molecular profiling in IDC management. Smaller tumors and receptor-positive cases are generally associated with more favorable outcomes. Additionally, emerging biomarkers such as Cyclin D1 and β-Catenin hold promise for refining prognostic models and optimizing individualized treatment plans. Incorporating these biomarkers into clinical practice can further enhance therapeutic decision-making and patient care.

Au@109Pd Core-Shell Nanoparticles Conjugated to Panitumumab for the Combined β--Auger Electron Therapy of Triple-Negative Breast Cancer.

Apart from HER2-positive, triple-negative breast cancer (TNBC) is the second most highly invasive type of breast cancer. Although TNBC does not overexpress HER2 receptors, it has been observed that EGFR protein expression is present in this specific type of tumor, making it an attractive target for immune and radiopharmaceutical treatments. In our current study, we used 109Pd (T1/2 = 13.7 h) in the form of a 109Pd/109mAg in vivo generator as a source of β- particles and Auger electrons in targeted radionuclide therapy for TNBC. 109Pd, obtained through neutron irradiation of the 108Pd target, was deposited onto 15 nm gold nanoparticles to form Au@109Pd core-shell nanoparticles, which were then conjugated to the panitumumab antibody. Au@109Pd-PEG-panitumumab nanoparticles were bound, internalized, and partially routed to the nucleus in MDA-MB-231 human breast cancer cells overexpressing EGFR receptors. The Au@109Pd-panitumumab radioconjugate significantly reduced the metabolic activity of MDA-MB-231 cells in a dose-dependent manner. In conclusion, we have found that Au@109Pd-PEG-panitumumab nanoparticles show potential as a therapeutic agent for combined β--Auger electron targeted radionuclide therapy of TNBC. The simultaneous emission of β-, conversion, and Auger electrons from the 109Pd/109mAg generator, similar to 161Tb conjugates, significantly enhances the therapeutic effect. The partial localization of these nanoparticles into the cell nucleus, provided by the panitumumab vector, ensures effective therapy with Auger electrons. This is particularly important for the treatment of drug-resistant TNBC cells.

Betulinic acid and oleanolic acid modulate CD81 expression and induce apoptosis in triple-negative breast cancer cells through ROS generation.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a lack of hormones receptors and the HER2 receptor, making it unresponsive to targeted therapy. Triterpenoids such as betulinic acid (BA) and oleanolic acid (OA) have anticancer effects by inducing apoptosis in TNBC cells. CD81 is a tetraspanin that affects the growth and metastasis of cancer cells. To examine the effect of BA and OA on the viability of TNBC cell line (MDA-MB 231) by analyzing the CD81 expression, intracellular ROS, and apoptosis. The MDA-MB 231 cells was cultured and treated by BA and OA. The viability cell was evaluated by the CCK8 assay. This study analyzed the binding of BA and OA with CD81 using molecular docking and evaluated CD81 expression, intracellular ROS, and apoptosis by flow cytometry. The result showed that BA and OA inhibited viability of MDA-MB-231 cells. BA and OA bind to CD81 in silico, with binding affinities of 9.0kcal/mol for BA and 7.2kcal/mol for OA. Flow cytometry results revealed that BA can downregulate CD81 expression. BA and OA also increased intracellular ROS levels and induced apoptosis. These findings suggest that BA and OA, especially BA, can modulate CD81 expression and promote apoptosis in TNBC cells through the generation of ROS, thereby offering a potential therapeutic strategy for the treatment of TNBC.

HER2-low breast cancer. Diagnostics, treatment and its adverse events

Introduction: Breast cancer is one of the most commonly diagnosed malignant tumors among women worldwide. HER2 receptor is a protein that plays a role in cell growth, division, and repair. Approximately 50% of HER2 –negative breast cancers express low levels of HER2 receptors. HER2-low breast cancer is a newly characterized subtype of breast cancers that express low levels of HER2 receptor but do not meet the criteria for HER2 positivity and HER2 negative with SCORE - 0 in immunohistochemistry. Recent studies have discovered that HER2-targeted therapies can be effective even at low HER2 expression levels. Aim of study: The purpose of this review was to increase awareness of HER2- low breast cancer. The objective was also to underscore the importance of detecting low and very low expression of HER2 receptors. The other goal of this project is to raise awareness of potential new directions in oncological treatments including antibody–drug conjugates. Materials and methods: The review was based on the analysis of materials collected in the „Pubmed” and Google Scholar databases. The search was performed using the keywords: „HER2-low breast cancer”, trastuzumab deruxtecan antibody–drug conjugates”, „HER2-low diagnostic algorithm”. Conclusion: The results of the DESTINY - Breast04 study shows that trastuzumab-deruxtecan significantly improved both progression-free survival and overall survival among all patients including hormone-positive patients cohort compared to chemotherapy. While trastuzumab-deruxtecan is highly effective, it does come with specific safety considerations that necessitate close monitoring.

