Li X, Janik T, Möbs M
… +8 more, Florian S, Schmitt WD, Dzakulic A, Sehouli J, Horst D, Dubois FPB, Braicu EI, Dragomir MP
Br J Cancer
· 2026 Jun · PMID 42231029
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BACKGROUND: Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for high-grade serous ovarian carcinoma (HGSOC). Patient selection for ADC therapy depends on tumour target expression, making it ess...BACKGROUND: Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for high-grade serous ovarian carcinoma (HGSOC). Patient selection for ADC therapy depends on tumour target expression, making it essential to characterize molecular, spatial, and temporal heterogeneity. METHODS: We analyzed two HGSOC tissue microarray cohorts: 100 genomically profiled cases (1565 cores) and 64 matched cases with paired adnexal (A), locally advanced (LA), and recurrent (R) samples (2395 cores). Associations between ADC target expression and molecular characteristics, sampling site, and survival were investigated. RESULTS: ADC targets showed no significant associations with homologous recombination deficiency (HRD) or TP53 mutation status; TROP2 was modestly lower in BRCA1/2-mutated tumours. Folate receptor-alpha (FolR1) showed notable spatial heterogeneity: 20.2% switched therapeutic-indication groups between centre and margin at A; 21.7% were reclassified between A and LA. Temporally, all markers showed ≥ 20% switching, reaching 38.4% for FolR1 between A and R. High FolR1 expression in A correlated with poorer survival, a pattern not observed in LA or R samples. CONCLUSIONS: ADC targets in HGSOC display limited molecular but significant spatial and temporal heterogeneity, with expression classifications varying by site and time. FolR1 expression in adnexal tumours associates with aggressive disease.
Mego M, Israelyan E, Hamilton RJ
… +19 more, Heidenreich A, Basso U, Giannatempo P, Buchler T, Dieckmann KP, Huddart R, Vincenzi B, Park K, Aparicio J, Tryakin A, Amiri A, Malcharkova P, Claps M, Miletic M, Chaloupkova L, Angerer M, Spiess PE, De Giorgi U, Global Society for Rare GU Tumors
Br J Cancer
· 2026 Jun · PMID 42231028
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BACKGROUND: Germ cell tumors (GCTs) are highly curable, yet a subset of patients with metastatic disease experience early death (ED) soon after starting first-line chemotherapy. These patients are underrepresented in tri...BACKGROUND: Germ cell tumors (GCTs) are highly curable, yet a subset of patients with metastatic disease experience early death (ED) soon after starting first-line chemotherapy. These patients are underrepresented in trials, and risk factors remain unclear. METHODS: We performed a retrospective multicenter cohort study including adults ( ≥ 18 years) with metastatic GCT who died within 3 months of completing their last cycle of first-line chemotherapy. Primary outcomes were cause and timing of death; secondary endpoints included clinical predictors of acute respiratory failure (ARF) and very early death ( ≤ 30 days). RESULTS: Among 102 patients (1.7% of treated cases), 69.6% had non-seminoma, 83.3% testicular primaries, and 67.6% poor-risk disease. Median time to death was 28 days (range, 2-179). Leading causes were ARF (34.1%), disease progression (16.7%), septic shock (15.7%), hemorrhage (12.7%), and cardiovascular events (4.0%). ARF correlated with > 50% lung involvement, dyspnoea, and haemoptysis, but not choriocarcinoma histology or bleomycin use. Mostly, ED (51%) was associated with liver metastases, massive lung involvement, β-hCG > 50,000 mIU/mL, ECOG 2-3, elevated neutrophil/lymphocyte ratio, and need for intensive care (all P < 0.05). CONCLUSIONS: Early death in metastatic GCT, though rare, remains a critical clinical issue. Early identification, adapted induction regimens, and optimized supportive care may help prevent avoidable mortality.
