BACKGROUND:HER2 status in heterogeneous breast cancer (BC) can change dynamically during treatment, and is associated with prognosis and clinical decisions. Understanding the patterns of these changes may inform risk stratification and treatment planning. METHODS:This retrospective study analyzed 3748 BC patients with residual disease following neoadjuvant therapy (NAT) (2015-2021). HER2 status was assessed according to ASCO/CAP guidelines and pathological response by the Miller-Payne grading system. Multinomial logistic regression and Cox models identified factors linked to HER2 conversion and its association with treatment response and survival outcomes. RESULTS:HER2 status post-NAT showed 22.9% overall discordance (11.2% loss; 11.7% gain), predominantly between HER2-0 and HER2-low. Multivariate analysis revealed that age ≥ 50 years was associated with reduced likelihood of HER2 gain (adjusted OR 0.69, p < 0.001), whereas HR-positivity was associated with increased likelihood (adjusted OR 1.35, p = 0.027). Intratumoral calcification (adjusted OR 0.75, p = 0.006) and clinical stage III (adjusted OR 0.77, p = 0.016) were associated with decreased risk of HER2 loss. Conversion from HER2-0 to HER2-low status was significantly associated with poorer pathological response (adjusted OR 0.47, p = 0.011) and independently predicted inferior RFS (adjusted HR 1.33, p = 0.009) and OS (adjusted HR 1.40, p = 0.032). The adverse prognostic impact of HER2 evolution was particularly pronounced in HR-positive patients (interaction p < 0.05). CONCLUSION:Dynamic alterations in HER2 status following NAT are significantly associated with treatment response and survival outcomes. For patients without pathological complete response, reassessment of HER2 status after NAT may help identify those with distinct prognostic profiles and who are potential candidates for emerging antibody-drug conjugate therapies.

Breast cancer remains a leading cause of cancer-related morbidity and mortality worldwide, driven by therapeutic resistance, recurrence, and metastasis. Patient-derived organoids (PDOs) have emerged as a robust platform that preserves histopathological, genetic, and functional features of parental tumors, enabling translational research and precision oncology. However, the lack of standardized procedures across laboratories limits reproducibility and clinical applicability. Here, we present a consensus-oriented standard for the establishment, characterization, quality control and application of human breast cancer organoids derived from diverse clinical sources, including surgical tissues, biopsies, pleural effusion, ascites, and circulating tumor cells (CTCs). This document defines key terminologies, outlines standardized workflows, and introduces quantitative validation criteria for successful organoid establishment. In addition, it provides structured guidance for advanced models, including immune–tumor, neuro–tumor, and microbiota−tumor organoid systems, with defined functional validation endpoints. Standardized protocols for drug sensitivity testing are also proposed, including seeding density, exposure duration, and response metrics such as IC50 and AUC. Representative validation strategies, including histological, molecular and functional concordance with parental tumors, are incorporated to enhance reproducibility and translational relevance. This standard aims to harmonize methodologies, improve cross−study comparability, and accelerate the clinical implementation of breast cancer organoid-based precision medicine.

[This corrects the article DOI: 10.3389/fonc.2021.614458.].

BackgroundTriple-negative breast cancer (TNBC) is characterized by high heterogeneity and poor prognosis. A particularly aggressive subset, termed ‘rapid relapse’ TNBC (rrTNBC), is defined by distant metastasis or death within 24 months of diagnosis. Understanding the unique recurrence patterns and prognostic determinants of rrTNBC is crucial for deciphering tumor evolution and optimizing therapeutic strategies. This study aims to delineate the clinicopathological features, recurrence patterns, and prognostic outcomes of rrTNBC compared to slow relapse TNBC (srTNBC).MethodsWe retrospectively analyzed 638 postoperative patients with recurrent or metastatic TNBC treated at Tianjin Medical University Cancer Institute & Hospital. Patients were categorized into rrTNBC (relapse ≤24 months, n = 478) and srTNBC (relapse >24 months, n = 160). Clinicopathological variables, recurrence sites, and survival outcomes, including disease-free survival (DFS), progression-free interval (PFI) after first salvage therapy, post-recurrence survival (PRS), and overall survival (OS), were compared between the two groups.ResultsCompared to srTNBC, rrTNBC was associated with higher TNM stage, T stage, N stage, and a lower proportion of stromal tumor-infiltrating lymphocyte expression (all p < 0.001). Regarding recurrence patterns, rrTNBC patients were more likely to present with visceral (74.90% vs. 22.50%, p < 0.001) and brain metastases (10.88% vs. 0.62%, p < 0.001) as the first event, whereas srTNBC patients had a higher incidence of first relapse in the chest wall or regional lymph nodes (90.00% vs. 62.13%, p < 0.001). Consequently, rrTNBC was characterized by a significantly higher rate of direct distant metastasis at first recurrence (93.10% vs. 28.12%, p < 0.001). Prognostically, rrTNBC patients had markedly worse outcomes across all metrics compared to srTNBC patients, including median disease-free survival (13.4 vs. 26.6 months), median PFI after first-line salvage therapy (2.27 vs. 8.43 months), median PRS (12.1 vs. 23.5 months), and median overall survival (26.5 vs. 52.0 months) (all p < 0.001). In the platinum-based first-line salvage therapy subgroup (n = 369), rrTNBC patients (n = 267) consistently demonstrated significantly shorter DFS, PFI, PRS, and OS compared to srTNBC patients (n = 102) (all p < 0.001).ConclusionrrTNBC represents a distinct, highly aggressive phenotype with a predilection for visceral and brain metastasis and a dismal response to conventional platinum-based salvage therapy. These findings are consistent with the aggressive clonal evolution within rrTNBC and highlight an urgent need for novel therapeutic strategies to be prospectively evaluated in this high-risk population.

