Breast Cancer Research最新文献

{"title":"Computational methods, clinical evidence, and translational readiness for artificial intelligence for HER2 assessment using silver in situ hybridization (SISH).","authors":"Wael Badawy","doi":"10.1186/s13058-026-02363-z","DOIUrl":"10.1186/s13058-026-02363-z","url":null,"abstract":"<p><p>Accurate determination of human epidermal growth factor receptor 2 (HER2) gene amplification is a cornerstone of precision oncology in breast cancer and an expanding range of solid tumors. While immunohistochemistry (IHC) remains the first-line screening modality, in situ hybridization (ISH) techniques are essential for resolving equivocal cases and providing quantitative assessment of HER2 gene status. Among ISH methods, silver-enhanced in situ hybridization (SISH) has emerged as a clinically relevant bright-field alternative to fluorescence in situ hybridization (FISH), offering permanent staining, high concordance, and compatibility with routine histopathology workflows. Despite these advantages, SISH interpretation remains labor-intensive and subject to interobserver variability, particularly in borderline and heterogeneous tumors. The rise of digital pathology and artificial intelligence (AI) has enabled automated analysis of whole-slide images (WSIs), supporting tasks such as nuclei segmentation, signal detection, HER2 copy-number estimation, and HER2/CEP17 ratio computation. However, current evidence remains heterogeneous, with limitations including small datasets, limited external validation, and insufficient methodological transparency. This systematic review synthesizes current literature on AI-assisted HER2 assessment with a specific focus on SISH and related bright-field ISH modalities. We examine computational workflows, validation strategies, performance benchmarks, and translational readiness while critically appraising limitations in the evidence base. The analysis demonstrates that AI can support reproducible and scalable HER2 assessment when aligned with clinical guidelines, but emphasizes that clinical deployment requires rigorous validation, uncertainty-aware design, and integration with expert pathology workflows.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"28 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic lethality of combination treatment with Trop2-directed antibody-drug conjugate sacituzumab govitecan and TRAIL agonists in triple negative breast cancer.","authors":"Yonit A Addissie, Yoshimi E Greer, Jayakumar Nair, Stanley Lipkowitz","doi":"10.1186/s13058-026-02318-4","DOIUrl":"10.1186/s13058-026-02318-4","url":null,"abstract":"<p><strong>Background: </strong>Sacituzumab govitecan (SG) is an antibody drug conjugate targeting trophoblast cell surface antigen 2 (Trop2) that is approved for treatment of patients with metastatic triple negative breast cancer (TNBC). Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) agonists are antitumor agents that interact with death receptors on the cell surface to induce apoptosis in cancer cells, often sparing normal cells. In this study, we investigated whether combination treatment with SG and TRAIL agonists inhibit TNBC cell growth.</p><p><strong>Methods: </strong>In vitro, 10 human TNBC cell lines and 4 non-modified, low passage patient derived TNBC cells were treated with SG and the TRAIL agonist Apo2L. Cell death was assessed via a propidium iodide-based assay while cell proliferation was measured using an ATP cell viability assay. The mode of cell death elicited by combination treatment was investigated by using inhibitors of apoptosis, necroptosis and ferroptosis. The drug effect on cell cycle was analyzed with flow cytometry. In vivo, NCr athymic nude (nu/nu) female mice bearing HCC1806 TNBC xenografts were treated with SG and TRAIL agonists after which the effect of treatment on tumor growth and survival was evaluated.</p><p><strong>Results: </strong>SG and TRAIL acted synergistically in all 10 TNBC cell lines as well as all 4 patient derived TNBC cells tested. Synergistic cell death and growth inhibition was observed in both Trop2 high-expressing and low-expressing cells, with data suggesting that the linker deconjugation and bystander effects of SG contribute to the efficacy in Trop2 low-expressing cells. Caspase-3/7 assays as well as cell death assays using cell death inhibitors demonstrated that the lethality of dual treatment is primarily mediated by apoptosis. Additionally, SG alone and in combination with Apo2L induced cycle arrest at the G2/M phase. Finally, xenograft models using HCC1806 bearing mice showed that dual treatment with SG and TRAIL agonists significantly inhibited tumor growth and caused a borderline significant benefit on survival with no toxicities noted for both drug treatments.</p><p><strong>Conclusions: </strong>Combination treatment with SG and TRAIL agonists induces synergistic lethality in TNBC cells in vitro and inhibits tumor growth in vivo, suggesting a potential clinical benefit of the combination therapy in TNBC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"28 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variation in chemotherapy use across healthcare regions in Sweden and its impact on prognosis in women with HR+/HER2- early breast cancer.","authors":"Balazs Acs, Xingrong Liu, Leo Gkekos, Emelie Karlsson, Anna L V Johansson, Per Karlsson, Anne Andersson, Antonios Valachis, Irma Fredriksson, Theodoros Foukakis, Johan Hartman","doi":"10.1186/s13058-026-02366-w","DOIUrl":"10.1186/s13058-026-02366-w","url":null,"abstract":"<p><strong>Background: </strong>Hormone receptor-positive/Human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer accounts for the majority of breast cancer cases. Although chemotherapy can reduce recurrence risk, its use in HR+/HER2- high-risk disease remains complex in clinical practice. We aimed to examine regional variation in chemotherapy use in Sweden and its association with prognosis.</p><p><strong>Methods: </strong>In this population-based cohort study, we included 61,935 women diagnosed with HR+/HER2- early breast cancer between 2007 and 2023, identified through the Swedish National Quality Register for Breast Cancer. Multivariable logistic regression was applied to identify factors that were associated with chemotherapy use across the Swedish healthcare regions. Overall survival was analysed using Kaplan-Meier estimates and regression standardisation based on Cox models, adjusting for clinicopathological and socioeconomic factors.</p><p><strong>Findings: </strong>Chemotherapy was administered to 28·0% of patients, with substantial regional variation (range 23·0-34·7%). Younger age, larger tumour size, node-positive disease, and higher tumour grade were associated with chemotherapy use. Regional differences in 10-year all-cause mortality persisted after adjustment among patients aged ≥ 65 years but were minimal among those aged < 65 years. The healthcare region with the highest chemotherapy use had the lowest mortality. Socioeconomic factors did not alter these associations.</p><p><strong>Interpretation: </strong>Chemotherapy use in patients with HR+/HER2- early breast cancer varies across the Swedish healthcare regions despite common guidelines. Among young and middle-aged patients, these differences were not associated with survival disparities. In contrast, among patients aged ≥ 65 years, regional differences in treatment remained associated with differences in prognosis also after socioeconomic adjustments, suggesting undertreatment in some regions. These findings support continued efforts to harmonize implementation of treatment recommendations to ensure equitable care for patients with HR+/HER2 - early breast cancer.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"28 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148725059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between adiposity and cardiac function in patients with early breast cancer receiving cardiotoxic therapies.","authors":"Gabriel Aleixo, Wei Ting Hwang, Rakesh Sharma, Wonyoung Jung, Congying Xia, Vivek Narayan, Yehoda M Martei, Ramy Sedhom, Walter Witschey, Bonnie Ky","doi":"10.1186/s13058-026-02350-4","DOIUrl":"https://doi.org/10.1186/s13058-026-02350-4","url":null,"abstract":"<p><strong>Background: </strong>Anthracyclines and HER2-directed therapies improve survival in early breast cancer but increase cardiovascular risk, which body mass index poorly characterizes. We evaluated longitudinal associations between pre-treatment CT-derived body composition and echocardiography-derived systolic and diastolic function in a prospective cohort of women with early breast cancer.</p><p><strong>Methods: </strong>In a prospective cohort of women with stage I-III early breast cancer treated with anthracyclines and/or trastuzumab, skeletal muscle index (SMI), muscle density (SMD), and visceral and subcutaneous adipose tissue area and density (VAT, SAT, VATD, SATD) were quantified from pre-treatment CT or PET-CT at L3 using automated segmentation. Longitudinal changes in LVEF and E/e' were analyzed using multivariable-adjusted GEE models. Time to incident systolic dysfunction (≥ 10% LVEF decline to < 50%) and diastolic dysfunction (E/e' ≥ 14) were analyzed using Cox proportional hazards models.</p><p><strong>Results: </strong>Across 177 participants (median age 50 years, 36.2% HER2-positive, 19.9% triple-negative), 145 (81.9%) received anthracycline-based therapy. Baseline body composition was not associated with longitudinal LVEF change. Higher baseline VAT (β 0.6, 95% CI 0.2-0.9; p = 0.001) and VAT/SAT ratio (β 0.5, 95% CI 0.2-0.7; p < 0.001) were associated with increased E/e' over time, while higher VATD (β - 0.4, 95% CI - 0.6 to - 0.1; p = 0.002) was associated with decreased E/e' during follow-up. No associations were observed for SAT or SATD.</p><p><strong>Conclusions: </strong>Pre-treatment visceral adiposity is associated with worsening diastolic function during breast cancer therapy. CT-derived body composition may refine cardiotoxicity risk assessment beyond BMI.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing lymph node metastases assessment in breast cancer post-neoadjuvant therapy using artificial intelligence-driven diagnostics.","authors":"Yan Ding, Juan Yu, Min Liu, Xiangyu Liu, Ling Kang, Liujing Huang, Jinze Li, Yanan Wang, Xin Xu, Min Zhao, Ping Wei, Shuangbiao Li, Zaibo Li, Yueping Liu","doi":"10.1186/s13058-026-02349-x","DOIUrl":"https://doi.org/10.1186/s13058-026-02349-x","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant therapy (NAT) is crucial for locally advanced breast cancer, but post-NAT lymph node assessment is challenging due to histological changes. Current methods like immunohistochemistry (IHC) are labor-intensive and imprecise in distinguishing isolated tumor cells (ITCs), micro-metastases (Micro), and macro-metastases (Macro). We aimed to develop and validate an AI-driven model for precise classification of lymph node metastasis status (negative, ITC, Micro, Macro) in breast cancer patients post-NAT.</p><p><strong>Methods: </strong>We used a weakly supervised Clustering-constrained Attention Multiple Instance Learning (CLAM) framework to analyze 7764 lymph node samples from 7 cohorts. The CLAM model identifies high-diagnostic-value subregions within whole-slide images (WSIs) and generates high-resolution interpretability heatmaps. Performance was evaluated using binary and multi-class metrics, with external validation on diverse datasets. A human-AI comparative analysis was conducted on 24 patient-derived lymph node sections.</p><p><strong>Results: </strong>The AI model achieved an AUROC of 0.97 (95% CI: 0.962-0.977) in binary classification and an overall accuracy of 0.8436 (95% CI: 0.8282-0.8562) for multi-class differentiation. In the human-AI comparison, the model outperformed junior pathologists, reducing diagnostic discrepancies by 83%.</p><p><strong>Conclusion: </strong>This study establishes a robust AI model that significantly improves the accuracy and efficiency of post-NAT lymph node metastasis assessment in breast cancer, automating classification and reducing pathologist workload.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic plasma protein signatures in sporadic and BRCA1/2 breast cancer patients via targeted proteomics.","authors":"Kristrun Y Holm, Yassene Mohammed, Valdis Gunnarsdottir Thormar, Finnur F Eiríksson, Christoph H Borchers, Stefan Sigurdsson, Jon G Jonasson, Margret Thorsteinsdottir, Sigridur K Bodvarsdottir","doi":"10.1186/s13058-026-02348-y","DOIUrl":"https://doi.org/10.1186/s13058-026-02348-y","url":null,"abstract":"<p><strong>Background: </strong>Early breast cancer diagnosis is critical, particularly for individuals at hereditary risk. The aim of this study was to identify blood-derived protein biomarkers for breast cancer diagnosis to improve current screening strategies.</p><p><strong>Methods: </strong>Absolute quantification of 98 plasma proteins was performed via a UPLC-MRM-MS assay on plasma samples from 135 breast cancer patients and paired controls, one-third of which were of hereditary BRCA1/2 origin, and from women diagnosed within 5 years from blood collection. Plasma protein concentration profiles were compared between patients and paired controls across breast cancer subgroups.</p><p><strong>Results: </strong>Proteomic analysis revealed four plasma proteins with elevated abundance and four other proteins with reduced abundance across different breast cancer subgroups. Haptoglobin (HP) was elevated in sporadic cases (n = 88) and cases with grade 3 tumors (n = 44), adipocyte plasma membrane-associated protein was elevated in cases with large tumors (n = 60) and grade 3 tumors (n = 44), lipopolysaccharide-binding protein (LBP) was elevated in node-positive (n = 58) and HER2 (n = 9) cases, and secreted protein acidic and cysteine rich was elevated in luminal B (n = 45) cases. Transthyretin was reduced in luminal B patients, and apolipoprotein A4 was reduced in HER2 patients. Immunoglobulin heavy constant mu (IGHM) and CD5 antigen-like (CD5L) were lower in BRCA1/2 (n = 47) and triple-negative (n = 17) patients than in paired controls. IGHM and CD5L were also lower in BRCA1/2 patients than in paired sporadic patients. Additionally, IGHM in plasma was lower among BRCA2 mutation carriers (n = 7) diagnosed with breast cancer within 5 years of blood collection than among paired controls and CD5L was also lower than among paired controls and sporadic patients diagnosed within 5 years of blood collection. The plasma proteins associated with breast cancer specific survival were LBP, HP, and IGHM.</p><p><strong>Conclusions: </strong>These findings indicate that plasma protein concentrations may have diagnostic and prognostic value for breast cancer screening and could provide valuable insights for biomarker discovery.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148498238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melanoma cell adhesion molecule (MCAM) mediates microtentacle generation, homotypic clustering, and reattachment of non-adherent breast tumor cells.","authors":"David A Annis, Keyata N Thompson, Julia A Ju, Makenzy Mull, Darin E Gilchrist, Jessica L Cornell, Destiny O Omili, Stuart S Martin, Michele I Vitolo","doi":"10.1186/s13058-026-02346-0","DOIUrl":"10.1186/s13058-026-02346-0","url":null,"abstract":"<p><strong>Background: </strong>Melanoma cell adhesion molecule (MCAM) was first identified in advanced primary tumors and metastatic lesions. MCAM expression has been shown in previous studies to promote aggressive cancer phenotypes, including migration, invasion, tumorigenesis, and induction of vimentin and slug, indicative of EMT. Furthermore, overexpression of MCAM has been linked to poor prognosis and aggressive metastatic phenotypes, particularly in triple-negative breast cancer (TNBC). Early work has shown that MCAM can alter the actomyosin cytoskeleton and intermediate filaments; however, the impact of MCAM on the microtubule network and non-adherent cells has not been well studied.</p><p><strong>Methods: </strong>Utilizing MCF-10A breast epithelial cell line engineered to overexpress MCAM and CRISPR MCAM knockouts in TNBC cell lines, we assessed the impact of MCAM on tubulin-driven cytoskeletal phenotypes in non-adherent conditions. TetherChip technology, xCelligence RTCA, and immunoblotting techniques were utilized to investigate the impact of MCAM overexpression.</p><p><strong>Results: </strong>Our results show that MCAM overexpression increases vimentin protein levels, α-tubulin post-translational modificaitons (PTMs), microtentacle (McTN) protrusions, homotypic cell clustering, cellular reattachment, and migration. These phenotypic increases can be inhibited with FDA-approved vinorelbine treatment. Conversely, the knockout of MCAM in TNBC cell lines sustains decreases of acetylated α-tubulin, implicating that MCAM expression may alter the microtubule cytoskeleton's stability directly. Knockout (KO) of MCAM also decreased microtentacle protrusions and McTN-supported phenotypes of homotypic cell clustering and cellular reattachment. Migration was also decreased in TNBC with MCAM KO.</p><p><strong>Conclusions: </strong>These findings suggest that MCAM can function through the microtubules in TNBC to impact McTN-supported phenotypes of homotypic cell clustering and cellular reattachment in non-adherent breast tumor cells.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epithelial-mesenchymal transition is associated with altered immune composition and cytotoxic function in triple-negative breast cancer.","authors":"Hanxu Lu, Meisam Bagheri, Fred W Kolling, Lucas A Salas, Xiaofeng Wang, Todd W Miller, Diwakar R Pattabiraman, Brock Christensen","doi":"10.1186/s13058-026-02309-5","DOIUrl":"10.1186/s13058-026-02309-5","url":null,"abstract":"<p><strong>Background: </strong>Epithelial-mesenchymal transition (EMT) is a dynamic process that contributes to breast cancer progression, metastasis, and therapy resistance. EMT also influences the tumor immune microenvironment, shaping immune cell infiltration and function. Although the immunological features of fully epithelial or fully mesenchymal tumor states have been characterized, the immune landscape associated with intermediate or partial EMT states remains poorly understood.</p><p><strong>Methods: </strong>To examine the relationship between EMT progression and immune cell composition and function, we established five single-cell-derived clonal populations from the triple-negative 4T1 mouse mammary tumor cell line, representing a spectrum of EMT phenotypes, and analyzed tumors derived from these clones using single-cell RNA sequencing.</p><p><strong>Results: </strong>Tumors derived from these clones retained their relative EMT states in vivo, and EMT progression was associated with a graded reduction in tumor immunogenicity, accompanied by alterations in immune cell composition and function. Along the EMT spectrum, tumor cells exhibited progressive downregulation of major histocompatibility complex (MHC) class I and II gene expression, along with decreased infiltration of cytotoxic CD8+ T cells and reduced expression of key effector and trafficking genes (Gzmb, Ccr5, Cxcr6). B cell composition also shifted, with decreased frequencies of IgG1-producing plasma cells and an enrichment of regulatory-like B cells. Natural killer (NK) cells similarly demonstrated progressive functional suppression, marked by reduced expression of cytotoxic molecules and the downregulation of specific effector pathways.</p><p><strong>Conclusions: </strong>These findings reveal that EMT is associated with immune cell recruitment and function in a graded manner, providing a rationale for integrating EMT phenotyping into therapeutic strategies to overcome immune resistance in breast cancer.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"28 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three ct-miRNA signature predicts disease outcome in early breast cancer women.","authors":"Giulia Cosentino, Mara Lecchi, Marta Giussani, Valentina Fogazzi, Angela Galardi, Claudia Tottone, Elisa Dell'Orto, Serenella M Pupa, Paolo Verderio, Elda Tagliabue, Marilena V Iorio","doi":"10.1186/s13058-026-02344-2","DOIUrl":"https://doi.org/10.1186/s13058-026-02344-2","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is still a leading cause of tumor mortality in women. Indeed, despite advancements in early diagnosis, molecular profiling and novel therapeutic approaches, the disease outcome is still not always predictable. This evidence underlines the need for validated biomarkers to predict recurrences, to personalize both disease monitoring and tailored therapies. And to this aim, miRNAs have shown promising applications as circulating biomarkers. Starting from plasma samples collected from women with early-stage breast cancer at the time of diagnosis, we explored the expression of ct-miRNAs to define a molecular signature predictive of recurrence.</p><p><strong>Methods: </strong>Two independent cohorts of plasma samples were retrospectively and prospectively collected at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT) for a total of 203 patients. Ct-miRNAs were previously profiled by using the OpenArray Human microRNA panel (OA) (Thermo Fisher Scientific). Relapse-free survival (RFS) was analyzed using Cox regression models adjusted for cohort to assess associations with clinicopathological variables and circulating miRNA levels. Models performance was evaluated using c-statistics (95% Confidence interval) and an internal validation was performed with bootstrap resamples. Clinicopathological variables were added to the signature in multivariate models to evaluate their independent prognostic value.</p><p><strong>Results: </strong>We identified a three ct-miRNA (miR-125b, miR-26b-3p and miR-532-5p) signature associated with disease outcome, with a hazard ratio of 2.803 (95% CI, 1.721-4.565). The c-statistic was 0.72 (95%, CI 0.62-0.83) and was confirmed by the resampling procedure, with a c-median bootstrap statistic of 0.73 (IQR, 0.65-0.81). The 3-circulating miRNA signature retained its significant prognostic performance with respect to RFS even after the inclusion of clinicopathological variables in multivariate models. Considering both ct-miRNA signature and Nottingham Prognostic Index (NPI), the c-statistic of the bivariate model was equal to 0.80 (95% CI, 0.70; 0.90).</p><p><strong>Conclusion: </strong>We identified a three ct-miRNA prognostic signature in early breast cancer women. Considering the accessibility and stability of ct-miRNAs, this signature might improve the recurrence risk prediction identifying who, despite the early diagnosis, might need a more intensive screening or secondary prevention strategies.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visceral adiposity and breast cancer outcomes: transcriptomic analysis of the tumor microenvironment by intrinsic subtype.","authors":"Anlan Cao, Sophia Fuller, Jorge Gómez Tejeda Zañudo, Wendy Y Chen, Deborah Dillon, Sandra McAllister, Elizabeth A Mittendorf, Rinath Jeselsohn, Bette J Caan, Charles Quesenberry, Elizabeth M Cespedes Feliciano","doi":"10.1186/s13058-026-02337-1","DOIUrl":"https://doi.org/10.1186/s13058-026-02337-1","url":null,"abstract":"<p><strong>Background: </strong>Obesity is linked to poor breast cancer outcomes, but evidence within molecular intrinsic subtypes is limited. We measured visceral and subcutaneous adipose tissue (VAT and SAT) on routine clinical imaging and examined survival and tumor microenvironment (TME) differences across PAM50 subtypes.</p><p><strong>Methods: </strong>We sampled 1,377 individuals diagnosed with stage II-III breast cancer at Kaiser Permanente Northern California between 2005 and 2015, enriched for HER2 + and ER- tumors. VAT and SAT areas (cm²) were quantified at L3-level from clinically acquired CT scans. Tumor RNA profiling (NanoString BC360™) provided PAM50 and TME-related signatures. Cox models estimated associations of VAT and SAT with overall and disease-specific outcomes. Differential expression and signature analyses were stratified by PAM50 subtype.</p><p><strong>Results: </strong>Participants had a mean (± SD) age of 56 ± 13 years. Intrinsic subtype distribution was: Basal-like (31%), HER2-E (25%), Luminal B (22%), and Luminal A (22%). Over a median follow-up of 11 years, patients with HER2-E tumors and high-VAT had higher breast cancer-specific mortality (HR = 2.14, 95%CI 1.25-3.65) and distant relapse (HR = 2.05, 95%CI 1.23-3.42). No VAT associations were observed in other subtypes. Transcriptomic analyses revealed enhanced abundance of cancer-associated fibroblasts (CAF) with corresponding stromal signatures exclusively in high-VAT HER2-E tumors. Higher CAF and stromal activation signatures were associated with worse outcomes in the full cohort. SAT showed no associations in any subtype.</p><p><strong>Conclusions: </strong>Visceral adiposity identified a high-risk subset of HER2-E breast cancer characterized by high CAF and stromal activation signatures and inferior survival, highlighting an opportunity for VAT-targeted interventions and mechanistic studies to clarify adiposity-TME interactions.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148425672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}