Higashiyama RI, Yoshida T, Shiraishi K
… +17 more, Miyakoshi J, Torasawa M, Shirasawa M, Masuda K, Shinno Y, Matsumoto Y, Okuma Y, Yoshida Y, Goto Y, Horinouchi H, Tuchida T, Hamamoto R, Yamamoto N, Watanabe SI, Yatabe Y, Kohno T, Ohe Y
Br J Cancer
· 2026 Jun · PMID 42231027
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BACKGROUND: Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may improve outcomes in metastatic EGFR-mutant NSCLC, but VEGF inhibitors are not universally...BACKGROUND: Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may improve outcomes in metastatic EGFR-mutant NSCLC, but VEGF inhibitors are not universally effective. We evaluated the impact of VEGFA and VEGFR2 expressions on EGFR-TKI outcomes. METHODS: EGFR-mutant NSCLC patients from the National Cancer Center Hospital, were retrospectively analysed. The early-stage cohort comprised stage I-IIIA patients (1997-2019). The advanced-stage cohort included metastatic patients (2018-2022). VEGFA/VEGFR2 expressions were dichotomised by median transcripts per million. RESULTS: Among 447 early-stage patients (median age 66), high VEGFA was associated with smoking, TP53 co-mutation, higher Brinkman Index, and higher tumour mutation burden (all p < 0.01). High VEGFA predicted shorter relapse-free survival (HR 2.10, 95% CI 1.63-2.71, p < 0.01) and overall survival (HR 2.07, 95% CI 1.46-2.95, p < 0.01). VEGFR2 expression showed no prognostic impact. In 146 relapsed patients receiving first-line EGFR-TKIs, high VEGFA was linked to shorter progression-free survival (PFS) overall (HR 1.70,95%CI 1.13-2.56, p = 0.009), particularly for first/second-generation EGFR-TKIs (HR 1.66,95%CI 1.08-2.54 p = 0.023), but not for osimertinib (p = 0.491). In 60 advanced-stage patients on osimertinib, PFS was unaffected by VEGFA (p = 0.102). CONCLUSIONS: High VEGFA is associated with aggressive biology and inferior outcomes, correlating with shorter PFS for first/second-generation EGFR-TKIs but not for osimertinib.
Br J Cancer
· 2026 Jun · PMID 42231026
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BACKGROUND: Despite therapy advances, better solutions for refractory bladder cancer remain an unmet need. Human cell-based models may aid in better treatment translation. We introduce 3D-UHU-TU, a bladder cancer microti...BACKGROUND: Despite therapy advances, better solutions for refractory bladder cancer remain an unmet need. Human cell-based models may aid in better treatment translation. We introduce 3D-UHU-TU, a bladder cancer microtissue model which incorporates spheroids derived from low- and high-grade human bladder cancer cell lines (RT112 and T24 respectively) into a healthy human urothelium. METHODS: After model characterisation with histopathology and immunofluorescence microscopy, we trialled both the conventional chemotherapeutic Mitomycin C (MMC), and a novel herpes simplex oncolytic virus (oHSV-GFP), each assessed using confocal microscopy and cytotoxicity assays. RESULTS: We observed correct expression of E- and N-Cadherin, CK7, CK20, GATA3 and Ki-67, alongside invasion and migration phenotypes. MMC treatment caused cell lysis and nuclear damage in cancer spheroids in both low- and high-grade models, with minimal damage to the surrounding healthy urothelium, and a significant increase in cleaved caspase 3 in low-grade models. oHSV-GFP co-localised in cancer spheroids and induced syncytia, spheroid disaggregation and cytotoxicity with minimal to no co-localisation or cytotoxicity in the healthy urothelium. CONCLUSION: 3D-UHU-TU model is useful for testing both treatment safety and efficacy on different grades of bladder cancer. Future use of primary tumour spheroids in place of cell lines may allow a personalised medicine approach.
