Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It accounts for ~15% of breast cancer diagnoses, and disproportionally affects young women and those of African and Hispanic ancestry. This review encompasses recent advances in the management of early and advanced-stage TNBC. The identification of distinct molecular subtypes of TNBC has allowed for the optimization of systemic therapy. Distinct drivers of TNBC have been identified, resulting in the regulatory approval of targeted therapies for early and advanced stage disease, including immunotherapy, PARP inhibitors, and antibody-drug conjugates. Literature search was performed using PubMed, and included publications between 01/2010 to 11/2025. Until recently, the only treatment available for TNBC was chemotherapy. Advances in the molecular characterization of TNBC has revealed distinct subtypes, enabling the development and approval of targeted therapies, including PARP inhibitors, immunotherapy, and antibody-drug conjugates. Treatment options for both early and advanced-stage TNBC are improving, although it remains the subtype with the poorest outcomes. Ongoing trials are focused on personalizing treatment through predictive biomarkers, response-adaptive strategies, and novel agents, with the goal of maximizing efficacy while minimizing toxicity.

Colorectal cancer (CRC) adjuvant therapy is evolving from tumor-node-metastasis stage-based strategies toward molecular-profiling-guided precision medicine. This minireview, based on a comprehensive literature search in PubMed and Web of Science using keywords related to CRC biomarkers and adjuvant therapy (from 2010 to 2025), examines how key biomarkers, including mismatch repair (MMR) status, rat sarcoma viral oncogene homolog/rapidly accelerated fibrosarcoma mutations, consensus molecular subtypes, and circulating tumor DNA, refine risk stratification and treatment selection. Despite consensus guidelines advocating individualized therapy, significant disparities persist in real-world implementation due to technical variability in testing, limited or evolving evidence for specific scenarios (e.g. , adjuvant immunotherapy for MMR-deficient/microsatellite instability-high patients, wherein phase 3 trials such as ATOMIC have yet to report mature overall survival data), and health economic barriers. The minireview analyzes gaps across testing, decision-making, and dynamic monitoring phases, and proposes integrated solutions involving technological innovation (e.g. , artificial intelligence-integrated multiomics, circulating tumor DNA monitoring), optimized clinical pathways, and supportive health policies. Bridging these gaps requires multidisciplinary collaboration to translate molecular insights into equitable, personalized adjuvant care for CRC patients.

Clear cell renal cell carcinoma (ccRCC) exhibits strong heterogeneity and variable therapeutic responses. PANoptosis, an integrated form of inflammatory programmed cell death, may influence tumor immunity and prognosis, yet its role in ccRCC remains unclear. Multi-omics data from TCGA database were analyzed to characterize PANoptosis-related genes (PRG), define molecular and gene subtypes, and construct a prognostic PRG score using Cox and LASSO regression. Immune infiltration, drug sensitivity, and predicted immunotherapy response were evaluated. Single-cell RNA sequencing analysis was used to map PRG expression across cell populations. In vitro experiments were performed to validate RBCK1 function in ccRCC. 14 PRG showed marked CNV alterations and differential expression. Three PRG molecular subtypes displayed distinct survival outcomes and immune landscapes. A three-gene PRG score (RIPK1, PYCARD, RBCK1) independently stratified prognosis and correlated with immune infiltration, mutation burden, and therapy sensitivity. Lower scores predicted better immunotherapy response and higher drug sensitivity. Single-cell analysis revealed broad PRG expression across macrophages, epithelial cells, endothelial cells, and stem-like cells. RBCK1 was significantly upregulated in ccRCC and promoted proliferation and migration, while its knockdown inhibited tumor cell growth. We delineated the PANoptosis landscape in ccRCC and developed a robust PRG score with strong prognostic and immunological relevance. RBCK1 functions as a key oncogenic regulator and potential therapeutic target. These findings offer a valuable framework for precision risk assessment and treatment optimization in ccRCC.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, abemaciclib, dalpiciclib) combined with endocrine therapy (ET) were a major advance in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) worldwide. Notably, clinical activity has also been observed in HR+HER2-positive (HER2+) MBC, with significant progression-free survival (PFS) benefits. Cyclin-dependent kinases 4/6 (CDK4/6) are downstream of HER2 and pathways driving resistance to HER2-targeted therapies. However, clinical development of CDK4/6i in HER2+ MBC slowed, given the advent of highly effective tyrosine-kinase inhibitors (TKIs) (i.e., tucatinib) and antibody–drug conjugates (ADCs) (i.e., trastuzumab deruxtecan), which currently dominate the treatment armamentarium. The observation that luminal disease defined by a predictive analysis of microarray 50 (PAM50) was independently associated with a significantly longer PFS versus nonluminal disease was important, with researchers inferring that intrinsic molecular subtypes could be used to identify patients most suitable for ET + CDK4/6i + HER2-targeted treatment. Subsequently, the phase III PATINA trial (which included patients with 1L HR+HER2+ MBC, treated with palbociclib vs. placebo with maintenance ET+ H[P]) noted a striking PFS improvement of >15 months in the palbociclib arm, renewing interest in CDK4/6i-based treatments for HR+HER2+ MBC. Herein, we review the development of CDK4/6i in HER2+ BC, discussing current challenges and potential future directions.

Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA). Approximately 10–16% of iCCA cases harbor FGFR2 fusions or rearrangements, defining a distinct molecular subtype characterized by sensitivity to FGFR-targeted therapies. Selective FGFR tyrosine kinase inhibitors, including the reversible inhibitor pemigatinib and the irreversible inhibitor futibatinib, have demonstrated clinically meaningful response rates and durable disease control in patients with previously treated FGFR2-altered iCCA, leading to regulatory approvals and the incorporation of FGFR inhibition into contemporary treatment paradigms. However, the development of acquired resistance—most commonly driven by secondary kinase-domain mutations and activation of bypass signaling pathways—remains a major limitation to sustained therapeutic benefit. This review summarizes the biological basis of FGFR2 alterations, highlights current clinical evidence supporting FGFR inhibition, and discusses the evolving landscape of resistance mechanisms. We further examine emerging therapeutic strategies aimed at overcoming resistance, including next-generation FGFR inhibitors and rational combination approaches. In addition, we highlight the growing role of circulating tumor DNA as a noninvasive tool for longitudinal molecular monitoring and treatment guidance. Together, these insights underscore the central role of FGFR2-directed therapy in precision oncology for biliary tract cancer and provide a framework for optimizing and extending targeted treatment in this molecularly defined disease subset.

Polyamine homeostasis is essential for normal cellular function and is maintained through coordinated regulation of polyamine biosynthesis, catabolism, and transport. This balance is frequently disrupted in breast cancer, a biologically heterogeneous disease comprising distinct molecular subtypes. However, whether polyamine metabolism and transport are differentially regulated across breast cancer subtypes remains poorly defined. Here, we systematically interrogate polyamine homeostasis across representative breast cancer subtypes by integrating cell line profiling combined with analysis of publicly available patient datasets. We found subtype-associated differences across the polyamine pathway and identify polyamine transport as a key contributor to inter- and intra-subtype heterogeneity. Notably, ATP13A3 emerges as a previously unrecognized adverse prognostic marker, particularly in basal-like breast cancer, where its expression associates with proliferative and oncogenic signaling programs. In contrast, ATP13A2 shows an opposing association with patient survival, suggesting divergent functional roles for these closely related transporters. Together, our findings demonstrate that polyamine regulation in breast cancer is highly subtype dependent and highlight the importance of molecular stratification when considering polyamine-directed therapeutic strategies in breast cancer.

Colon adenocarcinoma (COAD) is a heterogeneous malignancy whose molecular complexity limits effective therapy. Existing transcriptome-based classifications capture only part of this diversity. To refine COAD stratification, we integrated genomic, epigenomic, and transcriptomic data from 297 The Cancer Genome Atlas patients. Ten complementary clustering algorithms were combined through a consensus ensemble framework to ensure robust and unbiased subtype discovery. The resulting molecular subtypes were characterized by genomic alterations, signaling pathways, tumor microenvironment features, and predicted therapeutic responses. As a result, four reproducible molecular subtypes (CS1-CS4) were identified. CS1 displayed enrichment of extracellular matrix organization and epithelial-mesenchymal transition signatures, suggesting invasive potential. CS2 exhibited transcriptional similarity to PD-1 responders, indicating potential benefit from immune checkpoint blockade. CS3 represented a mutation-driven subtype with frequent APC, TP53, and KRAS alterations and extensive copy number gains. CS4 showed the highest immune infiltration, elevated tumor mutational burden, and enhanced sensitivity to 5-fluorouracil and cetuximab. Validation across four independent cohorts confirmed the reproducibility of these subtypes. This integrative multi-omics framework refines the molecular taxonomy of COAD, revealing immunologically active and therapeutically distinct subgroups. The classification not only bridges genomic, epigenomic, and transcriptomic regulation but also provides a practical roadmap for precision oncology by linking molecular features to potential treatment strategies.

