Breast Cancer Research最新文献

Accurate assessment of Human Epidermal Growth Factor Receptor 2 (HER2) immunohistochemistry (IHC) expression, particularly the precise identification of "HER2 ultra-low" status, is critical for guiding antibody-drug conjugate (ADC) therapies, such as trastuzumab deruxtecan (T-DXd) in breast cancer. Given the difficulty and poor consistency in interpreting HER2 ultra-low expression, this study evaluated an artificial intelligence (AI) tool for assisting pathologists in diagnosing HER2 ultra-low expression in breast cancer. The analysis included 188 breast cancer cases (376 whole-slide images), consisting of 136 matched core needle biopsy (CNB)-surgical excision (SE) pairs from patients without neoadjuvant therapy (NAT) and a separate cohort of 52 matched CNB-post-NAT SE pairs with HER2 IHC scores of 0 or 1+. All slides were scanned using the Roche VENTANA DP 600 scanner. The resulting whole-slide images (WSIs) were subsequently analyzed and scored for HER2 IHC expression using AI assistance via the Roche Navify^® Digital Pathology platform. Expert consensus diagnosis served as the ground truth. Nine pathologists of varying experience re-evaluated their assigned slides with and without AI assistance, assessing changes in diagnostic accuracy, efficiency, and confidence. Additionally, an external cohort of 89 slides from two independent hospitals was used to validate the generalizability of the AI-assisted HER2 interpretation. Among 92 HER2 ultra-low slides (40 biopsy and 52 SE sections) identified by experts, AI assistance significantly improved pathologists' detection performance, increasing the F1-score from 0.78 to 0.98, precision from 0.39 to 0.91, and recall from 0.72 to 0.96 against expert consensus. In non-NAT matched pairs, AI improved the concordance between CNB interpretation and SE ground truth from 0.37 to 0.48, primarily by reducing HER2 underestimation. In post-NAT SE specimens, AI increased classification consistency from 0.63 to 0.92. Furthermore, AI assistance significantly elevated diagnostic agreement among pathologists, reduced interpretation time, and increased the proportion of high-confidence assessments. These findings demonstrate that AI support enhances the accuracy, consistency, and efficiency of HER2 ultra-low identification across biopsy, resection, and post-treatment specimens, potentially improving patient selection for novel ADC therapies. With AI support, pathologists can deliver more precise and confident diagnoses of HER2 ultra-low breast cancer.

Background: Among breast cancer subtypes, triple-negative breast cancer (TNBC) stands out for its aggressiveness and high frequency of brain metastases. However, the mechanisms driving BrM remain poorly understood.

Methods: We performed integrated single-cell RNA sequencing (scRNA-seq) analysis of TNBC among 15 patients (8 with metastases, 7 without) and combined these data with transcriptomic profiles of BrM from public datasets. B cell heterogeneity was characterized, and the prognostic value of cycling B cells (CD19⁺Ki67⁺) was validated in two independent RNA-seq cohorts (TCGA, GSE65194) and a Xiangya real-world cohort. Functional assays were performed using TNBC-derived organoids co-cultured with CD19⁺Ki67^+/- B cells, and multiplex immunofluorescence was used to evaluate activation of signaling pathways.

Results: scRNA-seq revealed significant enrichment of cycling B cells in metastatic TNBC. High abundance of CD19⁺Ki67⁺ B cells correlated with poor overall survival across cohorts. Functional experiments demonstrated that CD19⁺Ki67⁺B cells enhanced TNBC organoid proliferation, invasion, and metastatic potential compared to CD19⁺Ki67^- B cells. Cell-cell communication analysis revealed that activation of the NAMPT/ITGA5/ITGB1 signaling pathway served as a critical mechanism by which B cells regulated crosstalk with cancer cells, which was further validated by multiplex immunofluorescence and a cohort of 74 patient samples.

Conclusions: CD19⁺Ki67⁺ B cells drive TNBC progression and brain metastasis by activating the NAMPT/ITGA5/ITGB1 pathway. These findings provide mechanistic insights into the immune regulation of TNBC BrM and identify potential therapeutic targets to improve clinical outcomes.

Background: Chidamide is an oral subtype-selective histone deacetylase inhibitor that has been used as an anti-cancer agent. This study evaluated the efficacy and safety of chidamide plus fulvestrant in the treatment of HR-positive and HER2-negative advanced breast cancer.

Methods: Eligible patients were women between the ages of 18-75 with HR + /HER2- advanced invasive breast cancer, whose disease relapsed or progressed after endocrine therapy with or without a CDK4/6 inhibitor (CDK4/6i). Eligible patients were treated with oral chidamide (30 mg twice weekly) plus intramuscular fulvestrant (500 mg on days 1 and 15 of cycle one, and then on day one of each subsequent 28 day cycle) until disease progression or toxicity related intolerance. Premenopausal women received a concomitant GnRH analogue. The primary endpoint was progression-free survival.