Tang H, Xu T, Liu L
… +9 more, Du Y, Liu D, Tan S, Shen P, Hu A, Shi X, Ma H, Wang J, Zhao W
Br J Cancer
· 2026 May · PMID 42209673
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BACKGROUND: Lactate promotes histone lactylation, which affects protein transcription and translation, thereby influencing tumour cell progression. However, the role of lactylation in pancreatic ductal adenocarcinoma (PD...BACKGROUND: Lactate promotes histone lactylation, which affects protein transcription and translation, thereby influencing tumour cell progression. However, the role of lactylation in pancreatic ductal adenocarcinoma (PDAC) remains underexplored and warrants further investigation. METHODS: Single-cell RNA sequencing (scRNA-seq) data (GSE154778) underwent quality control, dimensionality reduction, and clustering. Lactylation scores were computed using the "AUCell" R package, and differential expression between high and low lactylation groups was analysed. A risk score model based on lactylation was developed using TCGA-PAAD, GSE57495, and GSE79668 datasets. The relationships between risk scores, clinical features, immune profiles, mutation burden, and biological functions were assessed. CUT&Tag analysis was employed to identify the target of TOP2A mediated by H3K18la. In vitro experiments, including CCK-8 assay, colony formation assay, wound healing assay, transwell migration assay, lactate quantification, Western blotting, and qRT‒PCR, in combination with subcutaneous xenograft models, were conducted to further validate the findings. RESULTS: We successfully established a lactylation-based prognostic risk score model for PDAC, which effectively distinguishes patient survival and biological characteristics. Additionally, we demonstrated that the lactate-TOP2A-H3K18la-NQO1 signalling axis forms a positive feedback loop that accelerates the malignant progression of PDAC. CONCLUSIONS: This study presents a lactylation-related risk score model with significant potential for improving the management of PDAC patients. The identification of the lactate-TOP2A-H3K18la-NQO1 axis enhances the understanding of lactylation mechanisms in PDAC, thereby providing a foundation for targeted therapeutic approaches.
Hobbs E, Ulrich L, Sharma A
… +17 more, Sherpa G, Howlett S, Maxwell A, Short D, Vazquez I, Agarwal R, Hrouda D, Mannion E, Wilkes EH, Lozano-Kuehne J, Maher E, Rustin G, Tin T, Gonzalez M, Sarwar N, Seckl MJ, Ghorani E
Br J Cancer
· 2026 May · PMID 42203894
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BACKGROUND: Most chemotherapy regimens for poor-risk non-seminomatous germ cell tumours (PRGCT) deliver a fixed number of cycles; the role of variable treatment duration aiming for maximal response is unknown. Since the...BACKGROUND: Most chemotherapy regimens for poor-risk non-seminomatous germ cell tumours (PRGCT) deliver a fixed number of cycles; the role of variable treatment duration aiming for maximal response is unknown. Since the 1970s, we have utilised POMB/ACE chemotherapy for PRGCT, treating until marker normalisation. From mid-1990s, treatment was limited to 7 cycles. We describe outcomes with POMB/ACE for PRCGT, evaluating the association between treatment duration and survival. METHODS: We conducted a retrospective cohort study across two UK tertiary cancer centres, identifying patients treated between 1978-2013. Complete response was defined based on normalisation of elevated tumour markers, absence of viable cancer in resection material and resolution of radiological abnormalities. Regression techniques were used to investigate the relationship between therapy duration and outcomes. RESULTS: 132 PRGCT patients completed POMB/ACE with 69.7% (n = 92) alive at 5 years. Number of cycles delivered significantly correlated with recurrence free survival (HR 0.52; 95% CI 0.38-0.71; p < 0.001) and complete biochemical response (OR 1.27; 95% CI 1.10-1.49; p = 0.0018). POMB/ACE discontinuation amongst patients with responding but not normalised tumour markers was associated with worse survival. Study limitations include the retrospective design. CONCLUSION: POMB/ACE is highly active for PRGCT. Treatment until maximal biochemical response is associated with superior survival outcomes and warrants further exploration.
