Xing Z, Xu H, Lin P
… +5 more, Hong Y, Shao S, Yang T, Li Y, Wei Y
Br J Cancer
· 2026 Jun · PMID 41957134
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BACKGROUND: Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer (BC). However, the development of cisplatin resistance limits its antitumor effects. While, the mechanism of...BACKGROUND: Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer (BC). However, the development of cisplatin resistance limits its antitumor effects. While, the mechanism of cisplatin resistance remains unclear. METHODS: Bioinformatics techniques were used to analyse genes and pathways associated with cisplatin therapy resistance. A variety of biological techniques were used to identify the role of ITGB4 in cisplatin sensitivity in BC and its potential molecular mechanism. RESULTS: In this study, we demonstrated that ITGB4 plays a key role in regulating the sensitivity of p53 wild-type (WT) BC to cisplatin therapy. Our findings revealed that ITGB4 inhibits the activation of p53 by suppressing the phosphorylation at the p53-S15 site and promotes the degradation of p53 by facilitating the binding of MDM2 to p53, thereby reducing the sensitivity of BC to cisplatin.Additionally, we showed that ITGB4 influences the antitumor effects of MDM2 inhibitors when they are combined with cisplatin therapy. Furthermore, we found that the elevated expression of ITGB4 in cisplatin-resistant BC cells were mediated by STAT3 activation. The combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin in BC. CONCLUSIONS: ITGB4 is a key molecule influencing cisplatin sensitivity in p53 WT BC, and the combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin.
Drew Y, Gilbert L, Martinez Bueno A
… +19 more, Oaknin A, Moreno V, Gaba Garcia L, Jayson GC, Kristeleit RS, Lakhani N, Banerjee S, Matei D, Oza A, Miller R, Yiannakis D, Barretina-Ginesta MP, Martínez García J, Wang G, Miriyala J, Franke A, Galvez E, Pandite L, Richardson DL
Br J Cancer
· 2026 Jun · PMID 41951722
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BACKGROUND: Platinum resistant ovarian cancer (PROC) is associated with poor survival. This clinical trial sought to determine whether the bispecific CD47 inhibitor and CD40 agonist, SL-172154, could be combined safely a...BACKGROUND: Platinum resistant ovarian cancer (PROC) is associated with poor survival. This clinical trial sought to determine whether the bispecific CD47 inhibitor and CD40 agonist, SL-172154, could be combined safely and improve the efficacy of mirvetuximab (MIRV) or pegylated liposomal doxorubicin (PLD) through enhanced tumor cell phagocytosis and antigen presentation to T cells. METHODS: Patients with PROC received MIRV (21-day cycle) or PLD (28-day cycle) on day 1 and SL-172154 (3 mg/kg) on days 8 and 15 of each cycle. Objectives included safety, anti-tumor activity, PK, and immunogenicity. RESULTS: 65 patients (60% folate receptor alpha (FRα) high and 40% medium/low) were enrolled in the MIRV cohort and 21 patients in the PLD cohort. Most common TEAEs ( > 40%) in the MIRV cohort were blurred vision, nausea, infusion related reaction, transaminase increase, diarrhea, and in the PLD cohort, nausea, constipation, neutropenia and fatigue. The objective response rate in the MIRV cohort was 33% (95% CI, 19%, 50%) for FRα high subgroup, and 15% (95% CI, 4%, 35%) for FRα medium/low subgroup, and in the PLD cohort was 20% (95% CI, 6%, 44%). CONCLUSIONS: Combination of SL172154 with MIRV did not improve upon the previously reported ORR for MIRV, while the combination with PLD resulted in a higher ORR than reported for PLD, albeit in a small number of patients. Limited tumor penetration of SL-172154, lack of durable CD47 blockade, inability to overcome T cell exhaustion and other mechanisms of resistance may explain these findings. Trial register number: NCT05483933.
Pougoue Ketchemen J, Monzer A, Njotu FN
… +8 more, Babeker H, Tikum AF, Nwangele E, Henning N, Hassani N, Ngong AF, Doroudi A, Fonge H
Br J Cancer
· 2026 Jun · PMID 41946831
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PURPOSE: Approved therapeutics targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) have unacceptably high recurrence rates. HER2 is amplified and overexpressed in 25-30% of BC. Actinium-...PURPOSE: Approved therapeutics targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) have unacceptably high recurrence rates. HER2 is amplified and overexpressed in 25-30% of BC. Actinium-225 (Ac) has ideal decay characteristics for targeted alpha therapy. To improve the therapeutic index, we describe the effectiveness and safety of an anti-HER2 antibody-drug radioconjugate (ADR) [Ac]Ac-Macropa-pertuzumab-PEG-DM1. AIM: To evaluate the effectiveness and safety of [Ac]Ac-Macropa-pertuzumab-PEG-DM1 against HER2-positive BC. EXPERIMENTAL DESIGN: The antibody-drug conjugate (ADC) pertuzumab-PEG-DM1 and the ADR [Ac]Ac-Macropa-pertuzumab-PEG-DM1 were developed. Safety and biodistribution were carried out in healthy female Balb/C mice and in mice bearing HCC1954/JIMT-1 xenografts, respectively. Radioimmunotherapy was done in nude mice bearing trastuzumab-resistant HCC1954 (high HER2-density), T-DM1/trastuzumab-resistant JIMT-1 (medium HER2-density) and MDA-MB-468 (negative control with very low HER2-density) xenografts. RESULTS: Internalisation in HCC1954 and JIMT-1 cells was HER2 density-dependent, with pertuzumab-PEG-DM1 2.5-22-fold higher than unconjugated pertuzumab. Pertuzumab-PEG-DM1 (8 mg/kg) and [Ac]Ac-Macropa-pertuzumab-PEG-DM1 (18 kBq) administered separately in healthy Balb/C mice, 10-days apart was well tolerated biochemically and haematologically for 20-days. Mice bearing HCC1954 tumours treated using [Ac]Ac-Macropa-pertuzumab-PEG-DM1 and pertuzumab-PEG-DM1 all had complete remissions, whereas those bearing JIMT-1 tumour showed significant % tumour growth inhibition of 72.1 and 29.4%, respectively. CONCLUSION: [Ac]Ac-Macropa-pertuzumab-PEG-DM1 is more potent than pertuzumab-PEG-DM1 against trastuzumab or T-DM1-resistant BC necessitating clinical investigation.