Results: Between Mar 19, 2021, and Mar 20, 2024, a total of 33 patients were enrolled. Of these, 30 patients who completed at least one post-baseline tumor assessment were included in the efficacy analysis. The median age was 54.5 years (range 31-70), with all 30 (100%) patients having an Eastern Cooperative Oncology Group Performance Status of 1. Visceral metastases were present in 80% (n = 24) of cases, and 50% (n = 15) exhibited metastases in > 3 anatomical sites. The median number of prior treatments was 2 (range 1-4). In total, 40% (n = 12) had undergone prior CDK4/6i therapy. The median progression-free survival for the entire cohort was 6.3 months (95% CI 5.0-9.0). The objective response rate (ORR) was 10%, with a disease control rate (DCR) of 83.3% (partial response + stable disease) and a clinical benefit rate (CBR) of 23.3%. Treatment related adverse events of any grade occurred in 30 (100%) patients, of those 9 (30%) were ≥ grade 3. The most frequent hematologic toxicities included leukopenia (all-grade: 67%; grade 3-4: 19%), followed by neutropenia (all-grade: 47%; grade 3-4: 19%) and thrombocytopenia (all-grade: 40%; grade 3-4: 6%). No treatment-related deaths occurred.

Conclusions: Chidamide combined with fulvestrant showed encouraging antitumor activity and tolerable toxicity in pts with HR + /HER2- advanced breast cancer that had progressed after previous endocrine therapy. Trial registration ChiCTR2100044282, registered on March 14th 2021.

HER2-positive breast cancer is characterized by aggressive tumor biology and intrinsic resistance to conventional therapies, underscoring the need for novel targeted treatment approaches. Pyrotinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), covalently binds to the intracellular kinase domains of HER1 (EGFR), HER2, and HER4, thereby inhibiting downstream signaling pathways and inducing tumor cell apoptosis. Clinical investigations have consistently demonstrated the substantial therapeutic efficacy of pyrotinib in both early-stage and advanced HER2-positive breast cancer. Moreover, its ability to traverse the blood-brain barrier confers potential therapeutic advantages in patients with brain metastases. This comprehensive review provides a systematic overview of the pharmacological profile and mechanism of action of pyrotinib, with emphasis on recent clinical trials assessing pyrotinib-based regimens in HER2-positive breast cancer.

Background: The aim of this study was to develop and characterize a novel ferroptosis-inducing nanocomplex, FBR-NDs (Fe³⁺-BMS-1-R848 Nanodrugs), and to evaluate its anti-tumor effects in breast cancer cells through induction of ferroptosis and modulation of immune responses.

Methods: FBR-NDs were synthesized by nanoprecipitation, followed by characterization using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared (FT-IR) spectroscopy to confirm their structure and composition. Drug loading, release, and redox-responsive properties were assessed using ultraviolet-visible spectroscopy, and the drug release profile was evaluated under acidic pH and glutathione (GSH) conditions. In vitro growth inhibition of breast cancer cells (BT549 and MDA-MB-231) was assessed by cell viability, colony formation, and apoptosis assays. Ferroptosis was evaluated by measuring reactive oxygen species (ROS) levels, lipid peroxidation, mitochondrial morphology via electron microscopy, and expression of ferroptosis-related markers. In vivo anti-tumor efficacy was assessed in a 4T1 breast cancer mouse model, and immune responses were evaluated by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assays.

Results: FBR-NDs demonstrated high drug loading efficiency and exhibited redox-responsive release behavior under acidic pH and GSH conditions. In vitro, FBR-NDs significantly inhibited breast cancer cell proliferation and induced ferroptosis, as evidenced by elevated ROS levels, lipid peroxidation, and mitochondrial damage. In vivo, FBR-NDs significantly reduced tumor growth, enhanced apoptosis, and induced ferroptosis in tumor tissues. Additionally, FBR-NDs treatment increased the infiltration of immune cells, including dendritic cells (DCs) and M1 macrophages, and promoted T-cell activation. Immunogenic cell death was observed, as evidenced by increased levels of high mobility group box 1 (HMGB1) and calreticulin in tumor tissues.

Conclusion: FBR-NDs are a promising therapeutic strategy for breast cancer, combining ferroptosis induction with immune modulation. The ability to induce ferroptosis, enhance immune responses, and promote anti-tumor immunity makes FBR-NDs a potential candidate for cancer immunotherapy.