BACKGROUND: The epithelial-mesenchymal axis frames gastric cancer heterogeneity but mainly captures phenotypic extremes. CCNE1 gain, encompassing amplification or Cyclin E1 overexpression, represents one intermediate sta...BACKGROUND: The epithelial-mesenchymal axis frames gastric cancer heterogeneity but mainly captures phenotypic extremes. CCNE1 gain, encompassing amplification or Cyclin E1 overexpression, represents one intermediate state linked to chromosomal instability and therapeutic resistance. However, its clinicopathologic identity and immune features in gastric cancer remain insufficiently characterised. METHODS: We analysed 1273 gastric cancer patients across six independent cohorts: ZSHS (n = 453), TCGA (n = 410), ACRG (n = 300), SMC (n = 43), MSKCC (n = 22), and ZSHS NGS cohort (n = 45). Tumours were classified into CCNE1 gain, epithelial, or mesenchymal subtypes using protein, copy-number, or transcript-level data. Clinicopathologic features, survival outcomes, treatment responses, and immune contexture were evaluated across subtypes. RESULTS: CCNE1 gain tumours retained E-cadherin positivity but showed increased proliferation, more nerve and venous invasion. They were associated with poor prognosis and reduced response to adjuvant chemotherapy, HER2-targeted therapy, anti-angiogenic agents, and PD-1 blockade independent of epithelial-mesenchymal classification. The immune contexture exhibited an immune-desert phenotype with reduced lymphocyte infiltration, impaired cytotoxicity, increased M2 macrophage polarisation, and elevated TGF-β. CONCLUSION: CCNE1 gain delineates a clinic-ready, therapy-refractory subtype of gastric cancer beyond the epithelial-mesenchymal framework, representing over one in ten patients. These tumours preserve epithelial morphology yet exhibit aggressive proliferative and invasive behaviour, coupled with immune desert and myeloid-driven suppression.
Br J Cancer
· 2026 Jul · PMID 42045541
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Adoptive cell therapies (ACT) and immune cell engagers (ICE) redirect or potentiate immune effector function against immune-tolerated antigens expressed on malignant cells, representing a distinct class of engineered imm...Adoptive cell therapies (ACT) and immune cell engagers (ICE) redirect or potentiate immune effector function against immune-tolerated antigens expressed on malignant cells, representing a distinct class of engineered immunotherapies beyond immune checkpoint blockade. These strategies have been particularly successful in hematologic malignancies; however, translation to solid tumours has been constrained by antigen heterogeneity, limited immune cell trafficking and persistence, an immunosuppressive tumour microenvironment, and on-target off-tumour toxicity. Despite these barriers, accumulating data and clinical experience with these therapies in solid tumours demonstrate feasibility, scalability, safety, and meaningful clinical activity. In light of recent regulatory approvals of ACT and ICE in solid tumours, we aim to provide a comprehensive clinician-oriented overview of these evolving therapeutic platforms. Herein, we review principles of antigen selection, mechanisms underlying investigational ACT and ICE, current barriers to clinical translation in solid tumours, strategies to overcome these limitations, and future prospects for immune-redirecting drug development in solid tumours.
Rigutto A, Núñez NG, Kienzler JC
… +10 more, Opitz I, Meerang M, Haberecker M, Fournier N, Lourenço J, Gottardo R, Silina K, Gupta A, Becher B, Curioni-Fontecedro A
Br J Cancer
· 2026 Jul · PMID 42045540
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BACKGROUND: Pleural mesothelioma (PM) is an orphan disease with poor prognosis. While T cell dynamics in the tumor microenvironment (TME) have been extensively studied, the role of B cells remains poorly characterized. T...BACKGROUND: Pleural mesothelioma (PM) is an orphan disease with poor prognosis. While T cell dynamics in the tumor microenvironment (TME) have been extensively studied, the role of B cells remains poorly characterized. Tumor-infiltrating B cells, particularly when organized into tertiary lymphoid structures (TLS), have been associated with improved outcomes of patients with cancer. METHODS: In this study, high-dimensional flow cytometry (HDCyto) and high-plex imaging were applied to analyze fresh-frozen and formalin-fixed paraffin-embedded (FFPE) PM tumor samples, enabling a comprehensive immune profiling of the TME. RESULTS: We identified 15 distinct immune cell subsets and stratified tumors into three subgroups with significantly different survival outcomes. Longer survival correlated with increased T and B cell infiltration, with B cells and CD4+ T cells forming TLS in specific cases. CONCLUSIONS: These findings underscore the heterogeneity of PM tumors and highlight the critical role of B cells and TLS in shaping anti-tumor immunity and influencing patient prognosis.