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, lacking effective targeted therapies, and whose underlying mechanisms are still unclear. The gene coding for Gametogenetin-binding protein (GGNBP2), also known as Zinc Finger Protein 403 (ZNF403), is located on chromosome 17q12-q23, a region known as a breast cancer susceptibility locus. We have previously reported that GGNBP2 functions as a tumor suppressor in estrogen receptor-positive breast cancer. The aim of this study was to evaluate the role and mechanisms of GGNBP2 in TNBC.MethodsThe effect of GGNBP2 on TNBC aggressiveness was investigated both in vitro and in vivo. The protein and mRNA expression levels were analyzed by western blotting and reverse transcription quantitative polymerase chain reaction, respectively. Fluorescence-activated cell sorting analysis was used to evaluate the cell cycle distribution and cell apoptosis. Immunohistochemistry was used to determine the expression of GGNBP2 in breast cancer tissues.ResultsWe find that GGNBP2 expression decreases in TNBC tissues and is associated with the outcome of breast cancer patients. Furthermore, experimental overexpression of GGNBP2 in MDA-MB-231 and Cal51 cells suppresses cell proliferation, migration and invasion, reduces the cancer stem cell subpopulation, and promotes cell apoptosis in vitro as well as inhibits tumor growth in vivo. In these cell models, overexpression of GGNBP2 decreases the activation of IL-6/STAT3 signaling.ConclusionOur data demonstrate that GGNBP2 suppresses cancer aggressiveness by inhibition of IL-6/STAT3 activation in TNBC.

‌To identify factors influencing margins, re-excision rates, and prognosis in breast-conserving surgery (BCS) patients, and compare the accuracy of ultrasonography (US), mammography (MG), and magnetic resonance imaging (MRI) in assessing tumor size, axillary lymph node status and margins using pathology as the gold standard.‌ A retrospective analysis was conducted on 2775 consecutive invasive breast cancer patients who receive BCS between June 2014 and June 2024. All patients underwent preoperative US, MG, and MRI. The positive margin rate was 18.2% (506/2775).‌ Independent predictors of margin status included pT, lymphovascular invasion (LVI), extensive intraductal component (EIC), US-measured tumor size, MRI-based abnormal enhancement extent, fibroglandular tissue (FGT), background parenchymal enhancement (BPE), non-mass-like enhancement (NME), and axillary lymph node metastasis (ALNM). Factors influencing margin status varied significantly across MRI tumor size subgroups and molecular subtypes. US demonstrated the highest accuracy for preoperative tumor size assessment, while MRI outperformed other modalities in evaluating resection margin status and ALNM. Among 2,450 patients who successfully underwent BCS, the reoperation rate was independently associated with HER2, EIC, MRI abnormal enhancement extent, FGT, BPE, and ALNM. The local-regional recurrence (LRR) rate was 2.5%, with independent predictors including age, molecular subtype, LVI, EIC, MRI abnormal enhancement extent, BPE, ductal pattern orientation, and radiotherapy status.‌ Preoperative imaging and molecular subtyping provide critical insights into margin status and recurrence risk in BCS patients. Tailored surgical planning and adjuvant therapy based on these factors may optimize clinical outcomes and reduce recurrence rates.

