Search Results (357)

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread faster than other BC subtypes, and is associated with a poor prognosis due to early visceral and neurological recurrences. Multidisciplinary management includes surgery, chemotherapy, radiation therapy, and immunotherapy with targeted immune checkpoint inhibitors (ICIs). The introduction of ICIs has improved outcomes in patients with TNBC, particularly in the metastatic and neoadjuvant settings. Despite these advances, a significant proportion of patients either do not respond to treatment or develop resistance to it. TNBC mortality remains high, underscoring the urgent need to identify novel prognostic and predictive biomarkers to overcome resistance to immunotherapy. Following a brief overview of the clinical features and established biomarkers of TNBC, the current review focuses on immune checkpoint proteins (ICPs) beyond PD-1 and PD-L1, and on the potential use of soluble ICPs rather than the well-established membrane-bound assays. These soluble ICPs are produced through the alternative splicing of messenger (m)RNA or the cleavage/shedding of membrane-bound proteins. This is followed by an overview of current treatment and novel predictive targets in TNBC. Additionally, the involvement of the B- and T-lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/CD160 pathway and its role in the pathogenesis of BC and TNBC are reviewed, highlighting the potential use of BTLA and HVEM as biomarkers. Full article

Metabolic changes in saliva are known to be closely associated with the presence of non-oral cancers, particularly breast cancer. The diagnostic and prognostic potential of salivary biomarkers in breast cancer has been demonstrated, but their applicability for assessing therapy response has not yet been established. The aim of this study was to comprehensively analyze clinical, pathological, molecular, and salivary characteristics when assessing the response to neoadjuvant chemotherapy for breast cancer. The study included 361 breast cancer patients undergoing their first course of chemotherapy and 127 healthy volunteers without breast pathologies. Saliva samples were collected from all volunteers before treatment. Saliva analysis results for amino acids, lipids, and tumor markers were compared with tumor pathomorphism assessment after breast cancer surgery. The proportion of patients with a complete response to therapy was statistically significantly lower after menopause, and in those with HER2-negative breast cancer, moderate tumor differentiation, and high estrogen and progesterone receptor expression. For the first time, a body mass index (BMI) greater than 25 and low HER2 expression (HER2-low) were shown to have an unfavorable prognosis. The criterion for selecting informative salivary metabolites was a multidirectional change in minimal and complete pathological responses to therapy compared to healthy controls. Thus, prognostically favorable signs were a decrease in the concentration of urea below 7.5 mmol/L (OR = 1.921; 95% CI 1.061–4.270; p = 0.0342), a decrease in the area of the absorption band at 2957 cm⁻¹ below 24 (OR = 3.875; 95% CI 1.160–12.70; p = 0.0003), and an increase in the concentration of cancer antigen CA27.29 above 3 U/L (OR = 2.138; 95% CI 1.021–7.273; p = 0.0343) and CA-15-3 above 39 U/L (OR = 3.896; 95% CI 1.062–14.07; p = 0.0072). With a simultaneous increase in both CA27.29 and CA15-3, the probability of a complete response to therapy increased (OR = 4.288; 95% CI 1.056–17.09; p = 0.0013). Multivariate analysis showed that an independent prognostic indicator, along with the expression status of HER2, estrogen receptors, differentiation degree, BMI, and menopause status, was the concentration of CA15-3 in saliva (AUC = 0.789, 95% CI: 0.737–0.842, p = 0.0001). Identifying new markers will help physicians formulate treatment plans tailored to a patient’s individual risk factors, leading to increased survival and improved quality of life. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The lack of actionable molecular targets contributes to limited therapeutic options, frequent recurrence, and a high propensity for distant metastasis. Metastatic dissemination remains the principal cause of mortality in patients with TNBC and is driven by complex molecular mechanisms involving multiple interconnected signaling networks. This review summarizes current knowledge of the molecular mechanisms underlying metastatic progression in TNBC, with particular emphasis on signaling pathways that regulate tumor invasion, migration, and colonization of distant organs. We discuss the roles of key pathways, including PI3K/Akt, TGF-β, Wnt/β-catenin, NF-κB, and Rho/ROCK signaling, in the regulation of epithelial–mesenchymal transition, cytoskeletal remodeling, cancer stem cell phenotypes, and tumor–microenvironment interactions. A deeper understanding of these signaling networks may facilitate the identification of novel therapeutic targets and support the development of more effective strategies to limit metastatic disease in TNBC. Full article

Background: Progesterone receptor (PR) status plays an important role in guiding hormone therapy decisions in breast cancer. In current practice, PR expression is assessed manually from immunohistochemistry (IHC) slides, which can be time-consuming and may vary between pathologists. This study aims to develop an automated and interpretable framework for PR-IHC analysis to improve consistency and efficiency. Methods: In this work, we developed an AI-assisted pipeline that combines nuclei segmentation, classification, and scoring for PR-IHC images. A fine-tuned Cellpose model was used to segment individual nuclei. The segmented nuclei were then analyzed using a DAB intensity-based approach to classify them into four categories: negative, weak, moderate, and strong. These results were further combined to generate Allred scores. The system was evaluated on 250 PR-IHC images with annotations provided by expert pathologists. Results: The framework achieved strong segmentation performance (F1-score = 0.85, IoU = 0.74) and high classification accuracy (macro F1-score = 0.95). The method also performed well when applied to ER-IHC images without additional retraining. Conclusions: The proposed framework provides a reliable and interpretable approach for automated PR-IHC scoring. It helps reduce manual effort, improves consistency in evaluation, and shows potential for practical use in digital pathology settings. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by the absence of estrogen and progesterone receptors, as well as the lack of human epidermal growth factor 2 receptor overexpression. TNBC is associated with early onset, high metastatic potential, therapeutic resistance, and poor clinical outcomes exacerbated by the limited availability of effective targeted therapies. Advances in multi-omics profiling have further stratified TNBC into distinct molecular subtypes, each exhibiting unique genomic, epigenomic, and immune-related features that influence therapeutic responsiveness. This review explores the interplay between TNBC molecular heterogeneity, immune evasion mechanisms, and epigenetic regulation. TNBC demonstrates variable immunogenicity, with tumor-infiltrating lymphocytes serving as important prognostic and predictive biomarkers. However, immune escape commonly occurs through tumor microenvironment remodeling, T-cell exhaustion, cancer stem cell enrichment, and immune checkpoint pathways activation. Although immune checkpoint inhibitors have improved outcomes in selected patients, particularly in combination with chemotherapy, primary and acquired therapeutic resistance remain a significant challenge. Emerging evidence highlights the central role of epigenetic mechanisms in regulating immune-related gene expression and shaping the tumor immune microenvironment. Epigenetic silencing of antigen presentation machinery, interferon signaling pathways, and chemokine expression contributes to immune evasion and immunotherapy resistance. Importantly, pharmacological modulation of epigenetic regulators can restore immune recognition and induce “viral mimicry” through reactivation of endogenous retroelements, thereby enhancing antitumor immunity. Collectively, this review underscores the therapeutic potential of integrating epigenetic therapies with immunotherapy and chemotherapy to overcome immune resistance in TNBC. A deeper understanding of epigenetic-immune interactions may facilitate the development of more precise and effective treatment strategies tailored to TNBC molecular subtypes. Full article

Background: Patients with estrogen receptor (ER)-positive ductal carcinoma in situ (DCIS) derive a greater benefit from endocrine therapy than patients with ER-negative disease. The relevance of ER status and progesterone receptor (PR) status in DCIS to radiation therapy has not been well explored. Methods: Patients undergoing breast-conserving surgery with or without radiation were grouped by ER and PR status and matched using rank-based Mahalanobis optimal matching with respect to lesion size and grade and patient age and race. Cumulative incidences were estimated and competing risk regressions with subdistribution hazard ratios (sHRs) were calculated. Results: Among patients who underwent breast-conserving surgery only, 369 patients with ER-PR- disease were matched to 738 patients with ER+PR+ disease (1:2 matching). In multivariate models, patients with ER-PR- disease were at increased risk of any invasive events (sHR = 2.47, p = 0.007) and early ipsilateral invasive events (sHR = 2.64, p = 0.02 in the 0-to-4-year period) relative to patients with ER+PR+ disease. Among patients who underwent breast-conserving surgery with adjuvant radiation, 1498 patients with ER+PR+ disease were matched to 1498 patients with ER-PR- disease. No significant differences were noted with respect to cumulative incidence of any invasive event (5.6% vs. 5.6%) or ipsilateral invasive events (1.9% vs. 2.9%). In multivariate models, no significant differences were noted. Patients with ER-PR+ lesions had similar cumulative incidences of ipsilateral invasive events to patients with ER-PR- disease in the absence of radiation (5.9% vs. 5.9%) and similar cumulative incidences of contralateral invasive events to patients with ER+PR+ disease when radiation was administered (3.2% vs. 4.2%). Conclusion: The statuses of ER and PR carry independent prognostic and therapeutic implications beyond those of traditional clinicopathologic risk factors. Given that ER and PR statuses are routinely collected for patients with DCIS, incorporation of these variables into clinicopathologic risk classification systems is warranted. Full article

Background/Objectives: Bone is the most common organ affected by distant metastasis in advanced breast cancer, and the development of skeletal-related events (SREs) often leads to significant deterioration in patients’ quality of life and survival outcomes. In this study, we aimed to explore the risk factors associated with bone metastasis in breast cancer and to develop a predictive nomogram for identifying high-risk patients, which may facilitate timely preventive interventions and improve clinical prognosis. Methods: A retrospective analysis was conducted on 672 patients with breast cancer who underwent surgery at the Fourth Hospital of Hebei Medical University (Shijiazhuang, China) between 2013 and 2023; this cohort served as the training set. Clinical and pathological characteristics potentially influencing bone metastasis—including age, menopausal status, histological grade, affected side, maximum tumor diameter, lymph node staging, TNM staging, ER status, PR status, HER-2 status, Ki-67, molecular subtypes, vascular tumor thrombus, nerve infiltration and visceral metastasis—were collected. The median follow-up time was 42 months. Patients were stratified into two cohorts based on whether postoperative bone metastasis occurred, with groups matched according to Tumor–Node–Metastasis (TNM) stage. Univariate and multivariate logistic regression models were applied to identify independent factors associated with breast cancer bone metastasis, and a nomogram prediction model was constructed using the variables retained in the final analysis. For external validation, data from 2814 patients with breast cancer who underwent surgery between 2013 and 2021 were extracted from the U.S. Surveillance, Epidemiology, and End Results database. Results: The multivariate logistic regression analysis revealed that histological grade (p = 0.002), progesterone receptor (PR) negativity (p = 0.001), human epidermal growth factor receptor 2 (HER-2) negativity (p = 0.002) and visceral metastasis (p < 0.001) were identified as independent predictors of bone metastasis in breast cancer. A nomogram predictive model was established using these four factors. The area under the receiver operating characteristic curve was 0.720 (95% confidence interval (CI): 0.6797–0.7607) for the training cohort and 0.701 (95% CI: 0.6813–0.7205) for the external validation cohort. Decision curve analysis further confirmed the clinical applicability of the model. Conclusions: The present study confirms that histological grade, PR status, HER-2 status and visceral metastasis are independent factors associated with bone metastasis in breast cancer. The constructed nomogram may effectively predict breast cancer-related bone metastasis and could serve as a practical tool for clinical decision-making. Full article

Triple-negative breast cancer (TNBC) represents 10–20% of breast cancers and is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, leaving cytotoxic chemotherapy as the main systemic treatment. However, rapid development of resistance, via drug efflux, enhanced DNA repair, apoptosis evasion, epithelial-to-mesenchymal transition, and tumor microenvironment protection, limit long-term efficacy. Small interfering RNA (siRNA) therapeutics can silence key resistance drivers, but their clinical potential is hindered by instability, poor biodistribution, and off-target effects. Nanocarrier-based delivery systems offer solutions by protecting siRNA, enhancing tumor accumulation, enabling targeted intracellular release, and permitting co-delivery with chemotherapeutics for synergistic effects. We conducted a narrative review in PubMed from database inception to August 2025. The included studies demonstrated that lipid, polymeric, inorganic, and hybrid nanocarriers can achieve efficient target knockdown, reverse drug resistance mechanisms, and significantly enhance antitumor responses in resistant TNBC models. Several platforms also reduced metastatic spread and improved survival in vivo. While preclinical results are compelling, clinical translation remains limited by incomplete safety profiling and heterogeneity in delivery efficiency. This review synthesizes mechanistic insights and delivery innovations, outlining a roadmap for translating siRNA-loaded nanocarriers into effective therapies for chemoresistant TNBC. Full article

Background/Objectives: EndoPredict is a second-generation prognostic assay for estrogen-receptor-positive, HER2-negative breast cancer that integrates molecular and clinical parameters for risk stratification. Multiple studies have reported its clinical utility, while differences in the proportion of patients classified as high- or low-risk have been observed across cohorts. This study aimed to characterize clinical, pathological, and demographic factors associated with these differences. Methods: We conducted a descriptive review of 17 published studies and analyzed a single-institution cohort of 140 patients. Associations between clinicopathological variables and high-risk classification were assessed, including tumor size, lymph node status, histological grade, Ki-67 expression, and reproductive and demographic factors. Differences in inclusion criteria and cohort characteristics were also examined. Results: Tumor size and lymph node involvement emerged as primary determinants of high-risk classification. A high histological grade and Ki-67 levels above 25% were significantly associated with high-risk status (p < 0.001). Conversely, age, age at menarche, menopausal status, Body Mass Index, progesterone receptor expression, molecular subtype, and histological type showed no significant association. A higher number of pregnancies correlated with a lower frequency of high-risk classification (p < 0.01). Heterogeneity in risk distribution across studies was largely attributable to differences in tumor size, nodal involvement, and histological grade. Additional variability was associated with inclusion criteria, sample selection, and regional demographic characteristics. Conclusions: Variability in EndoPredict risk classification reflects both tumor biological features and population-specific factors. These findings emphasize the importance of interpreting genomic risk scores within their clinical and demographic context and support the comparison of risk distributions across heterogeneous patient cohorts. Full article

Background and objectives: Early biomarkers that can reliably predict treatment outcomes during CDK4/6 inhibitor therapy remain an unmet clinical need in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (MBC). Metabolic changes on ^18F-FDG PET/CT may precede radiologic response and provide insight into tumor biology and early treatment resistance. Methods: This two-center retrospective study included 203 patients with HR+/HER2− MBC who received first-line CDK4/6 inhibitors (ribociclib or palbociclib) plus endocrine therapy between 2018 and 2024. Baseline and interim ^18F-FDG PET/CT scans performed after 2–4 cycles were evaluated. Early metabolic response was defined as a ≥30% reduction in SUVmax on the most metabolically active lesion, consistent with PERCIST 1.0. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and multivariable Cox models. ROC analysis assessed the discriminative performance of ΔSUVmax for predicting disease progression. Results: Among 203 patients, 153 (75.4%) achieved a ≥30% SUVmax reduction. Responders had significantly longer PFS (median 44.4 vs. 4.8 months; p < 0.001) and OS (median not reached vs. 32.0 months; p < 0.001). Metabolic response remained independently associated with improved PFS (HR 0.24; 95% CI 0.15–0.37; p < 0.001) and OS (HR 0.37; 95% CI 0.20–0.67; p = 0.001) after adjustment for tumor grade, endocrine resistance, and visceral disease involvement. Non-responders demonstrated more aggressive baseline features, including higher rates of liver (34.0% vs. 15.0%) and brain metastasis (10.0% vs. 1.3%), as well as lower progesterone receptor expression (median 30% vs. 60%). Conclusions: Early metabolic response assessed by SUV-max on interim ^18F-FDG PET/CT is independently associated with substantially improved PFS and OS in HR+/HER2− MBC receiving treatment with CDK4/6 inhibitors. Although the predictive accuracy of ΔSUVmax alone was modest, the strong survival gradient suggests meaningful prognostic value. Prospective studies with standardized imaging time points and comprehensive metabolic metrics are warranted to define the role of PET-guided treatment adaptation: Full article

Cutaneous metastases are an uncommon but clinically relevant manifestation of breast cancer (BC), often indicating advanced disease and biological progression. Temporal heterogeneity between primary tumors and metastatic lesions, particularly involving hormone receptors (HRs) and HER2 status, may influence prognosis and treatment decisions. We retrospectively analyzed BC patients with cutaneous metastases diagnosed at a tertiary care center between 2015 and 2024. Clinical data, histopathological features, and immunohistochemical profiles of estrogen receptor (ER), progesterone receptor (PgR), and HER2 were evaluated in paired primary tumors and cutaneous metastatic lesions under uniform pre-analytic and analytic conditions. Receptor discordance and survival outcomes were assessed. Among 660 patients with metastatic BC, 28 (4.2%) developed cutaneous metastases. Median age at diagnosis was 63 years, with chest wall as the most frequent site of skin involvement. HR-positive/HER2-negative tumors were predominant, while triple-negative breast cancer accounted for 19.4% of cases and was associated with a shorter disease course and earlier cutaneous metastatic spread. Receptor discordance occurred in 18.2% for ER, 36.4% for PgR and 41.4% for HER2, mainly involving transitions to or from HER2-low status. After skin involvement, prognosis remained poor. Cutaneous BC metastases show marked receptor heterogeneity, reflecting dynamic tumor evolution. These findings support re-biopsy and biomarker reassessment to guide personalized treatment in metastatic BC. Full article

Background/Objective: Breast cancer (BC) management has traditionally relied on static clinicopathologic and immunohistochemical biomarkers (hormone receptor status, HER2 expression, and proliferative activity assessed at diagnosis). However, these biomarkers are typically evaluated at a single time point and may not reflect therapy-induced molecular evolution. This study evaluates whether longitudinal molecular profiling before and after treatment better characterizes tumor dynamics and provides clinically actionable insights into treatment response, resistance, and prognosis. Methods: Thirty-two patients with invasive breast carcinoma were analyzed using histopathology, immunohistochemistry, tissue-based next-generation sequencing, and plasma circulating tumor DNA (ctDNA) analysis. Paired tumor tissue and plasma samples were collected before and after treatment when available. Changes in biomarker expression, molecular subtype, and genomic alterations were assessed to characterize molecular plasticity under therapeutic pressure. Results: The cohort had a median age of 54 years (range 29–86), predominantly invasive ductal carcinoma (>85%), and high-grade disease. Hormone receptor-positive tumors accounted for 78.1%. Molecular subtypes were Luminal A (34.4%), Luminal B HER2− (40.6%), Luminal B HER2+ (6.3%), HER2-enriched (6.3%), and triple-negative breast cancer (12.5%). Initial tissue sequencing identified PI3K/AKT pathway alterations in 28.1% of cases. Post-treatment analyses revealed substantial molecular discordance, including progesterone receptor loss (33.3%), HER2 status changes (33.3%), and Ki67 variability (77.8%). Plasma ctDNA analysis was informative in 53.1% of patients and identified additional clinically relevant alterations, including FGFR1 amplification and BRCA1/2 variants not detected in tissue. Conclusions: BC molecular profiles are dynamic and frequently altered by therapy. Longitudinal molecular assessment reveals clinically actionable changes overlooked by static subtyping, supporting a dynamic model of molecular classification, highlighting the potential value of adaptive molecular subtyping to improve treatment stratification and resistance monitoring. Full article

The risk of developing some types of head and neck squamous cell carcinoma (HNSCC) is seven times higher in males, and such disparities may not be associated only with tobacco and alcohol consumption or HPV infection. Therefore, the endocrine microenvironment is considered another risk factor, as epidemiologic studies have unequivocally shown the protective effect of estrogen in women. This research was focused on progesterone receptors (PRs), the least-studied sex hormone receptors in HNSCC. Our study included fresh tissue samples from 95 primary tumors, 25 metastatic lymph nodes and 40 healthy oral mucosa. Gene expression of nuclear (PGR) and seven membrane PRs (PAQR5, PAQR6, PAQR7, PAQR8, PAQR9, PGRMC1 and PGRMC2) was analyzed by qRT-PCR and associated with clinicopathological characteristics. The results showed that, compared to control tissue, PGR was increased in metastatic lymph nodes, while PAQR5, PAQR7, PAQR8 and PAQR9 were decreased in primary tumors (all p < 0.05). The expression of almost all PRs was greater in older patients and showed moderate to strong positive mutual correlations in both tumors and controls. PARQ8 and PAQR9 were increased in females and pT4 tumors (all p < 0.05). Survival analysis showed that higher PAQR5 (hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.19–6.57, p = 0.019) and PAQR7 (HR 2.0, 95% CI 1.01–3.81, p = 0.048) were associated with worse overall survival, but their independence was not proven in multivariate analysis. Although most PRs were reduced in primary tumors, an increased PAQR5 expression, also associated with tumor invasion markers, could likely mark a specific aggressive, advanced stage of primary tumors and potentially serve as a negative prognostic biomarker for HNSCC. Full article

Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes, lacking expression of estrogen receptor, progesterone receptor, and HER2. Conventional chemotherapy and immune checkpoint inhibitors provide some benefit, but resistance and relapse are frequent. The search for novel targets has therefore become central to developing more effective and durable therapies. Recent advances in proteomics, structural biology, and targeted protein degradation are rapidly expanding the repertoire of actionable molecules in TNBC. This review summarizes current and emerging therapeutic strategies for TNBC, with a focus on targeted approaches designed to address tumor heterogeneity and resistance mechanisms. To this end, recent advances in targeted therapies are examined, including immune checkpoint inhibitors, PARP inhibitors, Trop-2–directed antibody–drug conjugates, anti-angiogenic agents, PI3K/Akt/mTOR pathway inhibitors, androgen receptor antagonists, and CDK4/6 inhibitors, highlighting results from completed and ongoing clinical trials. In addition, we explore novel targets identified through integrative omics approaches, as well as the role of the tumor metabolism and microenvironment in modulating therapeutic efficacy. Finally, we outline innovative radiotherapy strategies based on targeted radiation delivery and biological integration with systemic therapies. Collectively, this review provides an updated and novel overview of the evolving TNBC therapeutic landscape and highlights promising directions for the development of next-generation, biomarker-driven treatment strategies aimed at improving patient outcomes, maintaining a broad perspective on a very large class of targets. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking estrogen, progesterone, and HER2 receptors. This characteristic limits the effectiveness of hormonal and targeted therapies, and despite advances in chemotherapy (ChT), radiotherapy (RT), surgery, targeted therapy (TT) and immunotherapy (IT), clinical outcomes remain poor, highlighting an urgent need for new therapeutic strategies. The development of advanced nanotechnology-based strategies has opened new avenues for the diagnosis and therapy of TNBC. This review focuses on photothermal therapy (PTT) combined with nanotechnology-based strategies. PTT constitutes an emerging modality for oncological treatment that leverages light irradiation, mostly in the near-infrared (NIR) spectral region, to induce the localized thermal ablation of malignant tissues. When combined with gold nanoparticles (AuNPs), PTT is significantly potentiated. AuNPs have distinctive optical and physicochemical characteristics, rendering them highly effective as multifunctional nanoplatforms. Upon irradiation, AuNPs act as efficient photothermal agents, inducing localized hyperthermia. This thermal effect disrupts cellular homeostasis and initiates a cascade of cell death pathways, including apoptosis and necrosis, culminating in tumor regression. This review describes the latest therapeutic advances of PTT and AuNPs. As this innovative approach progresses toward clinical application, future studies and trials will be crucial in determining its potential for TNBC management and improving patient outcomes. Full article