Choi E, Luo S, Ding VY
… +7 more, Graber-Nadich A, Wu JT, Popat R, Cheng I, Neal JW, Wakelee HA, Han SS
Br J Cancer
· 2026 Jul · PMID 42045539
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BACKGROUND: Lung cancer survivors have a high risk of second primary lung cancer (SPLC). While air pollution is associated with the risk of initial primary lung cancer (IPLC), especially in never smokers, its effect on S...BACKGROUND: Lung cancer survivors have a high risk of second primary lung cancer (SPLC). While air pollution is associated with the risk of initial primary lung cancer (IPLC), especially in never smokers, its effect on SPLC risk is unknown. METHODS: We identified 2439 IPLC patients from the UK Biobank, followed through 2017, linking baseline addresses to 2005-2007 annual average exposures of particulate matter (PM10) and nitrogen dioxide (NO) from the EU-wide Land Use Regression model. Associations with SPLC risk were assessed using cause-specific Cox models adjusted for co-pollutants, socioeconomic factors, smoking, and tumour characteristics. RESULTS: Of 2439 IPLC patients, 92 (3.7%) developed SPLC over 6561 person-years. The 10-year cumulative incidence of SPLC was 3.98% (3.11-4.85%). A dose-response relationship was observed between PM10 and SPLC risk, with an adjusted hazard ratio (aHR) of 6.43 (2.38-17.32) in the highest vs. lowest (aHR = 1.69 [0.68-4.19]) quintile; a co-pollutant NO showed an aHR of 0.96 (0.93-0.99). The PM10 effect was pronounced in never-smoking (aHR = 2.26 [1.22-4.18]) vs. ever-smoking IPLC patients (aHR = 1.42 [1.21-1.68]) on the risk of non-small cell SPLC. INTERPRETATION: Exposure to PM10 may increase SPLC risk in lung cancer survivors, highlighting the potential value of incorporating environmental factors into SPLC surveillance to identify high-risk individuals.
Stegenborg F, Bidstrup PE, Rostgaard K
… +6 more, Davidsson ÒB, Niemann CU, Gögenur I, Jakobsen E, Dalton SO, Hjalgrim H
Br J Cancer
· 2026 Jul · PMID 42045538
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BACKGROUND: Sex differences in cancer incidence and survival have been documented, but underlying mechanisms remain unclear. We examined sex differences in incidence and survival for non-sex-specific cancers and the role...BACKGROUND: Sex differences in cancer incidence and survival have been documented, but underlying mechanisms remain unclear. We examined sex differences in incidence and survival for non-sex-specific cancers and the role of socioeconomic factors and comorbidity. METHODS: All individuals living in Denmark from 2004-2020 were included. Incidence rate ratios (IRRs) and excess mortality ratios (EMRs) for 35 cancers were estimated using Poisson regression adjusted for age and year. Modification of associations between sex and death by cohabitation, education and comorbidity was assessed. RESULTS: A total of 7,339,667 individuals were followed for 99,832,998 person-years, during which 355,339 were registered with a primary malignancy (197,375 males, 157,964 females). Males had a 52% higher risk of cancer and upon cancer diagnosis 10% higher mortality than females. IRRs were elevated (with confidence intervals excluding the null) for 24 cancers and EMRs for 16 cancers in males. One in six cancers and one in five cancer deaths in males could have been avoided if male rates matched female rates. Disparities were greatest among males living alone, particularly for alcohol- and smoking-related cancers. CONCLUSION: Sex differences in cancer must be addressed and translated into interventions that promote equality between sexes, specifically focusing on socioeconomically vulnerable males.
