Shouman Wang

Background: Bone marrow necrosis (BMN) is rare, and malignancy-associated BMN often reflects high tumor burden, rapid progression, and poor prognosis. BMN after definitive treatment for early triple-negative breast cancer (TNBC), followed by visceral progression and coagulation-fibrinolytic abnormalities, is rarely reported. Case Description: A 33-year-old woman underwent breast-conserving surgery and sentinel lymph node biopsy for a 1.8 cm grade 3 invasive carcinoma of no special type. One of four sentinel nodes was positive (pT1cN1a, cM0); the surgical specimen was estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, human epidermal growth factor receptor 2 (HER2) 0, with Ki-67 approximately 90%, consistent with TNBC. She completed four cycles of epirubicin plus cyclophosphamide followed by four cycles of liposomal paclitaxel and adjuvant radiotherapy. Six days after radiotherapy, recurrent fever, bone pain, and progressive thrombocytopenia developed, followed by pancytopenia. Bone marrow biopsy on October 23, 2025 showed extensive necrosis with only a few degenerating nucleated cells and no clearly identifiable viable malignant cells. Contrast-enhanced computed tomography (CT) on November 21 showed liver metastases. On November 25, white blood cell count (WBC) was 1.9×10⁹/L, hemoglobin 54.0 g/L, platelets 4×10⁹/L, aspartate aminotransferase (AST) 308.9 U/L, total bilirubin 60.8 μmol/L, and lactate dehydrogenase (LDH) 2758.1 U/L. D-dimer was 19.49 mg/L, approximately 39 times the laboratory upper reference limit of 0.5 mg/L; prothrombin time (PT) was 15.3 s, below the documented upper reference limit of 21 s; and fibrinogen was 2.11 g/L. Retrospective application of the 2025 International Society on Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) score yielded 5 points, meeting the scoring threshold. D-dimer later exceeded 40.00 mg/L, activated partial thromboplastin time (APTT) and thrombin time increased, and fibrinogen fell to 1.11 g/L. Hepatic and renal dysfunction and multiorgan failure ensued, and she died on December 2, 2025, 288 days after surgery. Conclusions: In aggressive breast cancer, persistent fever, progressive bone pain, rapidly falling blood counts, and elevated LDH should prompt early evaluation for BMN and possible marrow involvement, with assessment for infection, coagulation disorders, hemophagocytic syndrome, and systemic progression. Marked thrombocytopenia with striking D-dimer elevation warrants dynamic DIC assessment even when PT remains within the local reference range. The temporal relationships among BMN, DIC, and prior therapy should be interpreted cautiously.

Background: To evaluate the efficacy and safety of a chemotherapy-free regimen consisting of monoclonal antibody trastuzumab, tyrosine kinase inhibitor pyrotinib, and CDK4/6 inhibitor dalpiciclib in patients with hormone receptor-negative/HER2-positive (HR-HER2+) early breast cancer (EBC). Materials and Methods: This open-label, single-arm, phase II study was designed using the Simon two-stage method (Registration Number: Chi-CTR-2200060748). Patients with operable HR-HER2+ EBC (T1-3 and N0–2) were enrolled. Eligible patients received trastuzumab (HLX02, 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks intravenously), pyrotinib (400 mg daily orally), and dalpiciclib (125 mg daily orally for 3 weeks, followed by 1 week off) for 16 weeks. Surgery was performed 3–6 weeks after the completion of drug treatment. The primary endpoint was total pathological complete response (tpCR, ypT0/Tis, and ypN0) rates at surgery, and secondary endpoints included breast pCR (bpCR) rates (ypT0/Tis), residual cancer burden (RCB), objective response rate (ORR), change of Ki-67 scores, survival, and safety. Results: Between June 2022 and June 2024, a total of 34 patients with a median age of 55 years (range: 35–67) were enrolled. Thirty patients received all cycles of treatment and underwent surgery with a median follow-up of 20 months. The tpCR was achieved in 19 patients (63.3%; 95% CI, 45.5–78.1%). The bpCR was 66.7% (20/30). The number of patients with RCB-0 or RCB-I was 22 (73.3%). The most common Grade 3 treatment-related adverse events were diarrhea (50.0%), neutropenia (20.6%), and leukopenia (17.7%). No Grade 4 events or treatment-related deaths occurred. Conclusion: In patients with HR-HER2+ EBC, the neoadjuvant therapy with trastuzumab, pyrotinib, and dalpiciclib has promising activity and manageable toxicity. Further investigation is needed.

Background: Despite significant advancements in treatment, patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) continue to face the challenge of drug resistance, highlighting the need to develop new drugs and treatment strategies. Pyrotinib has exhibited notable efficacy in managing HER2-positive MBC, especially in individuals with brain metastasis (BM). However, real-world evidence on the effectiveness of pyrotinib re-treatment remains limited. Objectives: This study aims to assess the efficacy of pyrotinib re-treatment—including treatment beyond progression (TBP) and rechallenge—in patients with HER2-positive MBC, particularly those with BMs, in a real-world clinical setting. Design: A retrospective, multicenter, real-world study. Methods: Patients with HER2-positive MBC who experienced progression during pyrotinib treatment and subsequently continued or resumed pyrotinib-based regimens were enrolled. Patients were divided into two groups according to the re-treatment pattern: the pyrotinib TBP group and the pyrotinib rechallenge group. The endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 226 participants received pyrotinib TBP, whereas 33 received pyrotinib rechallenge. The median PFS of pyrotinib re-treatment (7.2 vs 6.3 months, p = 0.31) and the median OS, measured from the start of pyrotinib re-treatment (31.6 vs 21.0 months, p = 0.062), were comparable between the two groups. Among patients with BMs before pyrotinib re-treatment, the median PFS for pyrotinib re-treatment was 7.2 months, and the median OS was 25.2 months. Conclusion: Pyrotinib TBP and pyrotinib rechallenge both demonstrate potential benefits for patients with HER2-positive MBC, including those with BM.

Epitranscriptomic data indicate that aberrant tRNA modifications in malignant diseases can promote tumor growth by facilitating oncogene translation. NSUN2, a 5-methylcytosine (m5C) methyltransferase of tRNA, is elevated in an array of solid cancers, including triple-negative breast cancer (TNBC). However, it remains unclear how NSUN2 drives aggressive behavior and if NSUN2 could be an effective therapeutic target for TNBC. Functional experiments, including RNA interference, lentivirus transduction, and in vivo xenograft models, were conducted to evaluate the role of NSUN2 in TNBC cell proliferation, metastasis, and chemoresistance. Ribosome sequencing (Ribo-seq), tRNA m5C bisulfite sequencing, and codon usage bias analysis were employed to explore the translational mechanisms underlying NSUN2-mediated tRNA modifications. Glycolysis assays and molecular docking were used to investigate metabolic reprogramming and protein interactions. NSUN2 was significantly upregulated in TNBC and correlated with poor patient prognosis. Mechanistically, NSUN2 mediates m5C modification of tRNAVal−CAC, enhancing the codon-frequency-dependent translation of key glycolysis-related genes, including ALDH3A2, ALDH7A1, HK1, and PFKM. Depletion of NSUN2 disrupted tRNAVal−CAC m5C modification, impairing the translation of these metabolic enzymes and suppressing glycolysis, which ultimately inhibited TNBC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, NSUN2 overexpression conferred resistance to docetaxel, while its inhibition sensitized TNBC cells to docetaxel treatment. Clinically, elevated expression levels of NSUN2 and glycolysis-related genes were observed in docetaxel-resistant TNBC tissues, further supporting the role of NSUN2 in chemoresistance. This study identifies NSUN2 as a critical regulator of TNBC progression through tRNAVal−CAC m5C modification and codon-biased translation of glycolysis-related mRNAs. Our findings reveal a novel NSUN2–tRNAVal−CAC axis that orchestrates metabolic reprogramming and translational control in TNBC, offering a promising prognostic biomarker and therapeutic target.

Background: Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and limited treatment options, with chemotherapy resistance posing a significant clinical challenge. UBR5, an E3 ubiquitin ligase, has been consistently reported to be amplified and overexpressed in breast cancers. Materials and methods: This study analyzed 185 TNBC patients to investigate the association between UBR5 expression levels and clinical outcomes. Experimental approaches included in vitro assays using UBR5 knockout or knockdown TNBC cell models treated with doxorubicin and cisplatin, alongside in vivo xenograft models to assess therapeutic responses. Results: High UBR5 expression correlated significantly with poor 5-year disease-free survival (44.0% vs. 82.0% in low UBR5 group) and reduced pathological complete response rates to anthracycline-based neoadjuvant chemotherapy (8.8% vs. 33.3%). In vitro , UBR5 knockout or knockdown sensitized TNBC cells to doxorubicin and cisplatin, enhancing apoptosis and DNA damage accumulation, as evidenced by elevated γ-H2AX levels and impaired DNA damage repair (DDR) pathways, including ATM/CHK2 signaling and key repair proteins (53BP1, RAD51, BRCA1). Mechanistically, UBR5 loss suppressed p38/NF-κB signaling, further compromising DDR and exacerbating chemosensitivity. In vivo , UBR5-deficient xenografts exhibited enhanced doxorubicin responsiveness, an effect mimicked by p38 inhibition. Conclusions: UBR5 serves as a critical mediator of chemoresistance in TNBC by regulating the DNA damage response through the p38 signaling pathway. Targeting UBR5 or p38 signaling presents a promising therapeutic approach to overcome treatment resistance.

Background: Inflammatory breast cancer (IBC), of which HER2 + is the predominant subtype, is extremely aggressive and difficult to treat. Previous studies have suggested that targeting the tumour microenvironment (TME) may provide new directions for IBC diagnosis and treatment. Methods: In this study, we used single-cell transcriptome technology (scRNA-seq) to investigate the molecular features of the TME of HER2 + IBC patients and performed a comprehensive and detailed comparison of the cellular components and molecular phenotypes of the TME between IBC patients and noninflammatory breast cancer (nIBC) patients to elucidate the cell types that are specifically enriched in the TME of IBC patients, as well as the molecular features that are responsible for the preferential remodelling of the cellular functional state in the TME. Results: A total of 15,832 cells, including epithelial cells, endothelial cells, stromal cells, T cells, B cells, antibody secreting cells (ASCs) and myeloid cells, were obtained from tumour tissues from 3 HER2 + IBC patients for scRNA analysis. By comparing the TME with that of HER2 + nIBC patients in a public database, we found that the TME of HER2 + IBC patients had a greater level of lymphocyte infiltration than that of nIBC patients did, and an especially significant enrichment of ASCs (mainly plasmablasts or plasma cells). In the TME of HER2 + IBC patients, tumour-infiltrating T cells exhibited a dual molecular phenotype of high activation and high exhaustion, with tumour-infiltrating B cells preferring the extrafollicular developmental pathway, and tumour-infiltrating myeloid and mesenchymal cells exhibiting a greater immunosuppressive status. By performing a cellular interaction analysis, we revealed that PTN molecules were significantly overexpressed in HER2 + IBC tumour cells and that the cellular interactions mediated by these molecules were strongly correlated with the functional polarisation of the cellular components in the TME. We observed that HER2 + IBC tumour cells have an active interferon response and epithelial mesenchymal transition (EMT) signalling, and that their malignant process is strongly correlated with the inflammatory response. Moreover, we found that HER2 + IBC tumour-infiltrating B cells promoted necroptosis of endothelial cells through high expression of TNF, thus promoting inflammatory responses. Conclusion: We found a strong correlation between high expression of PTN molecules in HER2 + IBC tumour cells and their highly invasive characteristics and highly immunosuppressive TME. These results suggest that HER2 + IBC tumour cells can promote an inflammatory response by upregulating the expression of TNF molecules in B cells via PTN molecules and that the enhanced inflammatory response in turn promotes tumour progression, a malignant cycle that shapes a more immunosuppressive TME. Therefore, diagnostic and therapeutic strategies targeting the PTN-TNF molecular axis may have considerable potential for development in HER2 + IBC patients.