Kashani E, Sadowski MC, Phour J
… +17 more, Hashemi Gheinani A, Hlavackova K, Haemmig S, Baumgartner U, Mueller-Wirth N, Trefny C, Sharf Den Abu Fakher B, Parvanova E, Nydegger C, Maragkou T, Schucht P, Perren A, Zinn P, Lüdi M, Marti TM, Krebs P, Vassella E
Br J Cancer
· 2026 May · PMID 42203893
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BACKGROUND: Glioblastoma is the most aggressive primary brain tumor. Although temozolomide induces DNA damage, its efficacy is limited by intrinsic resistance mechanisms, leading to tumor relapse. In this study we aimed...BACKGROUND: Glioblastoma is the most aggressive primary brain tumor. Although temozolomide induces DNA damage, its efficacy is limited by intrinsic resistance mechanisms, leading to tumor relapse. In this study we aimed to identify microRNA-mediated resistance mechanisms. METHODS: MicroRNA screens were performed to identify temozolomide resistance mechanisms. Temozolomide response was evaluated using clonogenic and spheroid assays in glioblastoma cell lines and patient-derived primary cells. DNA damage response was assessed by γH2AX foci formation. Cell cycle distribution, senescence and ferroptosis were assessed following miR-19b attenuation. An orthotopic xenograft and a syngeneic mouse model were used to confirm findings. RESULTS: Our screen and subsequent phosphoprotein analysis identified miR-19b and its target PPP2R5E, a subunit of the phosphatase PP2A, as modulators of temozolomide response. Attenuation of miR-19b upregulated PPP2R5E, inducing genotoxic stress, thereby enhancing temozolomide response. Mechanistically, DNA damage correlated with elevated nuclear ROS, promoting senescence and ferroptosis. Consistently, pharmacological activation of PP2A with FTY720 phenocopied the effects of miR-19b suppression. Conversely, knockdown of PPP2R5E reversed temozolomide sensitisation in vitro, in vivo, and ex vivo models, confirming the critical role of the miR-19b/PPP2R5E axis in modulating drug response. CONCLUSIONS: Therapeutic targeting of the PPP2R5E/PP2A complexes holds promise for enhanced temozolomide efficacy in glioblastoma.
Park SS, Lee HW, Kwon MR
… +14 more, Ju EJ, Shin SH, Park J, Ko EJ, Son GW, Kim YJ, Moon GJ, Kim DH, Choi YJ, Rho JK, Park YY, Kim TW, Song SY, Jeong SY
Br J Cancer
· 2026 May · PMID 42185638
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BACKGROUND: Osimertinib (OSI), a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is the standard first-line treatment for non-small cell lung cancer (NSCLC) patients harbouring epidermal grow...BACKGROUND: Osimertinib (OSI), a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is the standard first-line treatment for non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor-activating mutations. Nevertheless, the emergence of acquired resistance to OSI in most patients limits long-term efficacy and yields only modest improvements in overall survival. We identified nucleoporin 62 (NUP62) knockdown as a potential strategy to overcome OSI resistance in NSCLC and investigated the underlying molecular mechanisms. METHODS: The role of NUP62 in OSI resistance was evaluated in parental and OSI-resistant NSCLC cell lines. mRNA expression of NUP62 was analysed in lung cancer patient cohorts, and survival rate of the patients was assessed using Kaplan Meier Plot. Mechanistic studies employed siRNA-mediated knockdown, CCK-8, clonogenic assays, immunohistochemistry, western blotting and flow cytometric assays in vitro. In vivo efficacy was examined in a xenograft mouse model. RESULTS: mRNA expression of NUP62 was significantly upregulated in lung cancer tissues and correlated with poor patient survival and increased recurrence. NUP62 knockdown using small interfering RNA (siRNA) sensitised OSI-resistant NSCLC cells to OSI, leading to reduced cell viability and impaired clonogenic potential. Combination of siRNA NUP62 and OSI induced apoptosis via activation of caspases, an effect abrogated by the pan-caspase inhibitor zVAD (carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone). Mechanistically, NUP62 knockdown markedly reduced survivin, a member of the inhibitor of apoptosis protein family. Survivin downregulation occurred through the ubiquitin-proteasome system, as shown by enhanced ubiquitination and a shortened protein half-life. Overexpressing survivin attenuated siRNA NUP62 plus OSI-induced cell death by inhibiting caspase-3 activity in OSI-resistant NSCLC cell lines. Furthermore, silencing of NUP62 significantly enhanced the antitumor activity of OSI and suppressed tumour growth in vivo. CONCLUSION: NUP62 knockdown reverses OSI resistance by promoting ubiquitination of survivin in OSI-resistant NSCLC cell lines. Silencing of NUP62 may, therefore, be an effective strategy to overcome OSI resistance and enhance therapeutic efficacy.