Ellis L, Eversfield C, Gray E
… +7 more, Hall PS, Hiom S, Jones DA, Lee LY, McPhail S, Spencer K, Halloran C
Br J Cancer
· 2026 Jul · PMID 42032201
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BACKGROUND: Cancer screening can reduce late-stage diagnoses, expand treatment options, and improve cancer outcomes. We modelled how introducing a multi-cancer early detection (MCED) screening programme in England could...BACKGROUND: Cancer screening can reduce late-stage diagnoses, expand treatment options, and improve cancer outcomes. We modelled how introducing a multi-cancer early detection (MCED) screening programme in England could impact cancer treatment patterns. METHODS: The proportions of cancers (19 types, diagnosed 2014-2019) treated with resection, radiotherapy, and systemic anti-cancer therapy (SACT) were applied to modelled stage-specific cancer incidence data with and without addition of MCED screening to existing screening. We modelled an initial screening round (first screen for individuals aged 50-79 years) and a steady-state programme (annual screening from age 50-79 years). RESULTS: Assuming test parameters are accurate, if MCED screening is introduced in England, more cancers would require resection compared with current annual usage (steady-state: +8900, +10.0%). The number of cancers receiving radiotherapy would decrease overall (-1200; -2.0%) due to a decrease in palliative radiotherapy (-2100; -23.0%); the number of cancers treated with curative radiotherapy would increase slightly (+932; +2.1%). Fewer cancers would receive cytotoxic chemotherapy (-5300, -9.8%) and non-cytotoxic SACT (-530, -12.2%). Increased use of curative treatment combinations is also predicted. CONCLUSIONS: Changes to future service delivery and workforce planning will be needed for the full benefits of an MCED screening programme to be realised.
Bojesson A, Brun E, Eberhard J
… +1 more, Segerlantz M
Br J Cancer
· 2026 Jul · PMID 42032200
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BACKGROUND: Patients with advanced gastrointestinal (GI) cancer experience a high symptom burden which frequently necessitates emergency care. Integration of early home-based specialised palliative care (SPC) with tumour...BACKGROUND: Patients with advanced gastrointestinal (GI) cancer experience a high symptom burden which frequently necessitates emergency care. Integration of early home-based specialised palliative care (SPC) with tumour-specific treatments may impact emergency healthcare use. METHODS: At the initiation of palliative chemotherapy, patients with advanced GI cancer were randomised to early home-based SPC integrated with tumour-specific treatment, or tumour-specific treatment with SPC referral when needed. The aim was to compare quality of life in the two groups. Here we present secondary outcomes; number of emergency department visits, hospitalisations, days of inpatient care, the time from the last chemotherapy treatment to death, and the place of death between the study groups. RESULTS: A total of 118 patients were randomised. Patients in the early SPC group had significantly fewer emergency department visits (median 1 versus 3), hospitalisations (median 1 versus 2), and inpatient care days (median 1.5 vs. 11.5) compared to the control group (p < 0.001). There was no significant difference between the study groups in either time between the last chemotherapy treatment and death, inpatient SPC or place of death. CONCLUSION: Early integration of home-based SPC in advanced GI cancer patients significantly reduces emergency healthcare use and hospitalisation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (ref: NCT02246725).
Ahmad S, Butle A, Karn A
… +10 more, Sunder R, Mishra R, Bawaskar B, Parab P, Raje V, Chaubal R, Shet T, Kundu G, Gupta S, Dutt A
Br J Cancer
· 2026 Jul · PMID 42020778
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BACKGROUND: Hormone receptor-positive (HR + ), HER2-negative breast cancer comprises ~70% of all breast cancer cases and is primarily treated with endocrine therapies such as tamoxifen, aromatase inhibitors, fulvestrant,...BACKGROUND: Hormone receptor-positive (HR + ), HER2-negative breast cancer comprises ~70% of all breast cancer cases and is primarily treated with endocrine therapies such as tamoxifen, aromatase inhibitors, fulvestrant, and CDK4/6 inhibitors. However, resistance arises in ~40% of patients, limiting therapeutic efficacy. METHOD: We performed integrated genomic, transcriptomic, and functional analyses of 186 HR + /HER2-tumors (88 sensitive, 98 resistant), to identify key drivers of endocrine hormone therapy resistance, Findings were validated functionally using in-vitro and in-vivo models. RESULTS: We identify frequent CDKN1B (p27) loss-of-function mutations or deletions as a key and clinically actionable driver of endocrine resistance. CDKN1B knockdown in cell lines induces resistance to tamoxifen and fulvestrant, while its restoration re-sensitizes resistant cells. Importantly, CDKN1B-deficient tumors remain responsive to CDK4/6 inhibition, in vitro and in vivo. Immunohistochemistry and transcriptomic analysis of clinical cohorts (n = 138) and TCGA-METABRIC data (n = 1398) identify low p27 as an independent predictor of early relapse and poor survival. CONCLUSION: Our results highlight CDKN1B as a prognostic biomarker to guide CDK4/6-targeted therapy and a predictor of endocrine resistance in HR + /HER2- breast cancer.