Altbürger C, Menzel M, Beck S
… +17 more, Lorenz K, Brygider ML, Ploeger C, Kahles A, Ball M, Kirchner M, Schnecko F, Jung A, Klauschen F, Grob T, Horst D, Hirsch D, Evert M, Schirmacher P, Budczies J, Kazdal D, Stenzinger A
Br J Cancer
· 2026 Jun · PMID 41946830
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BACKGROUND: Molecular characterisation of solid tumours contributes to a precise diagnosis and can uncover a range of drug targets and biomarkers, improving patient management. Whole genome sequencing (WGS) combined with...BACKGROUND: Molecular characterisation of solid tumours contributes to a precise diagnosis and can uncover a range of drug targets and biomarkers, improving patient management. Whole genome sequencing (WGS) combined with whole transcriptome sequencing (WTS) is the most comprehensive approach in molecular cancer diagnostics and is therefore becoming increasingly integrated in clinical care. A critical challenge in implementing WGS/WTS as a clinical-grade test is its high cost compared to targeted sequencing approaches, prohibiting wider use and access. METHODS: To dissect this limitation, we performed a micro-costing analysis of an established WGS/WTS workflow based on short-read sequencing technology. We categorised the costs as follows: consumables, equipment and maintenance, personnel, and data processing/storage. We considered various scenarios, including sample volumes, personnel and equipment redundancy, inflation and mean coverage. RESULTS: We have developed a multidimensional costing model that identified consumable costs, particularly flow cells, as the main cost drivers. While personnel and equipment costs decreased with larger case volumes processed (scaling effects), consumable and data processing/storage costs did not change significantly. CONCLUSIONS: Thus, falling prices of consumables would facilitate the broad implementation of WGS/WTS as a clinical-grade test.
Huismans MA, Gort EH, van der Heijden LT
… +14 more, Guven Mese SM, Klein Wolterink HM, Braat MNGJA, Elias SG, de Vos FYFL, Devriese LA, Verheul HMW, Opdam FL, Koopman M, Nienhuis HH, Crommelin HA, Snippert HJG, Huitema ADR, Roodhart JML
Br J Cancer
· 2026 Jun · PMID 41946829
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BACKGROUND: Treatment options for RAS-mutant metastatic colorectal cancer (mCRC) remain limited. Based on preclinical work with patient-derived organoids, we investigated a triple therapy of binimetinib, lapatinib, and v...BACKGROUND: Treatment options for RAS-mutant metastatic colorectal cancer (mCRC) remain limited. Based on preclinical work with patient-derived organoids, we investigated a triple therapy of binimetinib, lapatinib, and vinorelbine in a Phase I/II trial. METHODS: Forty patients with RAS-mutant mCRC received escalating doses of binimetinib and lapatinib with vinorelbine 17.5 mg/m² in three-weekly schedules. Phase I aimed to determine the Recommended Phase II Regimen (RP2R), while Phase II evaluated Overall Response Rate using Simon's two-stage design. Pharmacokinetic analyses were performed on cycle 1 day 3. RESULTS: The Maximum Tolerated Dose was established at lapatinib 750 mg QD and binimetinib 30 mg BID (both 5 days on/2 days off), with vinorelbine 17.5 mg/m² on days 3 and 10 every 21 days. Toxicities included diarrhoea (75%), rash (65%), and increased CPK (57%). Among 33 evaluable patients, no objective responses occurred, with 9 (27%) achieving stable disease, lasting beyond 3 months (maximum: 297 days) in three patients. Pharmacokinetics showed dose-proportional exposure for binimetinib but not lapatinib. Binimetinib absorption may be affected by colostomy and loperamide-induced constipation. CONCLUSIONS: The triple combination showed moderate tolerability and termination occurred after the first stage of Phase II due to insufficient efficacy. Our findings highlight challenges in translating organoid-derived drug combinations to clinical practice. CLINICAL TRIAL REGISTRATION:EUDRACT: 2019-004987-23.
Zeng Z, Gandini A, Bhatt R
… +17 more, Proctor M, Goh NL, Vora S, Walsh TP, Wu SY, Ferguson K, Coward JI, Kumari S, Haass NK, Wells JW, Hardy J, Perrin L, He Y, Hooper JD, Ho GY, Gonzalez Cruz JL, Gabrielli B
Br J Cancer
· 2026 Jun · PMID 41946828
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BACKGROUND: High-grade serous ovarian cancer (HGSOC) is characterized by elevated replication stress and an immunosuppressive microenvironment. A synergistic combination of checkpoint kinase 1 inhibitor (CHK1i) with low-...BACKGROUND: High-grade serous ovarian cancer (HGSOC) is characterized by elevated replication stress and an immunosuppressive microenvironment. A synergistic combination of checkpoint kinase 1 inhibitor (CHK1i) with low-dose hydroxyurea (LDHU) promotes a unique ATR-independent moderate replication stress response with potent anti-tumour effects. The ability of this approach to reprogram the tumour immune microenvironment (TIME) to overcome the immunosuppression and promote an anti-tumour immune response in HGSOC is the focus of this study. METHODS: We investigated the therapeutic potential of CHK1i+LDHU in established HGSOC cell cultures, fresh tumour cell explants from HGSOC patient ascites, and syngeneic mouse models, assessing tumour cell killing, immunogenic cell death, pro-inflammatory cytokine/chemokine expression, and anti-tumour immune responses. RESULTS: CHK1i+LDHU effectively killed ovarian cancer cells regardless of prior chemotherapy responses, BRCA2 mutation and homologous recombination repair status in vitro. In vivo, treatment significantly reduced tumour burden and ascites accumulation. CHK1i+LDHU enhanced expression of pro-inflammatory cytokines/chemokines and triggered immunogenic cell death in tumour. In syngeneic models, treatment promoted CD8 cytotoxic T cell-dependent anti-tumour responses and reduced immunosuppressive signalling within the TIME. CONCLUSIONS: CHK1i+LDHU is a promising therapy for chemotherapy-resistant HGSOC, combining direct cytotoxic effects with reprogramming the TIME to reduce immunosuppression and activate a CD8 T cell-dependent anti-tumour response.
Rahkola O, Tuomisto A, Elomaa H
… +22 more, Karjalainen H, Äijälä VK, Kastinen M, Tapiainen VV, Kehusmaa A, Ojanperä A, Pohjanen VM, Ahtiainen M, Helminen O, Wirta EV, Rintala J, Meriläinen S, Aro R, Häivälä R, Saarnio J, Rautio T, Seppälä TT, Böhm J, Mecklin JP, Mäkinen MJ, Väyrynen JP, Sirniö P
Br J Cancer
· 2026 Jun · PMID 41942612
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BACKGROUND: Neutrophils are the most abundant granulocytes in the tumor microenvironment and exert both pro- and anti-cancer effects. Activated neutrophils can release neutrophil extracellular traps (NETs) that have been...BACKGROUND: Neutrophils are the most abundant granulocytes in the tumor microenvironment and exert both pro- and anti-cancer effects. Activated neutrophils can release neutrophil extracellular traps (NETs) that have been proposed to promote tumor progression and metastasis. We aimed to clarify the significance of NETs and granulocytes in colorectal cancer. METHODS: Our study population consisted of three independent colorectal cancer cohorts (N = 1927). We identified NETs showing positivity for citrullinated histone H3 (Cit-H3) and granulocytes expressing CD66b (CEACAM8) with multiplex immunohistochemistry and used digital image analysis and machine learning tools to calculate their densities in tumor samples. Associations between NET and granulocyte densities with clinicopathologic characteristics, tumor-infiltrating immune cells, prognosis, and systemic inflammation markers were examined. RESULTS: The densities of Cit-H3 NETs positively correlated with macrophage densities and mesenteric serum levels of CX3CL1 and ANGPT2, but were not associated with survival. Higher CD66b granulocyte density was associated with longer colorectal cancer-specific survival independent of conventional prognostic parameters. In the largest cohort (N = 1090), multivariable HR for high vs. low CD66b granulocyte density was 0.53 (95%CI 0.38-0.73, P < 0.001). CONCLUSION: Our findings indicate that while neutrophil infiltration is associated with favorable colorectal cancer outcomes, the presence of intratumoral Cit-H3 NETs does not predict survival.
Chen L, Sun X, Zhang H
… +9 more, Zhang X, Muhetarijiang M, Wen Z, Li C, Chen M, Ying Z, Yuan S, Zheng L, Chen T
Br J Cancer
· 2026 Jun · PMID 41942611
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BACKGROUND: Doxorubicin (Dox) is a widely-used anthracycline drug for various cancers, but its clinical application is limited due to cardiotoxicity. Targeting ferroptosis is a new and effective strategy for treating Dox...BACKGROUND: Doxorubicin (Dox) is a widely-used anthracycline drug for various cancers, but its clinical application is limited due to cardiotoxicity. Targeting ferroptosis is a new and effective strategy for treating Dox-induced cardiomyopathy (DIC). The arachidonate lipoxygenase 5 (ALOX5) metabolism axis is closely linked to ferroptosis, but its role in DIC remains unknown. METHODS: In vivo and in vitro DIC models were established to investigate the role of the ALOX5 metabolism axis in DIC and to clarify the underlying mechanism using genetic and pharmacological approaches. RESULTS: Our findings revealed that ALOX5 and 5-hydroxyicosatetraenoic acid (5-HETE) levels were increased in DIC. Overexpression of Alox5 exacerbated Dox-induced cardiac dysfunction and myocardial injury, whereas pharmacological inhibition and genetic knockdown of ALOX5 alleviated these effects by modulating ferroptosis. Mechanistically, elevated ALOX5 catalyzed the metabolism of arachidonic acid to generate 5-HETE, which facilitated NRF2 ubiquitination-dependent degradation via PI3K/AKT/GSK-3β signaling, thereby contributing to cardiomyocyte ferroptosis. CONCLUSIONS: This study suggests that targeting cardiomyocyte ferroptosis mediated by the ALOX5 metabolism axis may represent a therapeutic strategy for DIC.