Cao J, Zhu F, Xu K
… +9 more, Liu Z, Chen L, Lv S, Fan L, Guo J, Tao M, Luo Y, Li G, Bo H
Br J Cancer
· 2026 May · PMID 42168362
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BACKGROUND: Testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men, yet effective biomarkers and therapeutic targets remain limited. The role of lncRNAs in TGCT remains poorly understood...BACKGROUND: Testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men, yet effective biomarkers and therapeutic targets remain limited. The role of lncRNAs in TGCT remains poorly understood at single-cell resolution. METHODS: We integrated single-nucleus RNA-seq, spatial transcriptomics, and bulk RNA-seq on TGCT samples. LINC00152 function was assessed by siRNA knockdown, functional assays, CHIRP-MS, RIP-PCR, and xenograft models. T cell exhaustion was assessed by co-culture experiments and recombinant protein rescue assays. RESULTS: LINC00152 was identified as a significantly upregulated lncRNA in TGCT, particularly in non-seminomas, and its high expression correlated with advanced tumour stage, lymph node metastasis, and poor prognosis. A LINC00152-high tumour subpopulation showed enhanced proliferation, migration, invasion, and antioxidant capacity. Mechanistically, LINC00152 directly bound to YBX1, inhibiting its proteasomal degradation and thereby activating AKT signaling. Silencing LINC00152 suppressed malignancy in vitro and in vivo. LINC00152-high tumour cells highly expressed HLA molecules and upregulated HAVCR2, promoting T cell exhaustion with reduced IFNG/GZMK expression, rescued by recombinant HAVCR2. CONCLUSIONS: LINC00152 serves as a promising prognostic biomarker and therapeutic target in TGCT. It promotes tumour malignancy via YBX1/AKT signaling and drives immune evasion by inducing HAVCR2-mediated T cell exhaustion, providing new insights for combination immunotherapy in TGCT.
López Mujica MEJ, Boonkaew S, Christensen NL
… +4 more, Abildgaard Pedersen M, Riegels Jørgensen K, Holm Vendelbo M, Ferapontova EE
Br J Cancer
· 2026 May · PMID 42162363
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BACKGROUND: HER2-positive (HER2+) cancers are associated with aggressive tumour development but also high response rates to targeted blockade treatments of the HER-2/neu signalling pathway leading to improved clinical ou...BACKGROUND: HER2-positive (HER2+) cancers are associated with aggressive tumour development but also high response rates to targeted blockade treatments of the HER-2/neu signalling pathway leading to improved clinical outcome for the patient. Current clinical analysis of the HER2 status primarily relies on solid tumour biopsies low-suitable for continuous real-time monitoring needed for possible adjustment of the treatment, while serum tests targeting blood-circulating HER-2/neu fragments often show conflicting tumour-serum relations. METHODS: A cellulase-linked aptamer sandwich assay was used for detection of total urokinase plasminogen activator (uPA) and its different forms in serum of cancer patients and healthy individuals. Serum uPA levels were correlated with solid biopsy results and relevant clinical data extracted from electronic patient records, and FDG-PET/CT scanning. RESULTS: We show that serum uPA precisely stratifies patients with HER-2/neu overexpressing (HER2+) and borderline-expressing cancers. Serum levels of total uPA 96.8% accurately informed about HER-2/neu tumour status in a cohort of 100 patients, with a HER2+/borderline expression cut-off value of 0.973 ng mL. CONCLUSIONS: The established liquid biopsy test for serum uPA has potential for accurate diagnosis and staging of patients with HER2+ and borderline-expressing cancers requiring further confirmatory (or rejection) testing.