Coptisine enhances the sensitivity of chemoresistant breast cancer cells by inhibiting the function and expression of ABC transporters.

Multidrug resistance (MDR), mainly caused by ATP-binding cassette transporters (ABCTs) efflux, makes it difficult for many anticancer drugs to treat breast cancer (BC). Phytochemicals can reverse cancer's MDR by modifying ABC transporter expression and function, as well as working synergistically with anticancer drugs to target other molecules. The reversal effect of the isoquinoline alkaloid coptisine (COP) was assessed on four breast cell lines; Two sensitive MCF-7 cell lines with positive estrogen, androgen, progesterone, and glucocorticoid receptors, as well as MDB-MB-231 cells with negative estrogen, progesterone, and HER2 receptors, and two doxorubicin-resistant cell lines, MCF-7/ADR and MDB-MB-231/ADR. The cytotoxicity of COP and its ability to improve doxorubicin (DOX) cytotoxicity were assessed using the MTT assay. The effectiveness of COP in reversing DOX resistance was evaluated by calculating resistance ratio (RR) values, combination index (CI), and isobologram (IB). The inhibitory effect of COP on ABCT efflux function in comparison to verapamil (VER) was evaluated by measuring the cellular accumulation of Rho123 using flow cytometry. The impact of COP, either alone or in combination with DOX, on the gene expression of ABCTs (P-gp/MDR1, BCRP, and MRP1) of investigated cell lines was assessed by RT-PCR. The COP showed modest cytotoxicity on the examined cell lines. In MCF-7/ADR and MDA-MB-231/ADR cells, COP (31μM) enhanced DOX cytotoxicity with CI (0.77 and 0.75), RR (2.58 and 3.33), and IB suggesting synergism. COP significantly inhibits ABCT function in resistant BC cell lines, increases Rho123 accumulation, and decreases efflux more than VER; 2.1 and 1.2-fold, respectively. The combination of COP and DOX had a strong inhibitory effect on ABCT function (3.1 and 3.9 times VER, P< 0.001) and downregulated the genes and protein expression of ABCT. COP reversed ABCT-mediated multidrug resistance in vitro, indicating its potential as a multidrug resistance-reversing agent in cancer chemotherapy.

Pexidartinib and standard neoadjuvant therapy in the adaptively randomized I-SPY2 trial for early breast cancer.

We investigated the small-molecule receptor tyrosine kinase-inhibitor of colony-stimulating factor-1 receptor pexidartinib in the stage II/III breast cancer in the I-SPY2 platform trial. I-SPY2 is an adaptive platform trial that features multiple arms of experimental agents administered on a background of standard neoadjuvant therapy with paclitaxel and adriamycin/cyclophosphamide, followed by definitive surgery. The adaptive randomization engine preferentially assigns patients based upon cumulative performance of each agent in a given breast cancer subtype based on hormone receptor and HER2 receptor status. The study endpoint is pathologic complete response. A total of 9 participants were randomized to receive pexidartinib with neoadjuvant paclitaxel before enrollment was halted due to a serious adverse event of vanishing bile duct syndrome. No participants received a full course of the study drug. Although there remains interest in agents targeting CSF-1, hepatic toxicity appears to be a limiting factor for their use in early breast cancer. NCT01042379 ( www. gov/ct2/show/NCT01042379 ).

Carcinoembryonic Antigen Expression in Human Tumors: A Tissue Microarray Study on 13,725 Tumors.

Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein serving as a drug target, diagnostic marker, and serum marker for cancer monitoring. However, prevalence data on CEA expression in cancer tissues vary considerably. This study was designed to determine CEA expression in normal and neoplastic tissues. A tissue microarray containing 13,725 samples from 120 different tumor types, as well as 76 different normal tissue types, was analyzed by immunohistochemistry (IHC). CEA was detectable in 65 (54.2%) of 120 tumor categories, including 49 (40.8%) tumor types with at least one strongly positive case. CEA positivity was most common in colorectal adenomas (100%) and carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1-80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), small-cell carcinomas of the lung (64.3%), and urinary bladder (38.9%). CEA overexpression was linked to high tumor grade and invasive growth (p < 0.0001 each) in urinary bladder cancer, and estrogen and HER2 receptor positivity (p ≤ 0.0158) in invasive breast cancer of no special type. In colorectal adenocarcinomas, reduced CEA expression was associated with mismatch repair deficiency (p < 0.0001). The comprehensive list of CEA-positive human tumor types demonstrates that CEA is expressed in a broad range of epithelial neoplasms, many of which might benefit from CEA serum monitoring and anti-CEA therapies.