Study DesignRetrospective cohort study.ObjectiveSpinal metastases are common in patients with breast cancer, and accurate estimation of postoperative survival is crucial for selecting appropriate candidates for metastasis surgery. This study investigated the association between breast cancer subtype, according to the St. Gallen classification, and survival after surgery for spinal metastases with the aim of improving prognostic assessment and supporting informed patient counselling.MethodsThis study included 110 patients with breast cancer who underwent surgery for spinal metastases identified from the Swedish Spine Register and the Swedish National Quality Register of Breast Cancer. Patients were categorized in terms of the breast cancer subtype according to the St. Gallen classification. Postoperative survival was analysed using Kaplan-Meier estimates and a Cox proportional hazards model.Results: The overall median survival following spinal surgery was 25months (95% CI 19-31), while the median postoperative survival by subtype was 39months (95% CI 28-50) for luminal A patients, 20months (95% CI 9-31) for luminal B patients, and 48months (95% CI 20-76) for luminal B/HER2+ patients. The median survival was not reached for the nonluminal HER2+ group, whereas patients with triple-negative breast cancer had a median survival of only 5months (95% CI 4-6). The St. Gallen subtype was significantly associated with postoperative survival according to univariable (P<0.001) and multivariable analyses (P = 0.011).ConclusionsBreast cancer subtype according to the St. Gallen classification was significantly associated with survival after surgery for spinal metastases. These findings indicate that the St. Gallen classification may serve as a valuable prognostic tool in the metastatic spine setting. Incorporation of molecular subtype information may improve estimation of postoperative survival and support informed patient counselling, expectation management, and individualized surgical decision-making in patients with breast cancer spinal metastases.

This study aimed to identify prognostic biomarkers for gastric cancer (GC) by analyzing the methylation status of multiple tumor suppressor genes. Using the Epi-TOP™ methylation detection system, we analyzed 51 genes in 169 matched tumor and adjacent normal tissue samples. Methylation levels were quantified as Percent Methylated Reference (PMR) in tumor (PMR-T) and normal (PMR-N) tissues; the differential methylation (PMR-D) was also calculated. Tumor tissues exhibited significantly higher DNA methylation levels than matched normal tissues across 51 tumor suppressor genes (all p < 0.001). Clustering analysis based on PMR-T identified four epigenetic subtypes associated with known molecular classifications (epithelial-mesenchymal transition (EMT) and microsatellite instability-high (MSI-H)) and overall survival (p = 0.030). In contrast, clustering based on PMR-N showed no significant association with molecular subtypes or survival outcomes, suggesting limited prognostic relevance. Two prognostic gene panels were constructed: one PMR-T-based panel (ALX, BMP3, CDKN2A, MINT25, PTGDR) and another PMR-D-based panel (ADCYAP1, SOCS1, SEPTIN9, CDKN2B). Both panels independently predicted overall survival in multivariate Cox regression. The PMR-D panel demonstrated stronger prognostic performance (hazard ratio (HR) = 0.329, p = 0.002), while the PMR-T panel also demonstrated significant prognostic value (HR = 0.512, p = 0.012), highlighting that tumor methylation profiles alone may provide meaningful survival predictions for patients with GC. This study demonstrates that tumor-specific DNA methylation changes, particularly when evaluated using multi-gene panels can enhance prognostic stratification in GC. These findings support the potential use of methylation-based biomarkers for personalized management of GC.

ABSTRACTObjectiveThe study is to investigate differential signaling pathways within the tumor microenvironment across molecular subtypes of breast cancer (BC).MethodsSingle‐cell RNA (scRNA‐seq) sequencing data of BC samples were obtained from the Gene Expression Omnibus database. Cell types were identified using the SingleR package, in conjunction with the analysis of marker genes. Subsequently, Monocle was used for pseudotime analysis of epithelial cells, fibroblasts, and macrophages to characterize their differentiation states. CellChat was employed to study the ligand‐receptor interactions among various cell types across different BC molecular subtypes. In addition, we used common bulk RNA sequencing data from The Cancer Genome Atlas to investigate the correlation between key signaling pathway factors identified by scRNA‐seq and clinical outcomes.ResultsInference of copy number variation analysis using T cells revealed significantly elevated copy number variation scores in epithelial cells and fibroblasts. In the communication between epithelial cells and fibroblasts, the ANGPTL pathway is critical in estrogen receptor‐positive breast cancer (ER+BC), while the PTN pathway plays a key role in both ER+BC and human epidermal growth factor receptor 2‐positive breast cancer (HER2+BC), and the GAS pathway is associated with poor prognosis in triple‐negative breast cancer (TNBC). In the interaction between fibroblasts and macrophages, the macrophage subpopulation supporting tumor angiogenesis exhibits significant activity in ER+BC, with the associated SPP1 and GRN pathways strongly influencing tumor progression. The SEMA3 pathway mainly acts through dividing tumor‐associated fibroblast clusters across all BC subtypes. When exploring the role of lymphocytes, the PTN pathway also plays a role in HER2+BC, while in TNBC, CXCL and CD70 pathways are significantly involved in immune response modulation.ConclusionOur comprehensive analysis of cell–cell communication networks among epithelial cells, fibroblasts, macrophages, and lymphocytes across BC subtypes focuses on ligand‐receptor interactions. This study revealed that certain molecules within these networks exhibit significant prognostic value and therapeutic promise.

Although hyperthermic intraperitoneal chemotherapy (HIPEC) added to cytoreductive surgery shows promise for colorectal cancer with peritoneal metastases (CRC-PM), effectiveness remains variable. Given the predominance of consensus molecular subtype 4 (CMS4) in CRC-PM and resistance to standard agents, we hypothesized CMS4 exhibits distinct drug sensitivities. Drug sensitivity data from the DepMap PRISM Repurposing Dataset for 34 CRC cell lines were classified into the 4 CMS subtypes. Five intraperitoneal agents were analyzed: mitomycin-C, oxaliplatin, irinotecan, 5-fluorouracil, and cisplatin. Differential drug response among CMS subtypes was assessed using log2 fold change (log2FC) in cell viability. The 34 CRC cell lines were classified into 4 categories: CMS1 (29%), CMS2 (18%), CMS3 (26%), and CMS4 (26%). CMS4 cell lines demonstrated higher sensitivity than CMS2 lines to mitomycin-C (median log2FC = -2.35 versus -0.21, p = 0.019). CMS4 and CMS3 cell lines were significantly more sensitive to irinotecan than CMS1 and CMS2 cell lines (p = 0.004). Oxaliplatin, 5-fluorouracil, and cisplatin showed no differential sensitivity across subtypes. CMS4 cell lines demonstrated sensitivity (sensitivity threshold log2FC < -1.74) to mitomycin-C and irinotecan but showed lack of sensitivity to oxaliplatin, 5-fluorouracil, and cisplatin. CMS4 exhibits distinct drug sensitivity patterns that could guide personalized HIPEC agent selection. This may explain the success of mitomycin-C and the limited efficacy of oxaliplatin in HIPEC trials. Future clinical trials should consider genomic subtyping and drug sensitivity testing to guide personalized HIPEC strategies for patients with CRC-PM.

Clinicopathologic and Molecular Features of Tubo-Ovarian Carcinosarcomas with an Emphasis on p53 Wild-Type, KRAS-Mutated Tumors.

Updated 5-year Survival Results from PURE-01, a Phase 2 Study of Neoadjuvant Pembrolizumab Followed by Radical Cystectomy in Patients with Muscle-invasive Bladder Cancer.

Introduction Ulcerative colitis (UC) is a lifelong, chronic inflammatory disorder, characterized by recurrent and diffuse inflammation of the rectal and colonic mucosa. Increasing evidence suggests that impaired mitophagy contributes to immune dysregulation and epithelial injury in UC. However, the mitophagy-related molecular landscape and its therapeutic potential remain largely unexplored. Methods Mitophagy-related genes (MRGs) were intersected with differentially expressed genes to identify UC-associated MRGs. Functional enrichment, immune infiltration, and consensus clustering analyses were performed to characterize molecular subtypes. Three machine learning methods were employed to identify diagnostic models. Candidate therapeutic agents were identified by the CMap database. Results A total of 35 UC-associated MRGs were identified, enriched in cell activation, fatty acid metabolism, and the PPAR signaling pathway, revealing strong immunometabolic coupling in UC. Consensus clustering stratified UC patients into two subtypes: a metabolism-dominant subtype (C1) and an inflammation-activated subtype (C2). Three hub genes—CD55, CPT1A, and SLC16A1—were screened and validated as robust diagnostic markers. Drug prediction and molecular docking revealed strong binding between galunisertib and CD55, which was further validated by molecular dynamics simulations. In vitro , galunisertib significantly suppressed inflammatory cytokine release in LPS-induced UC cell models. Discussion This study delineated the mitophagy-related molecular signatures of UC and identified CD55, CPT1A, and SLC16A1 as key biomarkers linking mitochondrial dysfunction, metabolic reprogramming, and immune activation. Furthermore, galunisertib was proposed as a potential therapeutic agent, providing a theoretical basis for UC therapy.

The development of endometrial cancer is a gradual malignant transformation process driven by multiple factors, and the immune microenvironment is closely related to clinical outcomes and immunotherapy responses. Under physiological conditions, the immune microenvironment of the normal endometrium undergoes periodic reshaping under the regulation of estrogen and progesterone, maintaining the balance between immune defense and reproductive capacity. However, continuous exposure to risk factors, such as non-antagonistic estrogen, may trigger endometrial intraepithelial neoplasia. During this period, the immune microenvironment becomes dysregulated, supporting malignant progression. For example, estrogen-stimulated interactions between endothelial cells and macrophages, elevated neutrophil/lymphocyte ratios, and the accumulation of regulatory T cells all combine to cause dysregulation of immune microenvironment. The abnormal immune microenvironment that occurs in the precancerous lesion stage interacts with systemic and genetic carcinogenic factors, ultimately shaping the unique immune microenvironment of each molecular subtype of endometrial cancer. POLE-mutated and MSI-H subtype endometrial cancer are immune-infiltrated tumors, whereas the copy-number high subtype is immune-suppressive tumor and the copy-number low subtype is immune-desert tumor. However, still little is known about the immune dysregulation that occurs during the precancerous stage and its impact on subsequent malignant progression. This review systematically describes the changes in the immune microenvironment during the process from normal endometrium to endometrial cancer, emphasizing that endometrial intraepithelial neoplasia is a key stage of immune imbalance, thus paving the way for early immune intervention and precise immunotherapy.

Background: Breast cancer has emerged as the most common malignancy among Indian women, increasingly affecting younger populations. Determination of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) status plays a pivotal role in molecular classification and therapeutic decision-making. Aims and Objectives: This study aimed to assess the expression of ER, PR, and HER2/neu receptors, evaluate tumor proliferative index using Ki-67, and classify molecular subtypes in patients with invasive breast carcinoma. Materials and Methods: A prospective cross-sectional study was conducted in the Department of General Surgery, Maharani Laxmi Bai Medical College, Jhansi, from October 2023 to March 2025. Fifty newly diagnosed patients of invasive breast carcinoma were included after histopathological confirmation. Immunohistochemistry was performed to evaluate ER, PR, HER2/neu, and Ki-67 status. Tumors were categorized into molecular subtypes (Luminal-A, Luminal-B, HER2-enriched, and triple-negative). Data were analyzed using the Statistical Package for the Social Sciences version-25.0, with categorical variables expressed as frequencies and percentages. Results: The majority of patients (54%) were aged 41–60 years, with breast lump as the commonest presentation. Molecular subtyping revealed 40% basal-like, 36% HER2-enriched, 20% Luminal A, and 4% Luminal B tumors. ER and PR expression were observed in 24% of cases, showing a significant inverse relationship with Ki-67 index (P=0.002), indicating higher proliferation in hormone receptor-negative tumors. HER2/neu positivity was noted in 56% but showed no significant correlation with clinicopathological features. Conclusion: This study highlights the predominance of aggressive subtypes – basal-like and HER2-enriched – in this Indian cohort. The low hormone receptor expression and high Ki-67 index support the need for routine molecular profiling to inform targeted treatment strategies, especially in resource-limited settings.

Toward accurate breast cancer classification: A review of multi-modal machine learning approaches.

Spatiotemporal profiling of endocytic regulators in the immunosuppressive TAM microenvironment of glioma.

A primate model revealed specific age-related changes in spiral ganglion neurons in the cochlea.

Unraveling the microbiome's role in breast cancer progression and treatment response.