Zhao K, Zhang J, Wang R
… +6 more, Wang B, Ye D, Huang X, Qiu L, Duan Y, Xu Z
Br J Cancer
· 2026 Jul · PMID 42020777
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BACKGROUND: EGFR-tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with non-small cell lung cancer (NSCLC); however, drug resistance limits their long-term efficacy. The role of STAT3 signaling in E...BACKGROUND: EGFR-tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with non-small cell lung cancer (NSCLC); however, drug resistance limits their long-term efficacy. The role of STAT3 signaling in EGFR-TKI resistance is not completely understood. METHODS: Using immunohistochemistry, we assessed changes in STAT3 phosphorylation levels in NSCLC before and after EGFR-TKIs treatment. Through gene editing and transcriptome sequencing experiments, we investigated the mechanism by which STAT3 signaling mediates drug resistance. We conducted cell proliferation and nude mice tumorigenesis experiments to verify whether STAT3 inhibitors enhanced the anti-tumor effect of EGFR-TKIs on NSCLC. RESULTS: We found that inhibition of the MAPK pathway by EGFR-TKIs triggers the rapid activation of STAT3 in NSCLC. RNA-seq analysis and cellular experiments confirmed that STAT3 regulates the expression of stemness markers, which contribute to drug resistance. Cancer stemness maintenance depends on telomerase. We found that STAT3 also mediates NSCLC resistance by regulating telomerase expression. Finally, we demonstrated in both cellular and animal models that icaritin, an anti-hepatocellular carcinoma agent, significantly potentiates the anti-tumor efficacy of EGFR-TKIs against NSCLC by inhibiting STAT3 activation. CONCLUSIONS: The combination of EGFR-TKIs and STAT3 inhibitors has the potential to be a better therapeutic strategy for EGFR-mutant NSCLC than EGFR-TKI monotherapy.
Peng Y, Yang Y, Chen K
… +5 more, Li B, Xu H, Guo S, Wei Y, Liu F
Br J Cancer
· 2026 Jul · PMID 42020776
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BACKGROUND: During laparoscopic major hepatectomy (LMH) for patients with hepatocellular carcinoma (HCC), an appropriate approach for hepatic hilum treatment is crucial. However, to date, there is still controversy about...BACKGROUND: During laparoscopic major hepatectomy (LMH) for patients with hepatocellular carcinoma (HCC), an appropriate approach for hepatic hilum treatment is crucial. However, to date, there is still controversy about whether the Glissonian approach or hilar dissection approach is more advantageous for hepatic hilum treatment. Thus, we performed this randomized controlled trial to compare the short- and long-term outcomes between the Glissonian and hilar dissection approaches for LMH. METHODS: Between November 2017 and July 2021, 256 HCC patients who initially met the criteria via preoperative evaluation were randomly assigned to this trial. After surgical exploration, 119 patients in the Glissonian group and 121 patients in the hilar dissection group were eventually enrolled in the modified intention-to treat (ITT) principled analysis. Perioperative data and survival outcomes between both groups were recorded and compared, and subgroup analysis was further performed. RESULTS: The 5-year OS rates and 5-year DFS rates were comparable between the two groups. In addition, postoperative overall complications, including bile duct injury, leakage, and stricture, did not differ between the groups. However, the operative time (P = 0.044) and the hilar dissection time (P < 0.001) were significantly shorter in the Glissonian group than the hilar dissection group. Additionally, for patients with liver cirrhosis, the Glissonian group had shorter operative time (P = 0.002) and less intraoperative blood loss (P = 0.004) than the hilar dissection group. CONCLUSIONS: The Glissonian approach for LMH in selected HCC patients is superior to the hilar dissection approach in short-term outcomes, but the survival outcomes were comparable between both groups. REGISTRATION NUMBER: ChiCTR-IOR-17013077.