Development and validation of a radiomics-based nomogram for predicting two subtypes of HER2-negative breast cancer.

Breast cancer is the most common malignant tumor among women, with an increasing incidence each year. The subtypes of human epidermal growth factor receptor 2 (HER2)-negative breast cancer, classified as HER2-low and HER2-zero based on HER2 receptor expression, show differences in clinical characteristics, therapeutic approaches, and prognoses. Distinguishing between these subtypes is clinically valuable as it can impact treatment strategies, including the use of next-generation antibody-drug conjugates (ADCs) targeting HER2-low tumors. This study aimed to develop a nomogram based on dynamic magnetic resonance imaging (MRI) and clinical indicators to differentiate between HER2-low and HER2-zero subtypes in HER2-negative breast cancer patients. This study included 214 breast cancer patients from two centers, Hospital A (Affiliated Hospital of Jining Medical University, n=178) and Hospital B (Ningyang No. 1 People's Hospital, n=36). HER2 status was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Among the participants, 112 cases were identified as HER2-low and 102 as HER2-zero. Patients from Hospital A were split into a training set and an internal test set in an 8:2 ratio, while the 36 patients from Hospital B were used as an external test set. Regions of interest (ROI) were delineated on phase 2 enhanced scans and diffusion weighted imaging (DWI) images, with features selected via Pearson correlation coefficients and least absolute shrinkage and selection operator (LASSO) regression. A K-Nearest Neighbor (KNN) model was employed to calculate the rad score, and clinical predictors (tumor maximum diameter and CA153) were identified through logistic regression analysis. These predictors, combined with the rad score, were incorporated into the final nomogram model. The model's accuracy was evaluated using area under curve (AUC) values in both the internal and external validation sets. The nomogram achieved AUC values of 0.873 and 0.859 in the internal and external validation sets, respectively, demonstrating superior performance over single-feature models. Decision curve analysis (DCA) indicated substantial net clinical benefits, and calibration curves displayed strong alignment between the model's predictions and actual outcomes in both sets. This nomogram shows high accuracy and stability in differentiating HER2-low and HER2-zero subtypes among HER2-negative breast cancer patients, suggesting potential clinical utility in refining treatment decisions and identifying candidates for ADC therapy in HER2-low cases.

Investigation of anticancer potential of a novel bioactive molecule from Trichosporon asahii VITSTB1 in breast cancer cell lines: an in vitro study.

The current study investigates the anticancer activity of protein derived from yeast against breast cancer. Yeast-derived proteins illustrate potential as an anticancer agent through mechanisms, such as immune system stimulation via beta-glucans, cytotoxic effects, and modulation of gut microbiota by probiotic strains. The antioxidant activity of yeast-derived proteins can aid in anticancer activity by neutralizing free radicals, thereby reducing oxidative stress and preventing damage to cellular DNA. Employing a comprehensive methodology encompassing yeast isolation, antioxidant screening, molecular characterization, bioactive protein purification, and MTT assay, the research provides crucial insights into the anticancer attributes of the protein extracted from the yeast. The findings reveal significant antioxidant activity that reduces reactive oxygen species (ROS) levels, which are implicated in cancer development. The MTT assay on MCF-7 breast cancer cell lines, characterized by estrogen receptor and progesterone receptor positivity and HER-2 negativity, determined an IC50 value of 54.89µg/ml, indicating a dose-dependent decrease in cytotoxic effects. These results suggest that the protein derived from Trichosporon asahii VITSTB1 exhibits promising anti-breast cancer properties. Further research is necessary to elucidate the underlying mechanisms, assess efficacy and safety profiles, explore synergies with existing therapies, and conduct animal model studies. Advancing this line of inquiry will significantly contribute to biomedical research and industrial innovation.

Combination therapy of Lapatinib/Letrozole-based protein-vitamin nanoparticles to enhance the therapeutic effectiveness in drug-resistant breast cancer

HER2-positive breast cancer constitutes 20% of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (α-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses—such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines.