bims-netuvo 2026-01-11 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2026–01–11
thirteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

A subcellular spatial atlas illuminates the microenvironmental remodeling of perineural invasion in distal cholangiocarcinoma.
Noninvasive Prediction of Perineural Invasion and Lymphovascular Invasion in Prostate Cancer Using bpMRI Radiomic Signatures.
Integrins as key regulators in tumor perineural invasion: mechanisms and clinical implications.
Notch1+ cervical cancer cells may promote perineural invasion by secreting neurotrophin-4.
Baseline Tumor Biology Predicts Survival After Recurrence in Gastric Cancer: Impact of LVI, PNI, and HER2 Status.
Beta-Blocker Use and Survival Outcomes in Pancreatic Cancer Patients: A Systematic Review and Meta-Analysis.
Intraoperative Molecular Imaging Can Detect Large Nerve Perineural Invasion: A Case Report.
Intracranial activity of antibody-drug conjugates in advanced non-small cell lung cancer: What have we accomplished so far?
KDM3B promotes neural invasion in colorectal cancer through TrkA upregulation by inhibiting H3K9 dimethylation.
Depression as a Prodromal Symptom of Pancreatic Cancer: A Narrative Review.
Longitudinal trajectories of cancer-related cognitive impairment and influential factors among patients with lung cancer.
An updated review on systemic therapy for brain metastases in non-small cell lung cancer.
Divergence of DNA tumor mutations in cerebrospinal fluid in metastatic breast cancer patients with leptomeningeal metastases.

J Hematol Oncol. 2026 Jan 08. 19(1): 6

A subcellular spatial atlas illuminates the microenvironmental remodeling of perineural invasion in distal cholangiocarcinoma.

Fansen Ji, Hao Chen, Huan Li, Jiawei Zhang, Sijia Li, Pengfei Wang, Hao Liu, Cui Ge, Bingjun Tang, Hongfang Yin, Xuedong Wang, Jiahong Dong.

  Distal cholangiocarcinoma (dCCA) arises from the distal bile duct and is anatomically embedded within the pancreatic head, adjacent to abundant autonomic nerve plexuses. This unique location renders dCCA particularly prone to perineural invasion (PNI), a pathological hallmark that contributes to its dismal prognosis. However, the spatial architecture and molecular drivers that orchestrate PNI remain poorly defined. Here, we applied Xenium subcellular resolution spatial transcriptomics platform to profile resected tumor tissues from dCCA patients stratified by PNI status pathologically. A spatially resolved atlas comprising a total of 20 cell types was generated, uncovering enrichment of Schwann cells, type 2 conventional dendritic cells (cDC2), M2-like macrophages, cancer associated fibroblasts (CAFs) and B/plasma cells in PNI-high tumors, along with depletion of exhausted CD8+ T cells. Heterogeneous malignant cells in PNI-high tumors demonstrated activation of extracellular matrix remodeling and axonogenesis pathways, in line with the initial pathological classification. Spatial mapping further revealed distinct PNI-associated niches, notably matrix-producing CAFs (mCAFs)-macrophage clusters exhibiting coordinated enrichment of inflammatory and fibrotic programs. We further identified the LAMB3-DAG1 axis as a potential mediator of dCCA cells-Schwann cell interaction, while the preferential proximity of arteries to Schwann cells suggested additional microenvironmental support for nerve invasion. Collectively, our study provides a comprehensive subcellular atlas of PNI in dCCA, uncovering coordinated epithelial, stromal, and immune remodeling that drives perineural invasion. The identified biomarkers not only hold promise for patient stratification but may also guide intraoperative navigation and surgical margin determination, offering new avenues for precision therapy.

Keywords:  PNI; Schwann cells; Spatial transcriptomics; TME; dCCA

DOI:  https://doi.org/10.1186/s13045-025-01773-4
Acad Radiol. 2026 Jan 08. pii: S1076-6332(25)01080-3. [Epub ahead of print]

Noninvasive Prediction of Perineural Invasion and Lymphovascular Invasion in Prostate Cancer Using bpMRI Radiomic Signatures.

Yun-Feng Zhang, Chuan Zhou, Di Liu, Hengxin Chen, Qidong Wang, Hongde Hu, Han He, Jia Wang, Wenbo Zhang, Xi Wu, Yongqi Ren, Fenghai Zhou.

   OBJECTIVE: Perineural invasion (PNI) and lymphovascular invasion (LVI) are critical predictors of aggressive behavior and poor prognosis in prostate cancer (PCa), yet their diagnosis relies on postoperative histopathology. This study aims to develop a noninvasive radiomic model based on biparametric magnetic resonance imaging (bpMRI) for preoperative prediction of PNI and LVI.
METHODS: A total of 256 patients with pathologically confirmed PCa who underwent radical prostatectomy were retrospectively enrolled. Patients from Center 1 (n = 179) constituted the training set, while those from Center 2 (n = 77) formed the external test set. A rigorous imaging-pathology correlation protocol was applied to ensure accurate lesion matching. Inter-observer variability in segmentation was assessed (ICC > 0.75 for 85% of features), with final ROIs determined by consensus. Radiomic features were extracted from T2-weighted and diffusion-weighted imaging. Feature selection was performed using Spearman's correlation and LASSO algorithm. Multiple machine learning classifiers were constructed and interpreted with SHAP.
RESULTS: The best-performing model for PNI prediction was Multilayer Perceptron (MLP), with an AUC of 0.805 (95% CI: 0.741-0.869) in the training set and 0.795 (95% CI: 0.698-0.896) in the test set. For LVI prediction, Logistic Regression achieved the highest performance, with an AUC of 0.859 (95% CI: 0.804-0.914) in the training set and 0.810 (95% CI: 0.714-0.906) in the test set. Calibration curves and decision curve analysis indicated good model accuracy and clinical utility.
CONCLUSION: Radiomic models derived from bpMRI can noninvasively and robustly predict PNI and LVI in PCa, demonstrating good generalizability across independent cohorts.

Keywords:  Lymphovascular invasion; Magnetic resonance imaging (MRI); Peripheral nerve invasion; Prostate cancer; Radiomics

DOI:  https://doi.org/10.1016/j.acra.2025.11.033
Clin Transl Oncol. 2026 Jan 08.

Integrins as key regulators in tumor perineural invasion: mechanisms and clinical implications.

Yuanyuan Li, Xiaoli Cao, Mei Wang.

  Perineural invasion (PNI) serves as an important prognostic indicator in various solid tumors, closely associated with tumor recurrence and reduced survival rates. At present, the molecular mechanisms of initiating PNI have been extensively studied but still lack targets employed for efficient diagnosis and treatment clinically. The integrins' family is major cell adhesion receptors linking the cytoskeleton to the extracellular matrix (ECM) and mediating bidirectional signaling involved in tumor development. Recently, emerging evidence has emphasized the crucial role of integrins in PNI. To comprehensively understand its potential regulatory mechanisms and application prospects, this review summarizes the latest research on integrins affecting PNI, covering their molecular characteristics, oncogenic mechanisms, and clinical significance. In addition, we also point out the current challenges and propose innovative strategies to promote the advancement of tumor diagnosis, prognosis prediction, and therapeutic strategies.

Keywords:  Diagnostic and prognostic potentials; Integrin; Regulatory mechanisms; Targeted therapy; Tumor perineural invasion

DOI:  https://doi.org/10.1007/s12094-025-04196-2
Sci Rep. 2026 Jan 08.

Notch1+ cervical cancer cells may promote perineural invasion by secreting neurotrophin-4.

Fengjie Li, Zhihao Wei, Muheng Tao, Kangning Zhao, Liangting Wang, Xiaowei Chen, Yanzhou Wang.



Keywords:  Cervical carcinoma; Neurotrophin; Notch1; Perineural invasion

DOI:  https://doi.org/10.1038/s41598-025-34812-8
Med Sci Monit. 2026 Jan 09. 32 e951829

Baseline Tumor Biology Predicts Survival After Recurrence in Gastric Cancer: Impact of LVI, PNI, and HER2 Status.

Gözde Ağdaş, Mehmet Salim Demir.

BACKGROUND Lymphovascular invasion (LVI) and perineural invasion (PNI) are established markers of aggressive disease in primary gastric cancer, but their specific prognostic role in patients who develop recurrence after curative surgery is less clear. This study aimed to evaluate clinicopathological and treatment-related factors associated with overall survival (OS) and disease-free survival (DFS) in a cohort of gastric cancer patients who experienced recurrence. MATERIAL AND METHODS This retrospective study included 70 patients who underwent curative gastrectomy and subsequently developed confirmed recurrence. OS (from diagnosis) and DFS (from surgery to recurrence) were analyzed using Kaplan-Meier curves and Cox regression. Multivariate models were constructed with a limited number of variables to avoid overfitting. RESULTS The median OS was 38.9 months, and the median DFS was 22.4 months. In multivariate analysis, LVI positivity (HR=3.39; 95% CI: 1.59-7.19; P=0.001) and advanced clinical stage were independent predictors of worse OS, while adjuvant chemoradiotherapy (HR=0.44; P=0.017) and receiving first-line systemic therapy after recurrence (HR=0.22; P<0.001) were protective. For DFS, PNI positivity predicted shorter DFS (HR=1.91; P=0.033). HER2 positivity was associated with longer DFS (HR=0.78; P=0.015); notably, 42.9% of HER2-positive patients received trastuzumab upon recurrence. CONCLUSIONS In gastric cancer patients who develop recurrence, baseline biological markers (LVI, PNI, HER2) retain significant prognostic value for OS and DFS from the time of diagnosis and surgery, respectively. Integrating these markers with treatment parameters may improve risk stratification. This study did not evaluate pure post-recurrence survival (PRS); OS was calculated from diagnosis and therefore reflects pre- and post-recurrence periods combined.

DOI: https://doi.org/10.12659/MSM.951829
Clin Med Insights Oncol. 2026 ;20 11795549251411762

Beta-Blocker Use and Survival Outcomes in Pancreatic Cancer Patients: A Systematic Review and Meta-Analysis.

Rui Li, Jie Chen, Yingkai Chen, Kai Jin, Yong Chen, Changyu Deng, Xuefen Liu, Yue Li.

   Background: Pancreatic cancers (PCs)-especially pancreatic ductal adenocarcinoma (PDAC)-are among the deadliest digestive system cancers, with a 5 year survival of approximately 13%. Beta blockers (BBs), which inhibit beta-adrenergic receptor-mediated angiogenesis and immunosuppression, are potential candidates for oncological drug repurposing. However, the clinical evidence is inconsistent, and robust subgroup analyses are lacking. This study systematically evaluated the association between BB use and survival in PC patients. Furthermore, subgroup analyses were conducted to clarify differential clinical effects.
Methods: This study was conducted in accordance with PRISMA guidelines and registered with PROSPERO (CRD420251106076). The PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify observational studies on all-cause mortality (ACM) and cancer-specific mortality (CSM). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using RevMan 5.3 and R, and the results were presented in forest plots.
Results: This analysis included nine retrospective cohort studies involving over 30 000 patients. There were no significant associations between BB use and ACM (HR = 1.07; 95% CI [0.95-1.20]) or CSM (HR = 0.89; 95% CI [0.70-1.14]). However, subgroup analysis revealed that BB use was significantly associated with increased ACM risk in surgical patients (HR = 1.18; 95% CI [1.05-1.31]). Moreover, non-selective BB (NSBB) use significantly reduced CSM risk (HR = 0.81; 95% CI [0.68-0.97]). Both sensitivity and trim-and-fill analyses confirmed the robustness and consistency of these results.
Conclusions: This meta-analysis presents the first systematic evidence regarding the potential role of NSBBs in mitigating CSM, thus providing support for their potential repurposing. In addition, these findings indicate that perioperative BB use may be associated with increased ACM risk, highlighting the need for careful perioperative risk assessment. To further substantiate these findings, future prospective studies should explore combined approaches, particularly those integrating immune or anti-angiogenic therapies.

Keywords:  Pancreatic cancer; all-cause mortality; beta blockers; beta-adrenergic receptors; cancer-specific mortality; drug repurposing; pancreatic ductal adenocarcinoma; perioperative management

DOI:  https://doi.org/10.1177/11795549251411762
Head Neck. 2026 Jan 07.

Intraoperative Molecular Imaging Can Detect Large Nerve Perineural Invasion: A Case Report.

Carleigh R Burns, Aviva S Mattingly, Kim Ely, Andreja Radevic, Nicole Meeks, Sydea Maria Ahmad Zaidi, Brandee Brown, Georgii Vasiukov, Michael Topf, Eben Rosenthal.

   BACKGROUND: Perineural invasion (PNI) in head and neck squamous cell carcinoma (SCC) results in worse overall survival. Diagnosis requires resection and microscopic evaluation.
METHODS: A 63-year-old male with persistent cT4aN0 p16-positive SCC of the left base of tongue following chemoradiotherapy underwent salvage total glossectomy. Fluorescence-guided imaging of the wound bed was performed with PDE-GEN3 near-infrared (NIR) imaging following infusion of an optically EGFR-targeted antibody, Panitumumab-IRDye800 (pan800).
RESULTS: The proximal resected hypoglossal nerve was imaged intraoperatively and demonstrated a strong green fluorescence signal, raising concern for subclinical PNI. Biopsy of the nerve revealed SCC on frozen section analysis. This was re-resected with subsequent proximal margin negative for carcinoma. Postoperatively, ex vivo imaging of the nerve using PDE-GEN3 NIR imaging again demonstrated the presence of pan800 within the initial positive nerve margin, confirming subclinical PNI.
CONCLUSIONS: This case shows the feasibility of intraoperative fluorescence as a method to help identify subclinical PNI.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05945875.

Keywords:  Panitumumab‐IRDye800; fluorescence‐guided surgery; head and neck squamous cell carcinoma; intraoperative visualization; perineural invasion

DOI:  https://doi.org/10.1002/hed.70160
Cancer Treat Rev. 2025 Dec 31. pii: S0305-7372(25)00205-1. [Epub ahead of print]143 103083

Intracranial activity of antibody-drug conjugates in advanced non-small cell lung cancer: What have we accomplished so far?

Seng Wee Cheo, Molly S C Li, Derek De-Rui Huang, Stephanie P L Saw, Lizza E L Hendriks, Jordi Remon, Jessica Menis, Alfredo Addeo, Pei Jye Voon.

  Antibody-drug conjugates (ADCs) represent a rapidly evolving class of therapeutics in non-small cell lung cancer (NSCLC), offering targeted delivery of cytotoxic payloads to tumor cells while minimizing off-target toxicity. Although ADCs have demonstrated promising results in NSCLC, their efficacy in treating central nervous system (CNS) metastases has been uncertain due to concerns over blood-brain barrier (BBB) penetration and the lack of dedicated CNS-specific evaluations in clinical trials. However, emerging evidence challenges this paradigm. While earlier-generation ADCs such as T-DM1 exhibited limited CNS efficacy, newer ADCs employing optimized linkers and cytotoxins demonstrate more favorable efficacy and toxicity profiles. Selected agents, including trastuzumab deruxtecan, datopotamab deruxtecan and patritumab deruxtecan, have all shown intracranial responses in patients with advanced NSCLC with brain metastases (BM). Proposed mechanisms facilitating CNS activity include BBB disruption by BM, membrane-permeable and highly potent cytotoxic payloads, and bystander effects that enable tumor cell killing beyond the target antigen. Nevertheless, several limitations remain, including variability in trial designs, limited number of patients with untreated CNS disease, and a lack of CNS-specific endpoints. Given the high incidence of BM in NSCLC and their significant impact on patient outcomes, there is an urgent need to better understand the intracranial activity of ADCs and whether they can prevent the development of CNS metastases, especially as some of these ADCS are being tested in the curative-intent setting. This review synthesizes current evidence and highlights ongoing trials, with a focused examination of the evolving role of ADCs in the management of BM.

Keywords:  Antibody-drug conjugates; Brain metastasis; Central nervous system; Intracranial activity; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.ctrv.2025.103083
iScience. 2025 Dec 19. 28(12): 114262

KDM3B promotes neural invasion in colorectal cancer through TrkA upregulation by inhibiting H3K9 dimethylation.

Juan Li, Sizheng Sun, Xing Wang, Yinchun Li, Huifeng Zhang, Xianhua Fu, Xiaojun Zhao, Guojie Chen.

  Since neural invasion (NI) is a key factor leading to poor prognosis of patients with colorectal cancer (CRC), exploring its mechanism in CRC is an urgent challenge. In this study, lysine demethylase 3B (KDM3B), a differential protein for NI in CRC, was detected by TMT-seq of clinical CRC tissues (control vs. NI). Cut-tag and ATAC-seq of CRC cell line (control vs. sh-KDM3B) found that KDM3B promoted the expression of TrkA-encoding sequence NTRK1 in CRC, which was then verified through in vivo and in vitro experiments. The results demonstrated that overexpression of KDM3B in CRC could inhibit H3K9me2, which in turn contributed to the upregulation of TrkA, enabling binding of nerve growth factor (NGF) to it and ultimately inducing CRC NI. The present study reveals the intrinsic mechanism of NI in CRC, which lays a solid theoretical foundation for using KDM3B as a prognostic indicator and therapeutic target for CRC.

Keywords:  Biological sciences; Cancer; Epigenetics

DOI:  https://doi.org/10.1016/j.isci.2025.114262
Cancers (Basel). 2025 Dec 19. pii: 16. [Epub ahead of print]18(1):

Depression as a Prodromal Symptom of Pancreatic Cancer: A Narrative Review.

Chiara Deori, Federica Andreis, Valentina Giubileo, Silvia Noventa, Ester Oneda, Fausto Meriggi, Alberto Zaniboni.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, typically diagnosed at an advanced stage. The identification of prodromal symptoms could support earlier detection. Among these, depression is frequently reported, raising the question of whether it may represent not only a reactive response but also a paraneoplastic manifestation.
METHODS: We conducted a narrative review of clinical, epidemiological and biological literature published between 1988 and 2025. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using predefined keywords related to pancreatic cancer, depression, prodromal symptoms, cytokines, and the kynurenine pathway. Eligible studies included clinical cohorts, population-based analyses, biological investigations, and case reports exploring the temporal or mechanistic link between depression and PDAC.
RESULTS: A substantial proportion of patients (10-20%) exhibit depressive symptoms in the months preceding the clinical diagnosis of pancreatic cancer. In several cases, depression occurs independent of weight loss and new-onset diabetes. Biological evidence highlights the involvement of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), NF-κB signaling, and activation of the tryptophan-kynurenine pathway (IDO), suggesting a link between tumor-related processes and mood alterations. These mechanistic findings are actually hypothesis-generating, deriving mainly from small clinical cohorts and preclinical models. Clinically, depression is associated with reduced adherence to treatment, poorer quality of life, and shorter survival. However, no specific depressive phenotype has been identified.
CONCLUSIONS: Depression may represent a potential prodromal symptom of pancreatic cancer, reflecting systemic biological processes as well as psychological reactions. Its utility as a standalone marker remains limited; future studies should integrate psychiatric, clinical and biological biomarker assessments to enhance early clinical diagnosis.

Keywords:  cytokines; depression; kynurenine pathway; pancreatic cancer; prodromal symptoms

DOI:  https://doi.org/10.3390/cancers18010016
Compr Psychoneuroendocrinol. 2026 Feb;25 100330

Longitudinal trajectories of cancer-related cognitive impairment and influential factors among patients with lung cancer.

Xiaoju Zhu, Yalan Huang, Haiwei Fu, Sixiong Luo, Yuanjing Jiang, Zonghua Wang.

   Objective: This study aimed to investigate longitudinal cognitive changes and identify factors associated with cancer-related cognitive impairment (CRCI) among lung cancer survivors.
Methods: Cognitive function was assessed using the FACT-Cog (subjective) and TICS-M (objective). The baseline assessment was completed before the use of chemotherapy drugs and recorded as T0. After completing the first cycle of chemotherapy, it was recorded as T1; after the second cycle, as T2; after the third cycle, as T3; after the fourth cycle, as T4; and after the fifth cycle, as T5. Linear mixed-effect models evaluated associations between clinical/sociodemographic factors and cognitive outcomes.
Results: Higher education level and later treatment progression were correlated with increased TICS-M scores. In contrast, Rural residence (β = -1.89, p = 0.021) and more comorbidities (β = -2.15, p = 0.033) were associated with reduced FACT-Cog scores. Treatment progression correlated with improved TICS-M scores (β = 0.716, p = 0.001). No significant differences were observed between the chemotherapy and chemoimmunotherapy groups (p > 0.05). A key finding was the observed discordance between stable subjective reports and modestly improving objective scores over time. There was a discrepancy between subjective and objective cognitive evaluations, as FACT-Cog scores remained consistent over time (mean 129.8 ± 20.2), while TICS-M scores showed a slight improvement (from 23.4 ± 4.9 to 24.4 ± 3.7).
Discussion: The influence of education, residence, and comorbidities on CRCI trajectories in lung cancer patients highlights the need for integrated evaluation tools. This longitudinal analysis not only identifies distinct risk profiles for CRCI but also underscores the critical need for proactive screening and tailored supportive care programs. These priorities provide a guide for improving cognitive health outcomes in lung cancer survivorship care.