Huang Y, Xi Y, Nie H
… +9 more, Wang Y, Hu J, Gao Y, Li J, Ma Y, Chu J, Tu L, Huang D, Cheng L
Br J Cancer
· 2026 Jun · PMID 41942610
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BACKGROUND: LRRC41 is critical for the progression of multiple cancers, especially hepatocellular carcinoma (HCC), yet its oncogenic mechanism in HCC remains unclear. This study aimed to explore the molecular mechanism b...BACKGROUND: LRRC41 is critical for the progression of multiple cancers, especially hepatocellular carcinoma (HCC), yet its oncogenic mechanism in HCC remains unclear. This study aimed to explore the molecular mechanism by which LRRC41 promotes HCC malignancy and investigate the therapeutic potential of inhibiting its mediated signalling pathway. METHODS: LRRC41 expression in HCC was analysed via the TCGA, HPA databases and experimental detection. Its biological functions were assessed by in vitro CCK-8, Transwell, colony formation assays and in vivo xenograft models. IP-MS, Co-IP and ubiquitination assays were used to elucidate the molecular mechanism, and the anti-tumour effect of the USP7 inhibitor P6620 was verified in vitro and in vivo. RESULTS: LRRC41 was abnormally overexpressed in HCC and correlated with poor prognosis, promoting HCC cell proliferation, invasion and tumorigenesis. USP7 stabilised LRRC41 via deubiquitination, and LRRC41 activated the NF-κB pathway by targeting HNRNPC in a K63-linked ubiquitination-dependent manner. P6620 inhibited the USP7/LRRC41 axis to suppress HCC malignancy, and its combination with lenvatinib enhanced in vivo anti-tumor efficacy. CONCLUSIONS: LRRC41 overexpression drives HCC progression and poor prognosis; the novel USP7/LRRC41/HNRNPC/NF-κB axis is identified in HCC. USP7 inhibitor P6620 blocks this axis and may serve as a potential agent for HCC combination chemotherapy. The regulatory mechanism of the USP7/LRRC41/HNRNPC/NF-κB signalling axis in HCC. Created with Figdraw.
Chen Y, Chen Q, Li Q
… +10 more, Guo J, Li Z, Li H, Hu Y, Guo G, Lu L, Li Q, Sun M, Liu X, Nie F
Br J Cancer
· 2026 Jun · PMID 41942609
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BACKGROUND AND PURPOSE: Lung adenocarcinoma (LUAD) has limited therapeutic targets and poor survival. Noncanonical open reading frames (ORFs) in long noncoding RNAs (lncRNAs) may encode functional microproteins, but thei...BACKGROUND AND PURPOSE: Lung adenocarcinoma (LUAD) has limited therapeutic targets and poor survival. Noncanonical open reading frames (ORFs) in long noncoding RNAs (lncRNAs) may encode functional microproteins, but their roles in LUAD remain unclear. This study aims to characterise the LINC00973-encoded microprotein L3EMP and to investigate its tumour-promoting mechanisms and therapeutic potential. METHODS: L3EMP was identified through ribosome profiling and RNA sequencing, with its expression confirmed by mass spectrometry (MS) and Western blotting. Its functional relevance was further validated using CRISPR/Cas9-mediated gene manipulation. Functional experiments were performed in LUAD cells and chimeric antigen receptor T (CAR-T) cell models to elucidate the underlying molecular mechanisms. The interaction between USP22 and SIRT1 was investigated via ubiquitination assays and signalling pathway profiling. Finally, immunotherapeutic potential was evaluated using synthetic L3EMP peptides and B7-H3-targeted CAR-T cells. KEY RESULTS: (1) L3EMP, a microprotein encoded by LINC00973, is overexpressed in LUAD and its expression level is correlated with poor prognosis. (2) L3EMP stabilises SIRT1 by promoting USP22-mediated deubiquitination. This forms a positive feedback loop involving YY1 that activates AKT/ERK signalling, thereby promoting proliferation and invasion. (3) L3EMP knockout suppresses tumour growth in PDX models. (4) Synthetic L3EMP peptide enhances antitumor immunity as a neoantigen. (5) L3EMP deletion synergises with B7-H3 CAR-T therapy via IFN-γ pathway activation. CONCLUSIONS AND IMPLICATIONS: L3EMP contributes to LUAD progression through the USP22/SIRT1 signalling axis and represents both a therapeutic target and an immunogenic neoantigen. Targeting L3EMP or its pathway inhibits tumour growth, while the synthetic L3EMP peptide can potentiate immunotherapy. The combination of L3EMP depletion and B7-H3 CAR-T therapy enhances antitumor efficacy, suggesting a promising combinatorial strategy for LUAD treatment.