Guerra P, Villano G, Rejano-Gordillo CM
… +23 more, Gil-Pitarch C, Ruvoletto M, Biasiolo A, Quarta S, Zapata-Pavas LE, Peña-SanFelix P, González-Recio I, Goikoetxea-Usandizaga N, Barrenechea-Barrenechea JA, Sanz-Parra A, Gambella A, De Siervi S, Oliviero B, Mantovani S, Nurcis J, Cagnin S, Martini A, Turato C, Cannito S, Guido M, Parola M, Martínez-Chantar ML, Pontisso P
Br J Cancer
· 2026 Jul · PMID 42020775
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BACKGROUND: MASLD and HCC are increasing challenges in hepatology. 1-Piperidinepropionic acid (1-PPA), a protease-activated receptor 2 (PAR2) inhibitor, downregulates SerpinB3, a molecule involved in fibrosis and HCC. Th...BACKGROUND: MASLD and HCC are increasing challenges in hepatology. 1-Piperidinepropionic acid (1-PPA), a protease-activated receptor 2 (PAR2) inhibitor, downregulates SerpinB3, a molecule involved in fibrosis and HCC. This study investigates the effects of 1-PPA on lipid accumulation and HCC development. METHODS: 1-PPA was employed in primary hepatocytes and human liver organoids cultured with steatogenic compounds and lomitapide, a VLDL-formation inhibitor. Antitumoral effects of 1-PPA were evaluated by proliferation and invasion assays in HepG2 cells and in human liver organoids treated with a tumorigenic compound. MASH-related carcinogenesis was studied in vivo using C57BL/6J mice overexpressing SerpinB3 (C57/TG) and BALB/c mice deficient in the reactive site loop of Serpinb3a (BC/KO). RESULTS: 1-PPA reduced tumour development and steatosis in vivo. Proteomic analysis showed decreased lipid synthesis and deposition post-treatment. Suppression of lipid accumulation was favoured by an increase in VLDL export, supported by an enhanced microsomal triglyceride transfer protein activity in vivo and by a competitive effect between 1-PPA and lomitapide in vitro. The compound 1-PPA also exhibited direct antitumoral effects, reducing proliferation, survival and invasion in liver organoids and HepG2 cells. CONCLUSIONS: 1-PPA administration prevents lipid accumulation and HCC development in MASH-related liver carcinogenesis.
Gordon A, Tran A, Fong C
… +18 more, Cromarty S, Piadel K, Zhitkov O, Leamon B, Cafferkey C, Davidson M, Das P, Petty R, Roques T, Hewish M, Morgan C, Waddell T, Darby S, Bradshaw A, Rao S, Starling N, Chau I, Cunningham D
Br J Cancer
· 2026 Jul · PMID 42014556
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BACKGROUND: PLATFORM is an adaptive phase II trial assessing maintenance therapies in advanced oesophagogastric adenocarcinoma (OGA). We evaluated maintenance capecitabine in patients with disease control after first-lin...BACKGROUND: PLATFORM is an adaptive phase II trial assessing maintenance therapies in advanced oesophagogastric adenocarcinoma (OGA). We evaluated maintenance capecitabine in patients with disease control after first-line chemotherapy. METHODS: HER2-negative patients with advanced OGA who had response or stable disease after 18 weeks of first-line chemotherapy were randomised (1:1) to surveillance or capecitabine. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. RESULTS: Between May 2015 and May 2024, 266 patients were randomised (129 surveillance, 137 capecitabine). Median follow up was 70.7 months. Capecitabine significantly improved PFS (HR 0.69; 95% CI 0.54-0.89; p = 0.002), with median PFS of 5.0 vs 2.8 months. One-year PFS rates were 19.9% vs 6.8%; and two-year rates 8.1% vs 4.3%. No OS difference was observed (median OS: 10.5 vs 10.0 months; HR 0.87; 95% CI 0.67-1.12; p = 0.143). One and two-year OS rates were similar (1-year: 44.1% vs 45.7%; 2-year: 18.8% vs 16.8%). Grade ≥3 adverse events were more frequent with capecitabine (46% vs 29%), with 21% experiencing grade 3 treatment related events. DISCUSSION: Maintenance capecitabine significantly prolonged PFS compared to surveillance, meeting the primary endpoint and supporting its use to extend disease control in advanced OGA.
Flanders L, Savy T, Ficial M
… +8 more, Al-Ghraibawi N, Barber L, Slater S, Pihlak R, Propper D, Begum S, Rodriguez-Justo M, Gerlinger M
Br J Cancer
· 2026 Jul · PMID 42000962
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PURPOSE: To explore why PD-L1 scores in metastatic gastro-esophageal adenocarcinomas (GEAs) were significantly lower in a real-world cohort compared with the CheckMate 649 (CM649) trial. METHODS: PD-L1 combined positive...PURPOSE: To explore why PD-L1 scores in metastatic gastro-esophageal adenocarcinomas (GEAs) were significantly lower in a real-world cohort compared with the CheckMate 649 (CM649) trial. METHODS: PD-L1 combined positive scores (CPS) were evaluated using validated assays in 100 consecutive patients with advanced/metastatic GEA at St Bartholomew's Hospital (SBH) and compared with CM649 (n = 1567). Clinicopathological factors and biopsy site were analysed to assess their impact on PD-L1 results. RESULTS: CPS ≥ 5 was substantially less frequent in SBH patients (30%) compared with CM649 (61%). Older age ( ≥ 65 years), non-diffuse histology, and MMR deficiency were associated with CPS ≥ 5 across both cohorts, yet these factors were more common at SBH and therefore did not explain the lower positivity rate. Metastatic biopsies were more frequent in CM649 (21% vs. 9%), but CPS ≥ 5 was lower in metastases (50%) than in primary tumors (60%). Importantly, PD-L1 positivity varied by metastatic site: lymph node metastases showed the highest rate (80%), while liver (50%) and other sites (44%) were significantly lower than primaries (60%). CONCLUSION: PD-L1 CPS is shaped by clinicopathological context and biopsy site. The persistently lower CPS ≥ 5 prevalence at SBH despite validated testing highlights assay variability and reinforces the urgent need for assay standardisation. Preferential use of primary tumor tissue may help reduce metastasis-specific bias.
Macdonald CJ, McWhirter A, Vaidyanathan A
… +5 more, Ferguson MJ, Eberl HC, Stronach EA, Sawers L, Smith G
Br J Cancer
· 2026 Jul · PMID 41998207
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BACKGROUND: Maintenance PARP inhibitor (olaparib or niraparib) treatment is commonly prescribed following carboplatin/paclitaxel chemotherapy in ovarian cancer patients, but response is compromised by adaptive drug resis...BACKGROUND: Maintenance PARP inhibitor (olaparib or niraparib) treatment is commonly prescribed following carboplatin/paclitaxel chemotherapy in ovarian cancer patients, but response is compromised by adaptive drug resistance [1]. We have shown that P-gp/ABCB1 influences resistance to paclitaxel and olaparib, but similar niraparib resistance mechanisms have not been described [2, 3]. METHODS: We used qRT-PCR, Western blot, RNASeq and LC-MS/MS proteomics analysis to compare drug transporter expression in sensitive and resistant immortalised and primary patient-derived cell lines. ABCB1 and ABCG2 expression was modified by shRNA-mediated knockdown and heterologous expression, with chemosensitivity changes assessed by MTT and clonogenic assays. Substrate specificity of P-gp and BCRP was assessed by efflux assays in polarised cells. RESULTS: P-gp/ABCB1 expression was not increased in A2780nirapR cells, which alternatively up-regulated BCRP/ABCG2. ABCG2 was consistently induced in niraparib-resistant patients, but ABCB1 only in patients pre-treated with paclitaxel. shABCG2 re-sensitised A2780nirapR cells, while heterologous expression in A2780 cells induced drug resistance. Efflux assays confirmed that olaparib and niraparib are both P-gp and BCRP substrates, suggesting that resistance results from transcriptional regulation of efflux transporters not substrate specificity. CONCLUSIONS: Treatment-induced BCRP/ABCG2 induction is a novel clinically relevant niraparib resistance biomarker. Routine inclusion of paclitaxel in first-line chemotherapy regimens may promote efflux transporter-mediated resistance, compromising response to PARPi maintenance treatment.
