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PubMed2026

Association of immune and proliferation gene signatures and stromal tumor-infiltrating lymphocytes with clinical outcomes in patients with stage I triple-negative breast cancer.

BACKGROUND: One-third of patients with triple-negative breast cancer (TNBC) are diagnosed with stage I tumors. Biomarkers to stratify prognosis in this setting remain a major unmet need. METHODS: Tissue samples and clinicopathologic data were retrieved from consecutive patients with stage I TNBC (defined as ER <10% and HER2-negative) who underwent upfront breast surgery and received standard of care adjuvant systemic therapy at Dana-Farber/Brigham Cancer Center between 2016 and 2021. The TNBC-DX assay (Core Immune Gene [CIG] signature, proliferation signature) was applied to tumor tissue, and stromal tumor-infiltrating lymphocytes (sTILs) were centrally reviewed. Both biomarkers were tested for association with clinical outcomes using the Kaplan-Meier method. RESULTS: A total of 253 patients with stage I TNBC were included. Most tumors were ductal (88.9%) and high-grade (73.1%); 65.2% of patients received adjuvant chemotherapy. With 18 recurrence events observed, the 3-year recurrence-free survival (RFS) in the overall cohort was 95.0% (95% confidence interval [CI]: 92.1% - 98.1%) and the 3-year overall survival was 97.9% (95% CI: 95.9% - 100.0%). No significant differences in RFS were observed by TNBC-DX (n = 117 patients) or sTILs (n = 123 patients) category. However, a 3-year RFS of 100% (95% CI: 100% - 100%) was observed among the 29 patients with the highest CIG score quartile. A favorable prognosis was also observed in patients with high sTILs (>20%), who experienced a 3-year RFS of 97.0% (95% CI: 90% - 100%). Conversely, a high TNBC-DX proliferation score was numerically associated with poor outcomes, with a 3-year RFS of 83% (95% CI: 68% - 100%). CONCLUSIONS: In this retrospective study, immune and proliferative features showed opposing prognostic trends in stage I TNBC. Their integration may improve risk stratification and warrants further investigation.

Stromal tumor infiltrating lymphocytes (sTILs)↗

PubMed2026

UNCX/SIN3A-Mediated H4K8 decrotonylation suppresses FOXO3 to drive TNBC progression and docetaxel resistance.

Triple-negative breast cancer (TNBC) remains a clinically challenging subtype characterized by aggressive behavior and limited treatment options. Though docetaxel remains a cornerstone chemotherapy for TNBC, the frequent emergence of resistance highlights the urgent need to identify novel therapeutic targets. In this study, we report that uncoordinated homeobox (UNCX) is upregulated in docetaxel-resistant breast cancer cells, genomically amplified in breast cancer, and associated with poor survival in breast carcinoma patients. Functional studies revealed that UNCX promotes breast cancer cell proliferation, migration and reduces the docetaxel sensitivity. Mechanistically, UNCX functions as a transcriptional repressor by recruiting the SIN3A complex. Genome-wide profiling indicated that the UNCX/SIN3A complex directly binds to the promoters of tumor-suppressor genes including FOXO3, and represses their transcription by removing histone H4K8 crotonylation (H4K8cr). Additionally, the UNCX/SIN3A complex enhances FOXO3 phosphorylation and inhibits its nuclear translocation, further inhibiting its activity. Notably, SIN3A knockdown, FOXO3 overexpression, or crotonylation restoration effectively reverses UNCX-induced malignant phenotypes. These findings collectively establish the UNCX/SIN3A-H4K8cr-FOXO3 axis as a pivotal epigenetic regulator of TNBC progression and chemoresistance, revealing new avenues for targeted therapeutic development against this aggressive breast cancer subtype.

Humans↗

PubMed2026

Multi-omics integration uncovers epigenetic control of metabolic reprogramming in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, limiting effective targeted therapies. Increasing evidence suggests that metabolic reprogramming, a hallmark of TNBC progression, is driven by underlying epigenetic mechanisms such as DNA methylation. The represented study performed an integrative analysis of transcriptomic (RNA-seq) and methylome data to uncover the metabolic-epigenetic interplay in TNBC. Differential gene expression analysis using DESeq2 revealed significant dysregulation of key metabolic genes, including upregulation of genes encoding glycolytic and serine biosynthesis enzymes and downregulation of metabolic tumor suppressors. Genome-wide methylation profiling identified extensive cytosine-phosphate-guanine (CpG) hypermethylation events associated with transcriptional repression, particularly in promoter regions. Integrative analysis pinpointed a subset of metabolism-related genes exhibiting both differential expression and methylation, such as FBP1, RASSF1A, and PHGDH. Pathway enrichment analysis highlighted aberrations in glycolysis/gluconeogenesis, fatty acid metabolism, and one-carbon pathways (adjusted p < 0.01). Importantly, TNBC patients with hypermethylated metabolic gene signatures displayed significantly shorter overall survival (log-rank p < 0.05). These findings reveal that DNA methylation-driven metabolic dysregulation contributes to TNBC aggressiveness and may provide novel biomarkers and therapeutic targets at the metabolic-epigenetic interface.

Humans↗

PubMed2026

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Precision oncology↗

PubMed2026

Integrated analysis reveals the impact of obesity on triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited therapeutic options. While the prevalence of overweight/obese (OW/OB) women continues to rise, the impact of obesity on molecular features of TNBC remains incompletely understood. We investigated clinicopathological and molecular data (including genomic, transcriptomic, proteomic and metabolomic profiling) using our original multi-omics database of TNBC (N = 465) for associations with patient body mass index (BMI). Multi-omics profiling revealed that OW/OB patients exhibited worse survival as well as elevated inflammation of tumor microenvironment, higher expression of immune checkpoints, and dysregulated lipid metabolism. Our in vivo experiments demonstrated that tumors in obese mice displayed faster growth rates, a higher proportion of PD-1+CD8+ T cells and enhanced responsiveness to anti-PD-1 treatment. In addition, we analyzed data from four independent clinical trials and discovered that OW/OB patients demonstrated higher pathological complete response rates and longer progression-free survival following anti-PD-1-based immunotherapy. In conclusion, our study systematically revealed that obesity is associated with coordinated immune-metabolic remodeling in TNBC, characterized by checkpoint enrichment and lipid dysregulation, which may help explain the enhanced anti-PD-1 responsiveness and should be taken into account in the field of precision medicine.

Immunity↗

PubMed2026

Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.

Doxorubicin remains an important component of chemotherapy for triple-negative breast cancer (TNBC), yet chemoresistance severely limits its clinical efficacy. Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin-treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1-SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN-induced putative kinase 1 (PINK1). This suppresses PINK1/Parkin-mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.

DNA methylation↗

PubMed2017

Predictors of BRCA1/2 genetic testing among Black women with breast cancer: a population-based study.

Evidence shows that Black women diagnosed with breast cancer are substantially less likely to undergo BRCA testing and other multipanel genetic testing compared to White women, despite having a higher incidence of early-age onset breast cancer and triple-negative breast cancer (TNBC). Our study identifies predictors of BRCA testing among Black women treated for breast cancer and examines differences between BRCA testers and nontesters. We conducted an analysis of 945 Black women ages 18-64 diagnosed with localized or regional-stage invasive breast cancer in Pennsylvania and Florida between 2007 and 2009. Logistic regression was used to identify predictors of BRCA 1/2 testing. Few (27%) (n = 252) of the participants reported having BRCA testing. In the multivariate analysis, we found that perceived benefits of BRCA testing (predisposing factor) ([OR], 1.16; 95% CI: 1.11-1.21; P < 0.001), income (enabling factor) ([OR], 2.10; 95% CI: 1.16-3.80; p = 0.014), and BRCA mutation risk category (need factor) ([OR], 3.78; 95% CI: 2.31-6.19; P < 0.001) predicted BRCA testing. These results suggest that interventions to reduce disparities in BRCA testing should focus on identifying patients with high risk of mutation, increasing patient understanding of the benefits of BRCA testing, and removing financial and other administrative barriers to genetic testing.

Adolescent↗

PubMed2026

Unveiling novel transcriptomic prognostic biomarkers for specific breast cancer subtypes and treatment regimens.

BACKGROUND: Breast cancer (BRCA) is the most common cancer in women worldwide, yet current gene expression panels offer limited insight into treatment responses across different subtypes and therapies. This study aimed to identify reliable biomarkers for predicting treatment outcomes in specific BRCA subtypes and treatment regimens. METHODS: This study analyzed transcriptomic data from The Cancer Genome Atlas to identify differentially expressed genes (DEGs) in patient groups treated with different combinations of hormone therapy (H), chemotherapy (C), radiotherapy (R), and targeted therapy (T). Non-negative matrix factorization clustering was performed to stratify patients into clusters representing different BRCA subtypes. Functional enrichment analysis was performed, and survival assessments were conducted using the METABRIC dataset. RESULTS: A total of 1,148 DEGs were identified across treatment regimens, with 75 common DEGs shared across multiple regimens. Among these, 12 candidate biomarkers were associated with luminal subtypes treated with H, including LRP1B, of which high expression predicted cancer recurrence. In triple-negative breast cancer (TNBC) treated with C, 76 candidate biomarkers were identified, including TTYH1 for recurrence and ANXA8L1 and MPZ for non-recurrence. Functional analyses identified intermediate filament organization and keratinization as pathways associated with specific candidate biomarkers of TNBC following C. Survival analysis using METABRIC strengthened the prognostic ability of LRP1B and TTYH1 to predict worse survival and ANXA8L1 and MPZ to predict prolonged survival, with four additional prognostic biomarkers. CONCLUSION: This study identified gene expression prognostic biomarkers for luminal and TNBC subtypes, thereby supporting personalized therapies. Further experimental validation is required to confirm these findings for clinical application. CLINICAL TRIAL REGISTRY: No.

Breast cancer↗

PubMed2026

Antibody-drug conjugates against multidrug-resistant cancers: Biomarker-guided patient selection, payload engineering, linker chemistry, and bystander effects.

Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.

Humans↗

PubMed2026

Integrin α3 (ITGA3) expression across breast cancer subtypes: Prognosis and therapeutic relevance.

BACKGROUND: Integrin α3 (ITGA3), which heterodimerizes with integrin β1, has emerged as a potential biomarker and therapeutic target in several epithelial malignancies; however, its clinical relevance in breast cancer remains incompletely characterized. This study evaluated ITGA3 expression across breast cancer molecular subtypes and assessed its prognostic and predictive significance. METHODS: Immunohistochemistry (IHC) was performed on archival breast cancer specimens using tissue microarrays (n = 148) and whole-tissue sections (n = 21). Complete clinicopathologic and outcome data were available for 108 patients, including hormone receptor-positive/human epidermal growth factor receptor 2-negative, HER2-positive, and triple-negative breast cancer (TNBC) subtypes. ITGA3 expression was quantified using H-scores and correlated with clinicopathologic features and survival outcomes. Independent transcriptomic analyses were conducted using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and the Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohorts to evaluate ITGA3 mRNA expression, co-expressed signaling pathways, and associations with therapeutic response. RESULTS: ITGA3 protein expression was detected in 85.2% of breast cancer specimens and was significantly higher in HR-positive/HER2-negative and HER2-positive tumors compared with TNBC (p < 0.0050). High ITGA3 expression was associated with shorter recurrence-free survival (p < 0.0001). In the METABRIC cohort, tumors with ITGA3 alterations demonstrated significantly worse relapse-free survival (p < 0.0001) and overall survival (p < 0.0500). Transcriptomic analyses revealed that ITGA3 co-expressed with estrogen receptor 1(ESR1), erb-b2 receptor tyrosine kinase 2 (ERBB2), and luminal markers, along with enrichment of estrogen receptor and phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathways. ITGA3 expression was not predictive of response to tamoxifen or trastuzumab. CONCLUSION: Elevated ITGA3 expression is associated with breast cancer recurrence and poor clinical outcomes, supporting its potential role as a prognostic biomarker and candidate therapeutic target.

Biomarkers↗

PubMed2026

Recent advances in immunotherapy for breast cancer: An updated review.

Immunotherapy has revolutionized the treatment landscape of breast cancer, particularly for triple-negative breast cancer (TNBC), yet primary and acquired resistance remain formidable obstacles limiting durable clinical benefit. This review provides a comprehensive update on recent advances in breast cancer immunotherapy, with a focused emphasis on the molecular and cellular mechanisms driving treatment resistance and emerging strategies to overcome them. We dissect tumor-intrinsic resistance pathways, including loss of tumor antigens, defects in antigen processing and presentation machinery, insensitivity to interferon-γ signaling, metabolic reprogramming, and epigenetic dysregulation. Tumor-extrinsic mechanisms, such as infiltration of immunosuppressive cells, abnormal angiogenesis, extracellular matrix remodeling, and FGF/FGFR genomic amplification, are highlighted as key barriers to effective immune checkpoint blockade. Emerging evidence implicates novel resistance mediators, including the DUSP22-LGALS1 axis, THSD4-driven T cell exclusion, and the MTDH-SND1 complex impairing antigen presentation, etc. We critically evaluate current strategies to surmount resistance, encompassing combination regimens with chemotherapy, targeted therapies, radiotherapy, and novel immunomodulators. The review also addresses challenges in managing immune-related adverse events, controversies surrounding patient selection biomarkers, and the urgent need for optimized efficacy evaluation systems beyond RECIST criteria. Finally, we discuss future directions, including novel immune checkpoints, microbiome modulation, artificial intelligence-assisted decision-making, and innovative trial designs. By integrating mechanistic insights with clinical evidence, this review provides a framework for understanding and overcoming immunotherapy resistance, advancing the paradigm from "effective" to "precise" immuno-oncology in breast cancer.

Humans↗

PubMed2026

Mature Tertiary Lymphoid Structures in Breast Cancers Are Associated With Antitumor Immunity and Better Prognosis.

Tertiary lymphoid structures (TLSs) are immune cells accumulated in nonlymphoid tissues, with an inner core of B cells encompassed by T cells. The aim of this study was to evaluate the clinical importance of mature TLSs in breast cancer, including their association with immunotherapy response and their role in modulating the tumor immune microenvironment. We analyzed histopathological data of 726 consecutive primary breast cancers and transcriptomic data of 824 breast cancer samples from the publicly available The Cancer Genome Atlas database to estimate the clinical and immunological values of mature TLSs in breast cancer. Additionally, we utilized pretreatment transcriptomic data of 69 patients with breast cancer from the publicly available I-SPY2 clinical trial to investigate the relation between TLS-related gene signatures and patient responses to immune checkpoint inhibitors. The existence of mature TLSs was identified in ⁓5.6% (41/726) of all patients with breast cancer (hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+HER2-): 0.92%; triple-negative breast cancer (TNBC): 14.96%; and human epidermal growth factor receptor-2 positive (HER2+): 10.98%) and was independently associated with improved recurrence-free survival after adjusting for subtypes, tumor-infiltrating lymphocyte levels, and tumor stage after the multivariable Cox regression analysis in our patient cohort. Notably, the presence of mature TLSs was related to immune cell infiltration in our breast cancer patient cohort. In line with these findings, TLS-related gene signatures analyzed through transcriptomic data reliably reflected the existence of mature TLSs and were related to better clinical responses to immune checkpoint inhibitors in patients with breast cancer. In conclusion, our findings show that mature TLS formation is linked with immune cell infiltration, contributes to a favorable prognosis, and may function as a potential complementary biomarker for immunotherapy response in breast cancer.

Humans↗

PubMed2026

Time- and Dose-Resolved DIA-PASEF Proteomics Maps the Transition from Adaptive Stress to Apoptotic Collapse in Melittin-Treated MDA-MB-231 Cells.

Melittin, the cytolytic peptide of honeybee venom, exhibits potent anticancer activity in triple-negative breast cancer (TNBC), yet the molecular programs underlying its cytotoxic effects remain incompletely defined. To address this gap, MDA-MB-231 TNBC cells were exposed to melittin at half-maximal inhibitory concentration(half IC50) and IC50 across early(0.5, 1, and 2 h), mid(3, 4 h), and late (12, 24 h) time windows. Proteomic profiling was performed using label-free data-independent acquisition(DIA) parallel accumulation-serial fragmentation(PASEF). Approximately 5800 proteins were quantified, revealing distinct dose-dependent stress responses. An integrative exploratory framework combining time-resolved log2 fold-change trajectories, area-under-the-curve(AUC) based temporal prioritization, and independent heatmap visualization identified proteins associated with melittin-induced stress remodeling. Half IC50 exposure showed a transient stress-adaptive signature characterized by chromatin remodeling(HMGN2, H2AZ1), structural and RNA-associated buffering(LRRC7), and indirect mitochondrial quality-control signaling(CPAMD8, SPATA4), which progressively weakened over time. In contrast, IC50 treatment induced rapid chromatin remodeling dominated by histone H1 variants(H1.4, H1.2), early RNA instability(LRRC7), and late-stage cytoskeletal disassembly marked by MICAL3 induction, consistent with progression toward apoptosis. These trajectories paralleled dose-dependent apoptotic phenotypes. Overall, data suggest that melittin elicits dose- and time-dependent proteomic stress responses in TNBC cells and identify candidate trajectory-associated proteins and pathways linked to adaptive stress remodeling or progression toward cytotoxic collapse.

Melitten↗

PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1⁺/PD-L1⁺ Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in γδ T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific γδ TCR clonotypes and 30 unique αβ TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗

PubMed2026

Efficacy and Genomic Analysis of HER2-Mutant Metastatic Triple-Negative Breast Cancer Treated with Neratinib Alone or with Trastuzumab in the SUMMIT Basket Trial.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) mutations occur in 1% to 3% of triple-negative breast cancers (TNBC), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib + trastuzumab (N + T; neratinib 240 mg/day, intravenous trastuzumab 8 mg/kg initially and then 6 mg/kg every 3 weeks). We report final results from the neratinib and N + T TNBC cohorts. PATIENTS AND METHODS: Primary endpoint: investigator-assessed objective response rate at first postbaseline tumor assessment (ORRfirst); secondary endpoints included confirmed ORR by investigator, clinical benefit rate (CBR), and progression-free survival (PFS); exploratory endpoint included circulating tumor DNA (ctDNA) collected at baseline, during treatment, and at the end of treatment. RESULTS: Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40% [95% confidence interval (CI), 12.2-73.8] for neratinib (n = 10) and 35.3% (95% CI, 14.2-61.7) for N + T (n = 17). CBRs were 40% (95% CI, 12.2-73.8) and 47.1% (95% CI, 23-72.2), respectively; median PFS times were 2.89 (95% CI, 0.95-5.52) and 6.24 months (95% CI, 2.10-8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase in on-pathway (ERBB3) and off-pathway (KRAS and TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation. CONCLUSIONS: N + T in patients with HER2-mutant metastatic TNBC seemed to prolong responses versus neratinib alone, representing a novel approach for patients with biomarker-defined metastatic TNBC. Based on these and previously published data, neratinib-based combinations are endorsed by the National Comprehensive Cancer Network guidelines for patients with hormone receptor-positive or -negative metastatic breast cancer with activating HER2 mutations. See related commentary by Lloyd et al., p. 3715.

Adult↗

PubMed2026

Proteomic signatures of adipocyte recruitment in breast cancer.

The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of breast cancer progression, with adipocytes functioning as active contributors rather than passive bystanders. Here, we investigated the proteomic and morphologic reprogramming of breast cancer-associated adipocytes (BrCAAs) in response to triple-negative breast cancer (TNBC). Using conditioned medium from HCC1143 cells, we established an in vitro BrCAA model and performed mass spectrometry-based proteomics. Comparative profiling revealed 256 differentially expressed proteins, enriched for pathways including fatty acid degradation, carbon metabolism, and glycogen turnover, consistent with a metabolic shift from energy storage to energy supply. Gene ontology and protein-protein interaction analyses further identified cytoskeletal remodeling, adhesion dynamics, and secretory pathway activation, supporting BrCAA-driven microenvironmental remodeling. In the MMTV-PyMT mouse model, morphometric analysis demonstrated progressive size reduction and increased contour irregularity of adipocytes adjacent to tumors, correlating with proteomic evidence of metabolic stress. Importantly, BrCAAs localized at tumor interfaces were associated with increased microvessel density and CD105+ endothelial activation compared to desmoplastic zones. Proteomic enrichment highlighted pro-angiogenic remodeling, with validation of basigin (BSG), integrin αV (ITGAV), and 2,4-dienoyl-CoA reductase 1 (DECR1). Collectively, our findings establish BrCAAs as metabolically and structurally reprogrammed stromal components that promote tumor metabolism and localized angiogenesis, representing potential therapeutic targets in aggressive breast cancer.

Female↗

PubMed2026

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗

PubMed2026

Integrated multi-omics analysis and functional experiments reveals PPAP2C as a potential prognostic biomarker and therapeutic target in breast cancer.

BACKGROUND: This study aims to systematically elucidate the clinical significance and biological function of the phospholipid phosphatase (PLPP) family member (PPAP2C) phosphatidic acid phosphatase type 2C in breast cancer, and to evaluate its potential as a prognostic biomarker and therapeutic target. METHODS: Gene expression data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases were integrated to characterize the expression profile of PLPP family members, focusing on PPAP2C in breast cancer. The prognostic value of PPAP2C, initially identified at the mRNA level (TCGA, (METABRIC) Molecular Taxonomy of Breast Cancer International Consortium, Gene Expression Omnibus (GEO)), was confirmed at the protein level by immunohistochemistry (IHC) on tissue microarrays (TMA). The oncogenic functions of PPAP2C were investigated in triple-negative breast cancer (TNBC) cells through CRISPR-Cas9-mediated knockout and ectopic overexpression, with assessment of key phenotypes including proliferation, colony formation, migration, and invasion. In vivo validation was subsequently performed using an MDA-MB-231 xenograft model. RESULTS: PPAP2C exhibits the most significant overexpression pattern across 33 cancer types (upregulated in 16 cancers, downregulated in only 3). Compared with normal tissues, PPAP2C showed specific overexpression in breast cancer tissues and was significantly associated with advanced clinical stages and aggressive subtypes (HER2+ and TNBC). Survival analysis demonstrated that high PPAP2C expression correlated with significantly shorter overall survival and disease-free survival, which was further validated in METABRIC and GEO cohorts. Tissue microarray analysis confirmed higher PPAP2C protein positivity in tumor tissues (94.7%) than in adjacent normal tissues (59.7%), with worse OS and RFS in high-expression groups. Multivariate analysis identified PPAP2C as an independent prognostic factor for OS. Functional experiments revealed that PPAP2C knockout (via 5-bp/1-bp frameshift mutations) suppressed TNBC cell proliferation, colony formation, migration, and invasion, while overexpression enhanced these phenotypes. In vivo studies further demonstrated complete tumor regression in MDA-MB-231 xenografts upon PPAP2C knockout. CONCLUSION: This study identifies PPAP2C as a key oncogenic driver and a robust independent prognostic biomarker in breast cancer. The findings provide compelling evidence that PPAP2C represents a promising therapeutic target, offering a new strategic avenue for precision therapy, particularly for aggressive breast cancer subtypes.

PLPP2↗