Azam S, Lamb LR, Eliassen AH
… +6 more, King TA, Specht M, Kraft P, Lindstrom S, Lehman CD, Tamimi RM
Br J Cancer
· 2026 Jun · PMID 41942608
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BACKGROUND: Mammograms contain imaging biomarkers that can predict future breast cancer risk using deep learning (DL) models. We evaluated whether adding a polygenic risk score (PRS) improves performance of the image-onl...BACKGROUND: Mammograms contain imaging biomarkers that can predict future breast cancer risk using deep learning (DL) models. We evaluated whether adding a polygenic risk score (PRS) improves performance of the image-only DL breast cancer risk model Mirai. METHODS: This nested case-control study within the Nurses' Health Study 2 included 902 women (270 cases, 632 controls) who underwent bilateral 2D digital screening mammography between 2001-2017. Risk was assessed using Mirai and, for clinical comparison, the Gail 5-year model. A PRS was calculated using 313 breast cancer-associated single-nucleotide polymorphisms. The primary outcome was incident breast cancer within five years of the index mammogram. Discrimination was evaluated using area under the receiver operating characteristic curve (AUC), with comparisons using the DeLong test. RESULTS: Mean age was 55.5 years(SD 5.3). Among cases, median time from index mammogram to diagnosis was 2.0 years (IQR0.5-4.0). Mirai alone achieved an AUC of 0.66 (95% CI: 0.62-0.70), increasing to 0.73 (95% CI 0.67-0.78; P = 0.05) with PRS. The Gail model improved from 0.52 (95% CI: 0.47-0.57) to 0.69 (95% CI: 0.62-0.76; P < 0.001) with PRS. Mirai+PRS significantly outperformed Gail+PRS (P < 0.001). CONCLUSIONS: Integrating PRS with DL-based mammographic models modestly improves risk discrimination and may enhance personalized screening.
Wang X, Xie Y, Hu J
… +6 more, Liu N, Yang L, Xu T, Xu S, Yu C, Fang S
Br J Cancer
· 2026 Jun · PMID 41942607
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BACKGROUND: Leptomeningeal metastasis (LM) after the development of third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is indicative of a poor prognosis in EGFR-mutant non-s...BACKGROUND: Leptomeningeal metastasis (LM) after the development of third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is indicative of a poor prognosis in EGFR-mutant non-small cell lung cancer (NSCLC), and no standardised treatments are currently available. The aims of this study were to evaluate the outcomes of combination therapy with bevacizumab plus high-dose furmonertinib in this setting and to assess the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) molecular response as a treatment response biomarker. METHODS: This real-world study included 104 patients with EGFR-mutant NSCLC who experienced LM progression after treatment with third-generation TKIs. Cohort 1 (n = 62) received combination therapy with furmonertinib (160 mg) + bevacizumab, and Cohort 2 (n = 42) received furmonertinib (160 mg) monotherapy. The primary endpoints were intracranial progression-free survival (iPFS) and overall survival (OS). In the longitudinal CSF ctDNA analysis, a molecular response was defined as follows: ΔctDNA ≤ 0.8 × baseline. RESULTS: Combination therapy with bevacizumab plus high-dose furmonertinib significantly improved the LM response compared to that of furmonertinib monotherapy (median iPFS: 6.77 vs 4.04 months, respectively, 95% CI: 0.41-0.98, p = 0.038; median OS: 15.31 vs 7.10 months, respectively, 95% CI: 0.29-0.82, p = 0.002). The CSF ctDNA analysis revealed that 31/47 patients (66%) achieved a molecular response; those that did experienced significantly prolonged survival outcomes compared to those of patients who did not (iPFS: 8.94 vs 6.67 months, respectively (HR = 0.40, 95% CI: 0.21-0.79); OS: 20.44 vs 8.71 months, respectively (HR = 0.34, 95% CI: 0.14-0.83)). A longitudinal decline in ctDNA across two time points further correlated with survival benefits (iPFS: 9.96 vs 7.33 months (HR = 0.42, p = 0.01); OS: 25.63 vs.15.31 months, (HR = 0.28, p = 0.03)). CONCLUSION: Bevacizumab synergises with high-dose furmonertinib to significantly improve survival outcomes in TKI-resistant LM. A positive CSF ctDNA molecular response (ΔctDNA ≤ 0.8 × baseline) is predictive of clinical benefits, supporting its utility for real-time monitoring. This combination therapy represents a promising strategy for the treatment of a population with unmet needs.
Chen X, Ma X, Yuan L
… +12 more, Wang F, Zhang Y, Fang J, Cao P, Wang T, Xiong M, Yang J, Zhang X, Chen J, Zhou X, Liu S, Liu H
Br J Cancer
· 2026 Jun · PMID 41935242
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BACKGROUND: TCF3::HLF-positive B-cell acute lymphoblastic leukemia (B-ALL) is a rare, highly aggressive subtype with historically poor outcomes. Despite its classification as a distinct entity, its clinical and molecular...BACKGROUND: TCF3::HLF-positive B-cell acute lymphoblastic leukemia (B-ALL) is a rare, highly aggressive subtype with historically poor outcomes. Despite its classification as a distinct entity, its clinical and molecular landscape remains poorly understood. METHODS: This study presents a single-center cohort of 34 TCF3::HLF-positive B-ALL patients, providing comprehensive clinical and molecular characterization by integrating clinical data, treatment responses, survival outcomes, whole-transcriptome sequencing (WTS), targeted sequencing, and flow cytometry. RESULTS: TCF3::HLF accounted for 1.59% of B-ALL cases. Three fusion isoforms were identified, with Isoform III likely arising from alternative splicing. No significant clinical or transcriptomic differences were observed between Isoform I and II. The 5-year overall survival (OS) was 35.2%. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly improved OS and event-free survival (p < 0.0001), while chimeric antigen receptor T-cell (CAR-T) therapy facilitated allo-HSCT but lacked durable efficacy. RAS pathway mutations were prevalent (85.7%), and CD33 expression was frequent (79.4%), suggesting potential therapeutic targets. WTS analysis revealed dysregulation of epithelial-mesenchymal transition, coagulation, and immune pathways. CONCLUSIONS: TCF3::HLF-positive B-ALL represents an ultra-high-risk leukemia requiring allo-HSCT for long-term remission. CAR-T serves as a bridge to transplantation, while RAS and CD33-directed therapies warrant further investigation. These findings provide critical insights into disease biology and potential treatment.
Vandecaveye V, Dresen RC, Baert T
… +5 more, Broeckhoven V, Van Nieuwenhuysen E, Van Gorp T, De Keyzer F, Vergote I
Br J Cancer
· 2026 Jun · PMID 41935241
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BACKGROUND: Prediction of surgical and survival outcomes following neoadjuvant chemotherapy (NACT) in ovarian cancer remains challenging. This study evaluated whole-body diffusion-weighted magnetic resonance imaging (WB-...BACKGROUND: Prediction of surgical and survival outcomes following neoadjuvant chemotherapy (NACT) in ovarian cancer remains challenging. This study evaluated whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) after NACT for predicting complete resection at interval debulking surgery (IDS), progression-free survival, and overall survival. METHODS: In this prospective, single-centre study, 105 patients with non-primary resectable ovarian cancer underwent WB-DWI/MRI following NACT. The performance of WB-DWI/MRI in predicting complete resection and survival was assessed. Prediction of complete resection was compared with computed tomography (CT) when available. RESULTS: Seventy-four (70%) patients achieved complete resection. WB-DWI/MRI-predicted complete resection with 97.3% sensitivity, 83.9% specificity and 93.3% accuracy. MRI-based complete resection prediction, complete resection at IDS, and serum CA-125 significantly affected progression-free survival (MRI: Hazard Ratio [HR] = 5.43, IDS: HR = 4.19, CA-125: HR = 1.68; p < 0.01) with the first two parameters also significantly affecting overall survival (MRI: HR = 4.24, IDS: HR = 2.87; p < 0.01). Multivariate analysis confirmed MRI-based complete resection prediction and serum CA-125 as significant for progression-free (p < 0.001 and p = 0.04) and MRI-based prediction significant for overall survival (p < 0.001). In a 69-patient subanalysis, WB-DWI/MRI-predicted complete resection was significantly better than CT (91.3% vs. 72.5% accuracy, p < 0.001). CONCLUSION: WB-DWI/MRI after NACT is accurate for predicting surgical and survival outcomes in patients with non-primary resectable ovarian cancer.
Figueroa V, Coianis MI, Sahores A
… +11 more, Pataccini G, Abba MC, Elía A, May M, Vanzulli SI, Martínez Vázquez P, Burruchaga J, Torres F, Sartorius CA, Lanari C, Lamb CA
Br J Cancer
· 2026 Jun · PMID 41935240
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BACKGROUND: Endocrine resistance is a major clinical challenge in luminal breast cancer. Nuclear fibroblast growth factor 2 (FGF2) and altered progesterone receptor (PR) isoform ratios have been identified as markers of...BACKGROUND: Endocrine resistance is a major clinical challenge in luminal breast cancer. Nuclear fibroblast growth factor 2 (FGF2) and altered progesterone receptor (PR) isoform ratios have been identified as markers of antiprogestin resistance. We investigated pathways associated with FGF2 upregulation to identify new targets for antiprogestin-resistant tumours. METHODS: PR T47D and T47D‑YA cell lines engineered to overexpress FGF2 were used to investigate FGF2‑driven antiprogestin resistance. Transcriptome profiling, qRT-PCR, immunohistochemistry, and in vivo assays assessed hormone receptor expression, pathway alterations, and therapeutic response. We evaluated nuclear androgen receptor (AR) and FGF2 in luminal breast cancer specimens. RESULTS: RNA-seq showed that FGF2 overexpression dysregulated Wnt signalling, downregulated oestrogen receptor (ER) and PR, and upregulated AR expression. PR isoform B (PRB) predominated, consistent with an antiprogestin-resistant phenotype. FGF2-overexpressing xenografts showed antiprogestin resistance, increased proliferation, and lung metastasis. AR and Wnt pathway blockade impaired tumour growth, and combined treatment further reduced tumour and metastatic burden. In clinical samples, nuclear FGF2 correlated with elevated AR levels in ERPR and PRB-high tumours. CONCLUSION: We identified a subset of luminal breast cancers characterised by nuclear FGF2, AR upregulation, and PR isoform imbalance. Dual AR and Wnt pathway targeting may offer a promising strategy for antiprogestin-resistant disease.
Zhang J, Liu Y, Yuan H
… +8 more, Zhan N, Deng J, Tang L, Li X, Liu Y, Zhao W, Liu S, Qi L
Br J Cancer
· 2026 Jun · PMID 41933195
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BACKGROUND: Small cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, exhibits high intertumoral heterogeneity and limited treatment options. Immune checkpoint inhibitors (ICIs) provide only modest benefits...BACKGROUND: Small cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, exhibits high intertumoral heterogeneity and limited treatment options. Immune checkpoint inhibitors (ICIs) provide only modest benefits for SCLC, underscoring the need for clinically actionable phenotypes. METHODS: Consensus clustering of bulk transcriptomic data identified SCLC molecular phenotypes. Bulk and single-cell RNA sequencing (scRNA-seq) revealed their molecular and immune characteristics, as well as tumor microenvironment interactions. Survival benefits of ICIs were assessed in 41 newly collected extensive-stage SCLC (ES-SCLC) patients treated with chemotherapy plus ICIs, integrated with a public dataset. RESULTS: We identified three distinct SCLC phenotypes, termed proliferative, iNotch, and infiltrated phenotypes, as they were characterized by high proliferation, inhibitory Notch signaling, and immune-rich microenvironments, respectively. These phenotypes were reproducible across three bulk independent datasets. Further intercellular communication analysis of scRNA-seq data revealed a subset with high ANXA1 expression in the infiltrated phenotype suppressed CD8 T cells via M2 macrophage polarization. Survival analyses showed that only ANXA1 infiltrated patients derived significant survival benefit from chemotherapy plus ICIs. CONCLUSIONS: This study identified three distinct SCLC phenotypes with unique therapeutic vulnerabilities. An ANXA1 subset within the immune-rich infiltrated phenotype showed ICI resistance, offering new strategies to enhance ICI efficacy.
Johnson ML, Fabbri G, Ciardullo C
… +22 more, Wang JS, Falchook GS, Jones S, Strickland D, Sands J, Gay CM, Cardnell RJ, Tobalina L, Willis SE, Rodriguez-Canales J, Nikolaou M, Jones EV, Schalkwijk S, Sainsbury L, MacDonald A, Overend P, Kennedy C, Pease JE, Szekeres P, Cosaert J, Burris H, Byers LA
Br J Cancer
· 2026 Jun · PMID 41933194
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BACKGROUND: Aurora kinase B (AURKB) is overexpressed in lung cancer and is associated with poor prognosis. AZD2811 is an AURKB inhibitor that demonstrated tolerability during a Phase I dose-escalation study in patients w...BACKGROUND: Aurora kinase B (AURKB) is overexpressed in lung cancer and is associated with poor prognosis. AZD2811 is an AURKB inhibitor that demonstrated tolerability during a Phase I dose-escalation study in patients with advanced solid tumours, including small-cell lung cancer (SCLC). Here we report the dose-expansion results. METHODS: Eligible patients received nanoparticle-formulated AZD2811 500 mg IV (Day 1; 21-day cycles) with granulocyte colony-stimulating factor (Day 8). Dose-expansion endpoints included: preliminary antitumour activity, safety/tolerability, pharmacokinetics, and biomarker-based disease monitoring. RESULTS: One of 21 enrolled patients achieved a partial response for an objective response rate of 4.8%; stable disease ≥6 weeks was observed in 10 patients (47.6%). The most common AZD2811-related AEs were decreased neutrophil and white blood cell count, anaemia, and decreased platelet count; grade ≥3 AZD2811-related AEs occurred in 15/21 patients. Baseline ctDNA levels were prognostic, and on-treatment ctDNA changes mirrored clinical response and identified progression early, suggesting it could be an effective surrogate for tumour tissue. Molecular profiling of paired tumour biopsies demonstrated AZD2811 pharmacodynamic activity and identified genes/pathways potentially linked to response. CONCLUSION: A personalised surveillance strategy may provide a novel avenue to monitor SCLC, supporting further investigation and potential broader clinical application. CLINICAL TRIAL REGISTRATION: NCT02579226.
McSorley ST, Burton P, Chantler D
… +9 more, Johnstone M, Nicholson BD, MacKay G, Mansouri D, Vella M, Susanti S, Rigg D, Winter J, Witherspoon P
Br J Cancer
· 2026 Jun · PMID 41927996
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BACKGROUND: Current BSG/ACPGBI and NICE guidance recommends that faecal haemoglobin (f-Hb) ≥10 ug/g measured by faecal immunochemical test (FIT) in symptomatic patients should prompt referral through cancer prioritised d...BACKGROUND: Current BSG/ACPGBI and NICE guidance recommends that faecal haemoglobin (f-Hb) ≥10 ug/g measured by faecal immunochemical test (FIT) in symptomatic patients should prompt referral through cancer prioritised diagnostic pathways. However, limited long term CRC outcome data exist. This study compared CRC specific survival (CSS) between patients by f-Hb concentration and referral priority in a large primary care f-Hb prioritised lower GI symptomatic pathway. METHODS: Retrospective single health board study of symptomatic patients submitting FIT in primary care, 2019-2022. CRC diagnoses up to 3 years after pathway entry, and CRC deaths (ICD10 18, 19, 20) to end 2024 were recorded from cancer audit and MCN datasets. Patients were grouped by f-Hb concentration and referral priority. Univariable and multivariable Cox regression estimated CSS. RESULT: Of 126,984 patients, 1453 (1%) were diagnosed with CRC within 3 years of f-Hb result or referral, of which 444 (31%) died due to CRC. At multivariable analysis, referral without FIT (HR 1.42, 95% CI 1.06-1.91), and f-Hb ≥10 ug/g diagnosed outwith CRC prioritised pathways (HR 1.47, 95% CI 1.03-2.10) were associated with worse CSS independent of TNM stage. CONCLUSION: Referral and investigation through cancer prioritised pathways guided by f-Hb concentration is safe in relation to CSS.
Guo WP, Yu X, Lu ZJ
… +7 more, Li YC, Wu C, Gu LW, Cao JN, Luo DH, Liu SL, Guo L
Br J Cancer
· 2026 Jun · PMID 41917212
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BACKGROUND: The optimal number of induction chemotherapy (IC) cycles for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is debated. This study investigates if early cell-free Epstein-Barr virus (cfEBV) DNA cle...BACKGROUND: The optimal number of induction chemotherapy (IC) cycles for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is debated. This study investigates if early cell-free Epstein-Barr virus (cfEBV) DNA clearance can personalise treatment. METHODS: We included 1590 LA-NPC patients treated with IC+ chemoradiotherapy (2010-2023) with complete early cfEBV DNA data. COX regression identified independent prognostic factors, and receiver operating characteristic curves assessed predictive accuracy. Propensity score matching (PSM) balanced covariates between groups receiving different IC cycles. The primary outcome, progression-free survival (PFS) was analysed using Kaplan-Meier and log-rank tests. RESULTS: After the first IC cycle, 45.5% of patients had undetectable cfEBV DNA. Combining cfEBV DNA clearance, N-stage, and overall stage yielded the highest AUC for 5-year PFS (0.632). Patients were stratified into high- and low-risk groups (p < 0.001). Post-matching, low-risk patients receiving three IC cycles had better 5-year PFS than those receiving two (85.2% vs. 76.0%, p = 0.024), with no significant increase in grade 3-4 toxicities (30.36% vs. 24.29%, p = 0.157). High-risk patients showed no PFS benefit from additional cycles (63.2% vs. 61.0%, p = 0.960). DISCUSSION: Early cfEBV DNA clearance predicts LA-NPC outcomes. Low-risk patients may benefit from an additional cycle of IC, while high-risk patients may require alternative strategies like immunotherapy or earlier chemoradiotherapy.
Lopez JS, Harrington KJ, Im SA
… +12 more, Lee KW, Postel-Vinay S, Thomas JS, Lukashchuk N, Willis SE, Irurzun-Arana I, Webb B, Nehra J, Lau A, Loembé AB, Dean E, Krebs MG
Br J Cancer
· 2026 Jun · PMID 41917211
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BACKGROUND: This multicentre, modular, Phase 1 study evaluated escalating doses of ATR (ataxia telangiectasia and Rad3-related kinase) inhibitor ceralasertib plus PD-L1 inhibitor durvalumab in patients with previously tr...BACKGROUND: This multicentre, modular, Phase 1 study evaluated escalating doses of ATR (ataxia telangiectasia and Rad3-related kinase) inhibitor ceralasertib plus PD-L1 inhibitor durvalumab in patients with previously treated advanced/metastatic non-small-cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC). METHODS: Patients received ceralasertib 80/160/240 mg twice-daily (BID) or 320 mg once-daily (QD) for 7 (Days 22-28) or 14 (Days 15-28) days, plus durvalumab 1500 mg (Day 1), per 28-day cycle. The primary objective was to investigate the safety/tolerability of the combination. RESULTS: Sixty patients were treated. Two patients had dose-limiting toxicities of: Grade 3 thrombocytopenia with Grade 3 anaemia (ceralasertib 320 mg QD for 14 days); and Grade 4 thrombocytopenia with Grade 3 neutropenia accompanied by systemic chest infection (ceralasertib 240 mg BID for 14 days). Overall, 59 (98.3%) patients had treatment-emergent adverse events; 31 (51.7%) had grade ≥3 events. The recommended Phase 2 dose was durvalumab 1500 mg (Day 1) plus ceralasertib 240 mg BID (Days 15-28). Five (8.3%) patients had objective responses; 31 (51.7%) had stable disease. Pharmacodynamic activity (pRAD50 increase) was observed in 10/14 paired biopsies. CONCLUSION: Ceralasertib plus durvalumab was tolerated and associated with antitumour activity in advanced/metastatic NSCLC and HNSCC. TRIAL REGISTRATION NUMBER: NCT02264678.