Page PM, Laperrière T, Dastous SA
… +4 more, Landry SE, Richard PO, Pavic M, Turcotte S
Br J Cancer
· 2026 Jul · PMID 41998206
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BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is primarily driven by chromosome 3p loss and inactivation of the von Hippel-Lindau (VHL) gene, which is frequently accompanied by chromosome 5q gain. However, the onco...BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is primarily driven by chromosome 3p loss and inactivation of the von Hippel-Lindau (VHL) gene, which is frequently accompanied by chromosome 5q gain. However, the oncogenic contribution of 5q remains unclear. This study examines how 5q gain affects the expression of microRNAs implicated in ccRCC. METHODS: Bioinformatic analyses were conducted to evaluate miRNAs associated with 5q gain and 3p loss. RT-qPCR validation was performed in tumour tissues and patient plasma. Mechanistic investigations integrated open-source ChIP-seq datasets and luciferase reporter assays. RESULTS: miR-1271-5p overexpression was significantly associated with both 5q gain and 3p loss and strongly correlated with its host gene, ARL10. RT-qPCR confirmed elevated levels of miR-1271-5p and ARL10 in ccRCC tumours and increased circulating miR-1271-5p in patient plasma. Mechanistically, these upregulations resulted from VHL loss and subsequent HIFα stabilisation. ChIP-seq datasets and luciferase assays demonstrated that HIF-1α, but not HIF-2α, directly binds within the intragenic region of ARL10. Importantly, this regulatory mechanism was specific to kidney cells. CONCLUSIONS: Coordinated upregulation of miR-1271-5p and ARL10 reflects key genomic events in ccRCC and is driven by kidney-specific HIF-1a activity. Our findings suggest their promise for early detection and disease monitoring.
Teke K, Özer C, Yaprak Bayrak B
… +15 more, Reyhancan İA, Vural Ç, Kasap M, Karabey AÜ, Akpınar G, Bosnalı E, Koyuncu N, Avcı İE, Erbay O, Sahip Kızıltaş M, Hunç F, Camtakan Z, Kara Ö, Aksu G, Dillioğlugil Ö
Br J Cancer
· 2026 Jul · PMID 41998205
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BACKGROUND: To investigate the antitumoral and pro-inflammatory effect of Boron Neutron Capture Therapy (BNCT) following systemic or intravesical borophenilalanine administration, and to compare it with conventional radi...BACKGROUND: To investigate the antitumoral and pro-inflammatory effect of Boron Neutron Capture Therapy (BNCT) following systemic or intravesical borophenilalanine administration, and to compare it with conventional radiotherapy (cRT) in an experimental bladder cancer (BC) model. METHODS: Sixty-four Wistar rats were used, of which half were exposed to carcinogen to induce BC. Radiation therapy (RT) was performed both in the MARK TRIGA-II reactor for BNCT and in the Radiation Oncology divison for cRT. After necropsy, bladder and perivesical tissues were collected. Tumour staging, tumour burden, proliferative, and apoptotic indexes were evaluated for bladder samples. Bladder and perivesical tissues (colon, uterus, and anterior abdominal wall) were also assessed for inflammatory changes in H&E-stained sections, and also bladder TNF-α expressions was examined by immunohistochemistry and Western blot. RESULTS: The animals with cancer had a 15-30% decrease in tumour burden after RT. The incidence of persistent papillary urothelial carcinoma was 100% in the Cancer-cRT group and 87.5% in the Cancer-BNCT-Sys group, whereas a lower incidence was observed in the Cancer-BNCT-IV group (71.4%). A lower proliferative and a higher apoptotic indexes were observed in Cancer-BNCT-IV group compared to Cancer-cRT. Immunohistochemistry and Western blot for TNF-α expression showed that pro-inflammatory response in bladder was lower in BNCT-IV group among cancer treated groups. Moreover, there were lower proinflammatory adverse findings in perivesical tissues, including colon and uterus, in animals receiving BNCT-IV. CONCLUSION: Similar to cRT, systemic or intravesical BNCT resulted in a partial decrease in tumour burden, but fewer adverse findings by intravesical borophenilalanine.
Zhuo G, Li S, Yang G
… +7 more, Hu S, Wu H, Qin K, Wei J, Wang H, Liu G, Pan Y
Br J Cancer
· 2026 Jul · PMID 41992060
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OBJECTIVE: This study investigates changes in NK cell subsets in the blood of NPC patients and explores JAB1's role in shaping the tumor immune environment. METHODS: We performed RNA sequencing analyses on NPC PBMCs and...OBJECTIVE: This study investigates changes in NK cell subsets in the blood of NPC patients and explores JAB1's role in shaping the tumor immune environment. METHODS: We performed RNA sequencing analyses on NPC PBMCs and tissue samples to identify genes associated with JAB1. Dimensionality reduction and clustering analyses were conducted on paired single-cell RNA sequencing data to explore differences in NK cell subsets. Functional assays assessed the roles of these subsets in various immune environments. Flow cytometry characterised NK cell subsets and cytokine profiles. A humanised immune system mouse model with NPC xenografts supported our findings. RESULTS: Higher levels of CD16 + CD57 + NK cells in blood correlated with better patient outcomes, while increased CD16- NK cells indicated worse prognoses. JAB1 enhanced NK cell cytotoxicity, indicating its role in immune regulation. NK subsets showed distinct distributions: CD16hiCD57- and CD16hiCD57+ cells were mainly in blood, while CD16loCD57- cells accumulated in tumors. Functional tests revealed some subsets promoted tumor growth while others suppressed it. Expression of JAB1 and CD107a in NK cells demonstrated superior diagnostic and prognostic value compared to traditional tumor markers like SCC and CEA. CONCLUSION: This study identifies key roles of NK cell subsets and JAB1 in NPC immunity, offering insights for biomarker and immunotherapy target development.