Cytosine base editors (CBEs) mediate precise C-to-T conversion and hold considerable therapeutic promise, yet their editing function and utility in oncology remain underexplored. Here, we integrate evolutionary scale modeling (ESM) with structure-guided mutagenesis to remodel human APOBEC3F (A3F), yielding a panel of high-performance CBEs. Our high-efficiency A3F-CBEs achieve up to 1.9- and 3.3-fold higher on-target editing within the canonical editing window than A3A- and Anc689-BE4max, respectively. The high-accuracy A3F-CBEs deliver up to 3.0-fold improvement over haA3A-G at the majority of surveyed loci without compromising specificity. To demonstrate therapeutic potential, we deploy a dual-AAV platform packaging A3F-BE4max and dual gRNAs co-targeting KRAS and MYC in pancreatic ductal adenocarcinoma (PDAC) models. It elicits robust oncogene silencing and inhibited PDAC cell proliferation both in vitro and patient-derived organoids (PDOs). In a PDAC mouse model, it markedly suppresses tumor burden and extends survival. Our work establishes ESM-guided A3F-based CBEs as a versatile, precise platform for cancer genetic therapy.

Background:To date, no robust, non-invasive biomarker for breast cancer (BC) diagnosis has been identified. The study aimed to develop a circulating microRNA (miRNA or miR)-based diagnostic model and explore potential mechanisms of miRNA regulating DNA damage sensitivity. Methods:A differential analysis was performed on The Cancer Gene Atlas (TCGA)-Breast Invasive Carcinoma (BRCA) and Gene Expression Omnibus (GEO) datasets. Three machine-learning algorithms were employed to screen key circulating miRNAs. The serum miRNA levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). The effect of miR-139-3p on sensitivity to DNA damage and the underlying mechanisms were investigated in vivo and in vitro. Results:Our diagnostic model was based on the identification of four miRNAs (i.e., miR-139-3p, miR-134-3p, miR-629-3p, and miR-191-3p). The model achieved high diagnostic performance in two external datasets and a clinical cohort, which had area under the curve (AUC) values of 0.952, 0.847, and 0.869, respectively. The survival analysis showed that high levels of miR-139-3p were only linked with a better prognosis in the subgroups of patients that underwent chemotherapy [hazard ratio (HR) =0.6, P<0.001]. The overexpression of miR-139-3p in BC cells enhanced cisplatin, olaparib, and irradiation (IR) sensitivity. MiR-139-3p was found to target RPA2 directly, and the overexpression of RPA2 counteracted the effect of miR-139-3p on homologous recombination (HR) repair and DNA damage sensitivity. Conclusions:The diagnostic model based on the four circulating miRNAs could serve as a tool for the liquid biopsy of BC. Targeting the miR-139-3p/RPA2 axis may have potential in modulating the DNA damage pathway in BC.

This study aims to investigate the incidence of and factors associated with bone metastasis (BM) in patients with lung cancer and provide guidance for the screening of BM in patients with lung cancer. Lung cancer patients who were treated at the Tianjin Medical University Cancer Institute and Hospital between 2009 and 2018 were retrospectively reviewed. Patients with synchronous BM were obtained to investigate the risk factors for BM development. Both demographic and clinical characteristics were included. Univariate and multivariate logistic regression analyses were performed to identify risk factors. A further scoring system was established to classify patients into 3 different risk groups. Five significant risk factors were identified, namely, male sex, Karnofsky score of 50 to 70, multiple primary lesions, lymph node metastasis, and adenocarcinoma. The total score was generated by the integration of the score based on each individual factor. The incidence of BM among patients with lung cancer with a total score >= 7 was 46.73%, the incidence among patients with a total score <= 4 was 16.59%, and the incidence of BM in patients with total scores between 5 and 6 was 34.23%. This scoring system can predict the risk of BM in patients with lung cancer and can guide the performance of BM screening.

Objectives: Autophagy-dependent cell death (ADCD) plays a pivotal role in solid tumors, ultimately influencing immunotherapeutic efficacy and cancer prognosis. However, its significance in hepatocellular carcinoma (HCC) remains underexplored.Methods: Through integrated analysis of single-cell and bulk transcriptomic data, this research systematically identified ADCD-associated genes in LIHC. This was achieved by applying AddModuleScore, ssGSEA, and WGCNA for robust gene screening. A prognostic model was developed for LIHC grounded in The Cancer Genome Atlas (TCGA) dataset. Its validity was confirmed through internal validation with an independent TCGA cohort and external validation using GEO datasets. Immune characteristics were assessed by adopting CIBERSORT and ESTIMATE algorithms. Through LASSO-Cox regression analysis, this research established a 9-gene ADCD signature and derived the ADCD-related risk score system (ADCDRS).Results: The ADCDRS demonstrated superior prognostic performance. Aside from that, this unique system was significantly associated with clinical features, immune infiltration patterns, and the tumor's local environment. To improve clinical applicability, this research constructed a nomogram incorporating the ADCDRS. Additionally, potential therapeutic agents targeting specific risk subgroups were identified.Conclusion: This study highlights the prognostic and therapeutic potential of ADCD-related biomarkers in LIHC.