Objective: Hormone receptor (HR)-low/HER2-negative breast cancers (BCs) are more likely to be basal-like BCs, with similar molecular features and gene expression profiles to HR-negative (estrogen receptor P = 1.000), ORR rate (76.9% vs. 78.3%, P = 0.827) and CBR rate (89.7% vs. 96.5%, P = 0.113) after NAC were similar between the HR-low/HER2-negative BC and the TNBC group. EFS in patients with non-pCR from the 2 groups was significantly inferior in comparison to patients with pCR (P = 0.001), and the 3-year EFS was 94.74% (95% CI = 85.21% to 100.00%) and 57.39% (95% CI =43.81% to 75.19%) in patients with pCR and non-pCR from the HR-low/HER2-negative BC group, respectively, and 89.70% (95% CI = 82.20% to 97.90%) and 69.73% (95% CI = 62.51% to 77.77%) in the TNBC patients with pCR and non-pCR, respectively.Conclusions: In the real world, the therapeutic effects of NAC for HR-low/HER2-negative BCs and TNBCs were similar. EFS of patients with non-pCR in the HR-low/HER2-negative BC group was inferior to that of the TNBC group with non-pCR, suggesting that it is necessary to explore new adjuvant intensive therapy strategies for these patients.

In the dynamic process of metastasis, circulating tumor cells (CTCs) emanate from the primary solid tumor and subsequently acquire the capacity to disengage from the basement membrane, facilitating their infiltration into the vascular system via the interstitial tissue. Given the pivotal role of CTCs in the intricate hematogenous metastasis, they have emerged as an essential resource for a deeper comprehension of cancer metastasis while also serving as a cornerstone for the development of new indicators for early cancer screening and new therapeutic targets. In the epoch of precision medicine, as CTC enrichment and separation technologies continually advance and reach full fruition, the domain of CTC research has transcended the mere straightforward detection and quantification. The rapid advancement of CTC analysis platforms has presented a compelling opportunity for in-depth exploration of CTCs within the bloodstream. Here, we provide an overview of the current status and research significance of multi-omics studies on CTCs, including genomics, transcriptomics, proteomics, and metabolomics. These studies have contributed to uncovering the unique heterogeneity of CTCs and identifying potential metastatic targets as well as specific recognition sites. We also review the impact of various states of CTCs in the bloodstream on their metastatic potential, such as clustered CTCs, interactions with other blood components, and the phenotypic states of CTCs after undergoing epithelial-mesenchymal transition (EMT). Within this context, we also discuss the therapeutic implications and potential of CTCs.

Background: Pegylated liposomal doxorubicin (PLD), epirubicin and pirarubicin are the main anthracyclines widely used in China. PLD demonstrates therapeutic response comparable to epirubicin and pirarubicin in neoadjuvant chemotherapy (NAC) of breast cancer. Objectives: The objectives of our study were to retrospectively assess the real-world effectiveness and prognostic characteristics of PLD as NAC for HR ⩽ 10%/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Design: This was a retrospective study. Methods: Our study enrolled patients with HR ⩽ 10%/HER2-negative breast cancer who received PLD-, epirubicin- or pirarubicin-based NAC from three centres in Hunan Province, China, between 2015 and 2022. We employed inverse probability of treatment weighting to balance the differences in patients’ characteristics among the PLD, epirubicin, and pirarubicin groups. The endpoints were pathological complete response (pCR), event-free survival (EFS), and overall survival (OS). Results: A total of 267 patients were included. After NAC, the pCR rates in PLD group were superior to epirubicin group (PLD, 34.1%; epirubicin, 20.8%, p = 0.038). The differences in EFS (log-rank p = 0.99) and OS (log-rank p = 0.33) among the three groups were not statistically significant. Among the three groups, non-pCR patients had worse EFS than pCR patients (log-rank p = 0.014). For patients with pCR, the differences in EFS (log-rank p = 0.47) and OS (log-rank p = 0.38) were not statistically significant among the three groups, and the EFS (log-rank p = 0.59) and OS (log-rank p = 0.14) of non-pCR patients in the PLD group were similar to those in the epirubicin and pirarubicin groups. Conclusion: PLD had a similar therapeutic response and prognosis compared to epirubicin or pirarubicin in NAC for patients with HR ⩽ 10%/HER2 negative breast cancer, which means that PLD represents a potential NAC option.