Keywords:  Cognitive function; Longitudinal study; Lung cancer; Quality of life

DOI:  https://doi.org/10.1016/j.cpnec.2025.100330
Transl Cancer Res. 2025 Dec 31. 14(12): 9053-9062

An updated review on systemic therapy for brain metastases in non-small cell lung cancer.

Shreya Louis, John Paul Aboubechara, Keshav Saigal, Toni Cao, Seema Nagpal.

  Brain metastases (BrM) are a frequent and devastating complication of non-small cell lung cancer (NSCLC), affecting up to 40% of patients during their disease course. Historically, treatment relied primarily on surgery and radiation, as systemic therapies were thought to have limited activity in the central nervous system (CNS). However, over the past two decades, the development of more targeted therapies has transformed the treatment landscape. Many of these newer agents have improved CNS penetration, which may offer patients the possibility of deferring or reducing the need for local therapies and their associated toxicities. Despite these advances, many challenges remain. There is still a lack of consistent inclusion of BrM patients in clinical trials, and when they are included, there are inconsistencies in measuring radiographic responses as well as in standardized CNS-specific endpoints, making it difficult to compare outcomes across therapies. As treatment options expand, the integration of systemic therapies with surgery and radiation requires nuanced, multidisciplinary decision-making tailored to individual patients. In this review, we aim to summarize the current treatment landscape of pertinent therapies for BrM in NSCLC patients while highlighting the need for broadening inclusion of these patients and creating well-designed prospective studies that intentionally include patients with active and untreated BrM alongside rigorously assess intracranial outcomes. Such efforts will be critical to developing treatment plans in order to ultimately improve survival and quality of life for NSCLC patients with BrM.

Keywords:  Brain metastases (BrM); antibody-drug conjugates (ADCs); immune-checkpoint inhibitors (ICIs); non-small cell lung cancer (NSCLC); tyrosine kinase inhibitors (TKIs)

DOI:  https://doi.org/10.21037/tcr-2025-1434
Breast. 2025 Dec 11. pii: S0960-9776(25)00893-8. [Epub ahead of print]85 104674

Divergence of DNA tumor mutations in cerebrospinal fluid in metastatic breast cancer patients with leptomeningeal metastases.

Peter H Wessels, Sten Cornellisen, Kim Monkhorst, Gabe S Sonke, Annegien Broeks, Dorothe Linders, Daan van den Broek, Mirjam C Boelens, Dieta Brandsma.

   PURPOSE: To study differences in genetic alterations between primary breast cancer, systemic metastases, and cerebrospinal fluid (CSF) in patients with leptomeningeal metastases (LM).
MATERIAL AND METHODS: Breast cancer patients with confirmed or probable LM and available primary tumor tissue were selected from a CSF-biobank study of the Netherlands Cancer Institute. Genetic analysis of cell-free DNA (cfDNA) in CSF and tissue from the primary tumor and/or systemic metastases was performed using Next Generation Sequencing (NGS). In patients with HR+/HER2-breast cancer, CSF and tumor tissues were also tested for ESR1 mutations with Sanger sequencing.
RESULTS: 27 breast cancer patients with LM (n = 23 confirmed LM; n = 4 probable LM) were included in the study. Fourteen patients had triple negative (TN), 11 HR+/HER2-and 3 HER2+ breast cancer. CSF-only genetic alterations were observed in 5 (20 %) of 25 evaluable patients. The majority of these genetic alterations were found in the PTEN-PI3K-AKT pathway, which were present in 3 of 14 evaluable patients with a TN breast cancer subtype (21 %) and in one patient wit HER2+ breastcancer. In one HR+/HER2+ patient, an ESR1 mutation was present in both CSF and systemic metastases, while it was absent in the primary tumor. All genetic alterations that were observed in either the primary tumor or systemic metastases were also observed in the CSF.
CONCLUSION: In 20 % of breast cancer patients with LM, genetic alterations in the CSF were discordant from the primary tumor and/or systemic metastases. These genetic alterations involved in particular the PTEN-PI3K-AKT pathway in TN breast cancer. No ESR1 mutation limited to CSF only was found in HR+/HER2-breast cancer. Divergence of genetic alterations in LM from breast cancer must be considered for optimization of future target treatment strategy.

Keywords:  Breast cancer; Cerebrospinal fluid; Divergence; Genetic alterations; Leptomeningeal metastases; Next generation sequencing

DOI:  https://doi.org/10.1016/j.breast.2025.104674