Abstract Background: Cadonilimab, a first-in-class bispecific antibody targeting PD-1 and CTLA-4, in combination with regorafenib, a multikinase inhibitor approved for second-line treatment of hepatocellular carcinoma (HCC), has demonstrated promising antitumor activity and manageable safety in heavily pretreated patients with advanced HCC (aHCC). We previously reported the updated clinical outcomes at the 2025 AACR Annual Meeting (Abstract #CT172, NCT05644379). Here, we present updated findings from an exploratory biomarker analysis focusing on the potential predictive role of BOLA3 in treatment response. Methods: Paired plasma samples were collected before and during treatment for cell-free RNA sequencing (cfRNA-seq) to evaluate transcriptional dynamics. Differential expression analysis was performed using DESeq2 (FDR ≤ 0.10), and Hallmark GSEA was applied to assess mitochondrial and immune-related pathway changes. ELISA quantified soluble PD-1 and CTLA-4 at baseline and early on-treatment, calculating individual values. In a prespecified patient subset, baseline tumor tissues underwent semi-quantitative BOLA3 immunohistochemistry (IHC). Multiplex immunofluorescence (mIF) was performed for BOLA3, TOMM20, PD-L1, CD8α, and DAPI, enabling cell-level quantification and comparison of tumor versus peritumoral spatial distribution. Results: ELISA detected stable levels of soluble PD-1 and CTLA-4 pre- and on-treatment, with early individual dynamics observed; however, these levels did not correlate with treatment response. cfRNA-seq revealed decreased BOLA3 in the PR patient and increased BOLA3 in the PD patient after treatment. Pathway analysis indicated PD-associated enrichment of mitochondrial signaling and weaker inflammatory response, whereas PR showed the opposite trend. Baseline BOLA3 IHC aligned with transcriptomic findings: higher BOLA3 expression was observed in patients with disease progression versus disease control, maintaining directional association when analyzed as a continuous variable. Preliminary mIF suggested that responders exhibited lower BOLA3/TOMM20 and higher PD-L1/CD8, while progressors showed the reverse phenotype. Conclusions: Integrated exploratory analyses nominate BOLA3 as a candidate outcome-associated biomarker and support a model in which responders exhibit a mitochondria-low, inflamed-high phenotype. These findings provide early, complementary evidence that BOLA3-related features may inform patient stratification, with further validation underway. Research Sponsor: The Joint Funds of the Natural Science Foundation of Tianjin (No.25JCLZJC00120). Citation Format: Yang Liu, Jin Zhang, Qi Qi, Dandan Wu, Linze Xu, Yueguo Li, Huikai Li. Updated exploratory biomarker analysis of cadonilimab plus regorafenib as second-line or later therapy in advanced hepatocellular carcinoma: Identification of Bola3 as a potential predictive biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5236.

Purpose:In breast cancer (BC) patients without pathological complete response (pCR) after neoadjuvant therapy, residual disease drives recurrence. The HER2 spectrum now includes HER2-low and HER2-ultralow. HER2-low tumors are eligible for HER2-targeted antibody-drug conjugates (ADCs), while T-DXd is approved for HR-positive HER2-ultralow metastatic BC after endocrine therapy. Evolution patterns of HER2-ultralow versus HER2-null from residual to metastatic disease remain unclear. Materials and Methods:We retrospectively studied 488 non-pCR patients with refined HER2 classification; 92 with HER2-0 residual disease formed the analytic cohort for HER2-ultralow/HER2-null comparison. HER2 status was tested in paired residual and metastatic lesions. Logistic regression was used to identify factors linked to HER2 evolution. Results:In the 92‑patient HER2‑0 analytic cohort, HER2-ultralow (46.7% of HER2-0) converted more frequently to HER2-low than HER2-null (51.2% vs 30.6%, p=0.045). This difference remained statistically significant in the multivariable logistic regression model. In the full 517-patient contextual cohort, HER2 expression gain in recurrent/metastatic lesions was independently associated with poorer post-recurrence survival (PRS) (adjusted HR=1.74, p=0.009). In the 488-patient primary cohort, conversion from HER2-0 to HER2-low was also associated with poorer PRS (adjusted HR=2.18, p<0.001). The broader HER2 expression evolution in the full 517‑patient cohort and the primary 488‑patient refined HER2 cohort was consistent with the core finding from the 92‑patient HER2‑0 analytic cohort and supported its biological plausibility. Conclusion:HER2-ultralow shows distinct evolution and high HER2-low conversion potential, affecting ADC eligibility. Routine HER2-0 subclassification and metastatic HER2 reassessment appear clinically useful and warrant prospective validation.

Background:Although the Chinese Society of Clinical Oncology (CSCO) guidelines list both the TCbHP regimen (taxane + carboplatin + trastuzumab + pertuzumab) and the carboplatin-sparing THP regimen (taxane + trastuzumab + pertuzumab) as category I neoadjuvant recommendations for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, TCbHP carries a significantly higher toxicity burden, and current guidelines do not clearly define which patients can safely omit platinum. Accordingly, this study aims to compare the efficacy and long-term outcomes of neoadjuvant TCbHP versus THP in HER2-positive breast cancer and to preliminarily identify patients who may safely forgo carboplatin. Methods:This retrospective cohort study included patients with HER2-positive breast cancer who received neoadjuvant TCbHP or THP at Tianjin Medical University Cancer Institute and Hospital between January 2019 and December 2022. Inclusion criteria were age 18 years, clinical stage II-III disease, completion of six cycles of neoadjuvant therapy (NAT), and no prior anticancer treatment or distant metastasis at diagnosis. Baseline clinicopathological characteristics were extracted from electronic medical records. The primary endpoint was pathological complete response (pCR). Secondary endpoints were event-free survival (EFS) and disease-free survival (DFS). Follow-up was conducted via outpatient records and telephone interviews, with data censored on June 30, 2025. Results:Of 427 screened patients, 148 matched pairs were generated by 1:1 propensity score matching using age, menopausal status, clinical T stage, lymph node status, HR status, HER2 status, Ki-67 and taxane. There was no significant difference in pCR rates between TCbHP and THP (53.4% vs. 43.2%, P=0.08). Exploratory subgroup analyses showed a significant benefit for the TCbHP regimen over the THP regimen in patients aged ≤60 years [odds ratio (OR) =0.56; 95% confidence interval (CI): 0.33-0.93; P=0.03], premenopausal patients (OR =0.47; 95% CI: 0.24-0.91; P=0.03), and those with Ki-67 >30% (OR =0.48; 95% CI: 0.28-0.82; P=0.007). But formal interaction tests revealed a statistically significant interaction only between the two Ki-67 subgroups (P for interaction =0.02). The estimated 3-year EFS rates were 96.6% (95% CI: 93.8-99.6%) in the TCbHP group and 96.0% (95% CI: 92.8-99.2%) in the THP group, with no significant difference between the two regimens [hazard ratio (HR) =1.26; 95% CI: 0.47-3.40; P=0.64]. Conclusions:No significant difference in efficacy or 3-year EFS was observed between TCbHP and THP. Exploratory subgroup analyses showed that TCbHP achieved a higher pCR rate than THP in patients aged ≤60 years, premenopausal patients, and those with Ki‑67 >30%. Furthermore, interaction tests suggested that patients with Ki‑67 >30% derived a greater benefit from the TCbHP regimen compared with those with Ki‑67 ≤30%.

Abstract Purpose: This randomized, double-blind phase 3 equivalence study aimed to evaluate the similarity of neoadjuvant pertuzumab biosimilar HLX11 versus reference pertuzumab plus trastuzumab and docetaxel for human epidermal growth factor receptor 2-positive, hormone receptor-negative early-stage or locally advanced breast cancer (BC). Patients and Methods: Eligible patients were randomly assigned (1:1) to receive 4 cycles of neoadjuvant HLX11 (HLX11 arm) or European Union-sourced pertuzumab, plus trastuzumab and docetaxel (EU-pertuzumab arm). Patients in the respective arms received adjuvant HLX11 plus trastuzumab or were re-randomized (1:1) to receive HLX11 or EU-pertuzumab plus trastuzumab. The primary endpoint was blinded independent central review (BICR)-assessed total pathological complete response (tpCR) rate. Results: In total, 908 patients were randomized to the HLX11 (n = 454) or EU-pertuzumab arm (n = 454); 192 patients in HLX11 arm received adjuvant HLX11; 200 patients in EU-pertuzumab arm were re-randomized to receive adjuvant HLX11 (n = 100) or EU-pertuzumab (n = 100). BICR-assessed tpCR rate (95% confidence interval [CI]) was 46.3% (41.6%–51.0%) and 45.8% (41.2%–50.5%), respectively. The equivalence criteria were met, with relative risk of tpCR (90% CI) of 1.01 (0.90–1.14) and relative difference (95% CI) of 0.47% (−5.99%–6.92%). No clinically meaningful differences were observed in other efficacy endpoints, safety, pharmacokinetics (PK), or immunogenicity. In the adjuvant phase, switching from EU-pertuzumab to HLX11 led to no notable differences in safety, PK, or immunogenicity. Conclusions: Compared with EU-pertuzumab, neoadjuvant HLX11 demonstrated a similar tpCR rate and no clinically meaningful differences in other efficacy endpoints, safety, PK, or immunogenicity in BC.

Abstract Background: Pancreatic cancer with liver metastasis (PCLM) accounts for most advanced pancreatic cancer cases and carries poor prognosis. While Gemcitabine plus Nab-paclitaxel (AG) remains the NCCN-recommended regimen for fit patients, outcomes remain suboptimal. Previous studies suggested that adding Nimotuzumab may improve conversion to resection, but the molecular determinants of response are unclear (2025 AACR# CT167, NCT06405685) . This study integrates clinical and correlative analyses to identify predictive biomarkers for Nimotuzumab + AG therapy. Methods: Treatment-naïve PCLM patients received Nimotuzumab (400 mg iv, qw) plus AG (Gemcitabine 1000 mg/m2 and Nab-paclitaxel 125 mg/m2, d1, d8, q3w). Primary endpoints were objective response rate (ORR) and disease control rate (DCR); secondary endpoints included conversion and R0 resection rates. In parallel, single-cell RNA-seq data from paired primary and metastatic lesions (GEO) were analyzed to identify PCLM-specific subpopulations via hdWGCNA and machine-learning algorithms (SVM, LASSO, random forest). For clinical validation, immunofluorescence staining of CXCR4 and LITAF was performed on PCLM tumor tissues. Spatial quantification was performed using an automated CK-pan-guided epithelial segmentation. Intensities were normalized and a hotspot-weighted aggregation produced a combined CXCR4/LITAF score per patient, reflecting co-activation. Results: Among 23 evaluable PCLM patients, the ORR was 17.4%, DCR 78.3%, and 43.5% achieved conversion surgery, consistent with previous findings. Single-cell analysis identified 22 cell clusters, including a distinct PCLM-specific subpopulation enriched in hepatic metastases. CXCR4 and LITAF emerged as central hub genes positively correlated with the abundance of these metastatic-specific cells and with poorer clinical outcomes. Imaging-based spatial quantification showed that patients with higher CXCR4/LITAF combined scores exhibited significantly worse treatment responses (progressive disease, PD). The automated pipeline—from epithelial segmentation (CK-pan-guided) to combined molecular scoring—achieved robust reproducibility across samples and accurately stratified responders versus non-responders. Preliminary analyses suggest that KRAS-mutant tumors may exhibit enhanced CXCR4/LITAF co-activation, contributing to therapeutic heterogeneity. Conclusions: Nimotuzumab plus AG demonstrates favorable disease control and conversion potential in PCLM. Integrative single-cell and spatial analyses identify CXCR4 and LITAF as candidate biomarkers linked to treatment response. The CXCR4/LITAF combined spatial score offers a quantitative imaging tool for predicting response to Nimotuzumab + AG in metastatic pancreatic cancer. Citation Format: Linze Xu, Yang Liu, Linlin Fu, Dandan Wu, Jin Zhang, Hao Wang, Huikai Li, Jihui Hao. CXCR4/LITAF as predictive biomarkers for nimotuzumab plus AG therapy in pancreatic cancer with liver metastasis: Integrative single-cell and spatial analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1051.

Abstract Background Clinical evidence for the use of paclitaxel liposome combined with anti–HER-2 drugs as first-line salvage treatment for HER-2–positive advanced breast cancer (BC) remains limited. Methods In this retrospective, single-arm, real-world study, patients with HER-2–positive advanced BC who received paclitaxel liposome combined with anti–HER-2 agents as first-line salvage therapy between January 2013 and December 2022 were identified from the National Cancer Center Oncology Information Database. The primary outcomes were real-world progression-free survival (rwPFS) and overall survival (OS). Results A total of 526 eligible patients were included, with a median age of 53.0 years; 296 (56.3%) were hormone receptor (HR)–positive. Treatment regimens mainly included paclitaxel liposome plus trastuzumab (53.2%), paclitaxel liposome plus trastuzumab and pertuzumab (32.1%), and paclitaxel liposome plus trastuzumab and tyrosine kinase inhibitors (TKIs) (11.0%). Median follow-up was 856 days. The overall median rwPFS and OS were 22.1 months (95% CI, 20.0 to 25.7) and 57.9 months (95% CI, 52.2 to 62.9), respectively. The overall rwORR was 55.9%, and rwDCR was 94.7%. Among HR + and HR–subgroups, median rwPFS was 24.5 months (95% CI, 20.8 to 28.7) and 17.7 months (95% CI, 14.7 to 21.8), respectively; mOS was 60.5 months (95% CI, 50.7 to not reached) and 53.5 months (95% CI, 49.9 to 63.3), respectively. Common adverse events included myelosuppression, gastrointestinal reactions, hepatic dysfunction, and neurotoxicity. Conclusions In real-world setting, paclitaxel liposome combined with various anti–HER-2 drugs demonstrated favorable effect and safety in patients with HER-2–positive advanced BC, regardless of HR status. Trial registration Registered on ClinicalTrials.gov under NCT06481553 on July 01, 2024 (retrospectively registered; https://clinicaltrials.gov/study/NCT06481553 ).

Traditional Chinese Medicine (TCM), as a long-standing therapeutic approach, holds unique advantages and potential in the treatment of allergic rhinitis (AR). Recent studies have highlighted its role in modulating the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor kappa B (NF-kappaB) signaling pathway in AR treatment. The multi-component, multi-target, and multi-pathway mechanisms of TCM have garnered significant attention in the medical community for their capacity to treat complex diseases like AR. This review aims to explore the current status and challenges of TCM monomers in regulating the specific p38 MAPK/NF-kappaB signaling pathway in AR treatment, further elucidate the crucial role of this pathway in AR progression, and provide new insights into the modern scientific interpretation of TCM. Literature was retrieved from PubMed and Web of Science databases using keywords such as “TCM,” “allergic rhinitis,” “TCM monomers,” and “p38 MAPK/NF-kappaB signaling pathway,” and the reviewed articles span from 2010 to 2025. Existing studies indicate that TCM monomers may significantly treat and prevent allergic rhinitis by modulating the p38 MAPK/NF-kappaB signaling pathway involved in AR development. These compounds mainly exert their effects by inhibiting p38 MAPK phosphorylation, suppressing IκBα degradation, and blocking NF-kappaB p65 nuclear translocation, thereby reducing the expression of inflammatory cytokines and allergic mediators, including IL-4, IL-5, IL-6, IL-13, TNF-α, IgE, and MCP-1.This pathway influences T cell differentiation, further driving AR progression and contributing to the anti-allergic effects of TCM. Overall, TCM plays a vital role in AR treatment and prevention by regulating the p38 MAPK/NF-kappaB signaling pathway, offering a promising therapeutic approach that bridges traditional practice and modern scientific understanding and may provide more effective treatment options for AR patients.