Rea B, Salehi M, Maiter A
… +11 more, Ochieng L, Lanham S, Kang J, Sinha S, Hawthorn J, Gill A, Johns C, Campbell MJ, Harley U, Quhill H, Salvi S
Br J Cancer
· 2026 Jul · PMID 41992059
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BACKGROUND: Liver surveillance imaging is essential for detecting early asymptomatic metastases in uveal melanoma, which predominantly involves the liver. Early detection may improve treatment opportunities, but variabil...BACKGROUND: Liver surveillance imaging is essential for detecting early asymptomatic metastases in uveal melanoma, which predominantly involves the liver. Early detection may improve treatment opportunities, but variability in imaging protocols and a lack of consensus on surveillance duration present challenges. This study aimed to evaluate our systemic surveillance protocol, optimise pathways, and assess risk factors for metastasis. METHODS: We retrospectively analysed patients diagnosed with uveal melanoma between 2006 and 2021 who underwent hepatic imaging surveillance at Sheffield Teaching Hospitals NHS Foundation Trust. Demographics, tumour characteristics, treatments, disease status, and survival outcomes were collected. RESULTS: Among 1086 patients (45% female, 79% White; median age 68 years), 315 (29%) developed metastases, with 293 (93%) detected within five years of ocular treatment. The number needed to scan (NNS) increased substantially after five years, indicating reduced detection efficiency. Higher T stage and ciliary body involvement were significantly associated with increased metastatic risk (P < 0.01). CONCLUSIONS: Most metastases from uveal melanoma occur within five years of treatment. Personalised, risk-based surveillance strategies considering tumour stage and location may improve efficiency and optimise healthcare resource use.
Wang DY, Jiang Z, Ben-David Y
… +2 more, Done SJ, Zacksenhaus E
Br J Cancer
· 2026 Jul · PMID 41986661
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BACKGROUND: Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated...BACKGROUND: Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated molecular pathways, and oncogenic drivers remains poorly defined. METHODS: We analysed TLR7 signature scores in human breast cancer across multiple datasets and evaluated their associations with prognosis, clinical outcomes, TNBC subtypes, metastasis, molecular signatures, oncogenic signalling, and pathological complete response. RESULTS: We demonstrate that the TLR7score signature is significantly elevated in triple-negative breast cancer (TNBC) - the most aggressive breast cancer subtype-compared with ER⁺ disease. Within TNBC, high TLR7 signalling characterises basal- and mesenchymal-like tumours relative to the luminal androgen receptor (LAR) subtype. Across multiple breast cancer cohorts, including TNBC, TLR7score alone does not uniformly predict prognosis, as both high- and low-scoring tumours are associated with reduced survival. Using sequential cut-off analysis in seven independent clinical cohorts, we show that both TLR7score-high (e.g. , SCAN-B: HR = 4.7, P = 0.01) and TLR7score-low (HR = 3.37, P = 0.038) tumours are associated with unfavourable outcomes relative to intermediate-score tumours. TLR7score-high lesions are enriched for cell proliferation, neuronal, and mast cell-related pathways, as well as RB1 and TP53 loss and elevated E2F, PI3K, MET, and MYC signalling. In contrast, TLR7score-low tumours show increased ER signalling and are enriched for T cell-associated but not neuronal pathways, delineating innervated versus non-innervated TNBC phenotypes. Moreover, TLR7score correlates with pathological complete response (pCR) in a treatment-dependent manner. CONCLUSIONS: Collectively, these findings suggest that TNBC progression involves both TLR7-dependent and TLR7-independent mechanisms and that TLR7score may enable patient stratification for distinct therapeutic strategies.