598 Background: For patients (pts) with triple-negative early breast cancer (BC), recommended neoadjuvant regimens include chemo with or without immunotherapy, which achieve a modest rate of pathological complete response (pCR). Emerging data suggest that anti-HER2 antibody-drug conjugates (ADCs) have antitumor activity in HER2-low advanced BC. Notably, DV (anti-HER2 ADC) has shown encouraging efficacy both as monotherapy and in combination with Tor (PD-1 inhibitor) in pts with HER2-low advanced disease. We evaluated the efficacy and safety of neoadjuvant DV-containing regimens in pts with hormone receptor (HR)-negative HER2-low BC in a randomized phase 2 trial. Here, we report results from the pts receiving DV plus Tor combined with concurrent/sequential chemo. Methods: Eligible pts were aged ≥18 years with untreated histologically confirmed HR-negative and HER2-low (centrally confirmed as IHC 1+, or IHC 2+/ISH-) BC (T1cN1-2M0 or T2-3N0-2M0 as per AJCC 8th edition) who were planned to undergo curative-intent breast cancer surgery. Pts randomized to group A received DV (2.0 mg/kg Q2W) + Tor (3.0 mg/kg Q2W) + carboplatin (AUC 3 Q2W or AUC 1.5 QW) for 18 weeks. Pts randomized to group B received DV + Tor for 12 weeks followed by epirubicin (90 mg/m 2 Q3W) + cyclophosphamide (600 mg/m 2 Q3W) + Tor for additional 12 weeks. Stratification factors were PD-L1 status (positive or negative) and clinical staging (stage II or III). After neoadjuvant treatment, surgery was performed. Enrollment in group B was closed after 28 pts had been randomized to this group, while enrollment in group A continued. The primary endpoint was total pCR (tpCR, defined as ypT0/TisN0) rate; secondary endpoints included breast pCR (bpCR, defined as ypT0/Tis) rate, objective response rate (ORR), and safety. Results: 40 pts were enrolled in group A (median age: 46.0 years; clinical stage III: 37.5%; clinical N+: 82.5%; IHC 1+: 72.5%; PD-L1 CPS < 10: 37.5%) and 28 in group B (54.0; 42.9%; 82.1%; 67.9%; 32.1%). The tpCR was achieved in 25 pts (62.5% [95% CI: 45.8-77.3]) in group A and 14 pts (50.0% [31.9-71.3]) in group B. The bpCR rate was 65.0% (95% CI: 48.3-79.4) and 53.6% (35.3-74.5) for groups A and B, respectively. The corresponding ORR was 92.5% (95% CI: 79.6-98.4) and 75.0% (55.1-89.3), respectively. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 29 (72.5%) of pts in group A and 23 (82.1%) in group B. Serious TRAEs occurred in 6 (15.0%) and 7 (25.0%) of pts, respectively. Immune-related adverse events occurred in 3 (7.5%) of pts in group A and 7 (25.0%) in group B. No grade 5 TRAEs occurred. Conclusions: Both treatment regimens showed manageable safety profiles; DV + Tor + carboplatin showed numerically better efficacy in pts with previously untreated, HR-negative, HER2-low, early BC. Clinical trial information: NCT06227117 .

636 Background: Upper Tract Urothelial Carcinoma (UTUC) presents a challenging prognosis even after Radical Nephroureterectomy (RNU), and postoperative renal insufficiency further limits the options for adjuvant therapy. The efficacy of neoadjuvant chemotherapy for UTUC remains uncertain as past studies have not shown satisfactory results and have mostly been retrospective. There is an urgent need for a more promising regimen. This phase II study aims to investigate the efficacy and safety of a combination of chemotherapy (Gemcitabine/Cisplatin) and PD-1 inhibitor (Toripalimab) as neoadjuvant treatment (NT) in UTUC patients. Methods: We planned to enroll 34 UTUC patients with either cT1N0M0 (high grade) or cT2-3N0M0, confirmed by ureterorenoscopy biopsy and imaging. The treatment regimen included three or four cycles of NT (Gemcitabine, 800mg/m 2 , days 1 and 8/Cisplatin, 60mg/m 2 , day 1/Toripalimab, 240mg, day 1 of a 21-day cycle), followed by RNU and pelvic lymphadenectomy. The primary outcome was the pathological complete response (pCR) rate, with secondary outcomes including significant downstaging (≤pT1) rate, disease control rate (DCR), and safety. Results: To date, 17 patients have been accrued since August 1st, 2020, and recruitment is ongoing. Fifteen patients have completed treatments and were preliminarily analyzed, with two patients still undergoing treatment. The median age was 66.0 years, with 53.3% being male. The majority of patients had unifocal tumors, with a median maximum diameter of 2.8cm (0.4-5.8). All patients experienced obstructed hydronephrosis. Clinical T staging was confirmed by multi-parameter MRI, indicating two T2 and thirteen T3 patients. Ureterorenoscopy biopsy revealed 13 high-grade and two low-grade urothelial carcinoma patients. All patients were classified as high-risk UTUC. Twelve patients completed 4 cycles, and three underwent 3 cycles. The median interval time from initiation of NT to RNU and from the end of NT to RNU was 18.3 (11.4-22.7) weeks and 6.3 (0.1-11.6) weeks respectively. The pCR rate was 20.0% (3/15), the ≤pT1 rate was 53.3% (8/15), and the DCR was 100%. No grade 4-5 chemotherapy-related adverse events were recorded, but 26.7% (4/15) experienced grade 2 myelosuppression, 20% (3/15) grade 3, and 6.7% (1/15) grade 4. Two patients experienced immune-related adverse events after 4 cycles, including hypothyroidism (grade 2) and adrenal insufficiency (grade 2). No surgery-related complications or readmissions within one month were reported. With a median follow-up of 25.6 months, all patients remained alive and tumor-free. Conclusions: Preliminary analyses suggest that the combination of chemotherapy and a PD-1 inhibitor as NT exhibits promising pCR rate for UTUC. The treatment was manageable in terms of safety, with immune-related adverse events potentially leading to prolonged treatment periods. Clinical trial information: NCT04099589 .