Skribek M, Livanou ME, Vathiotis I
… +6 more, Strandman V, Thorell A, Koulouris A, Syrigos K, Ekman S, Tsakonas G
Br J Cancer
· 2026 May · PMID 42162362
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BACKGROUND: Lung cancer is the leading cause of cancer-related mortality, with brain metastases (BMs) significantly worsening prognosis. While Immune checkpoint inhibitors (ICIs) have transformed treatment for non-small...BACKGROUND: Lung cancer is the leading cause of cancer-related mortality, with brain metastases (BMs) significantly worsening prognosis. While Immune checkpoint inhibitors (ICIs) have transformed treatment for non-small cell lung cancer (NSCLC), robust prognostic tools are still lacking. METHODS: The Brain-Lung Immunotherapy Prognostic (BLIP) score was developed using a retrospective cohort of NSCLC patients with BMs treated with ICIs at Karolinska University Hospital, Sweden. Prognostic factors were identified via univariate and multivariable Cox regression. Internal validation employed bootstrap resampling, penalized Cox regression and ROC analysis. External validation was conducted using an independent cohort from Sotiria Thoracic Diseases Hospital of Athens, Greece. RESULTS: Of 1844 screened patients, 131 from Karolinska and 109 from Sotiria were included. Key variables were histology, age at BM diagnosis, and number of BMs. The BLIP score stratified patients into "Good" and "Poor" prognosis groups, with median overall survival (OS) of 14.5 and 7 months (hazard ratio [HR]: 0.4; p < 0.0001). External validation confirmed these findings (HR: 0.5; p = 0.0099). CONCLUSION: The BLIP score is a validated prognostic tool for NSCLC patients with BMs receiving ICIs. Incorporating clinical factors, it enhances personalized risk stratification. HIGHLIGHTS: The BLIP score is a novel prognostic tool for NSCLC with brain metastases undergoing immunotherapy. Integrates key clinical factors like histology, age, and metastasis count. Internal validation demonstrates strong prognostic power and reliability. External validation shows effectiveness across diverse patient populations. Stratifies patients into "Good" and "Poor" groups, aiding in personalized treatment decisions.
Wiest IC, Dreikhausen L, Keller R
… +18 more, Marin-Galiano M, Albiges L, Meran J, Leucht K, Rieken S, Esteban E, Zengerling F, Tintelnot J, Grimm MO, Bozorgmehr F, Christopoulos P, Stein A, Binder M, Härtel N, Klinghammer K, Grünwald V, Pogorzelski M, Ebert MP
Br J Cancer
· 2026 May · PMID 42156980
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BACKGROUND: We explored the association of immune-related adverse events (irAE), along with prior and concomitant antibiotic and steroid use, on oncological outcomes following immune checkpoint inhibitor (ICI) treatment...BACKGROUND: We explored the association of immune-related adverse events (irAE), along with prior and concomitant antibiotic and steroid use, on oncological outcomes following immune checkpoint inhibitor (ICI) treatment in various solid tumours. METHODS: Pooled data from seven trials on ICI therapy across multiple cancer types (head and neck, non-small cell lung cancer, gastroesophageal junctional adenocarcinoma, oesophageal, renal cell, and urothelial carcinoma) was analysed, focusing on overall survival (OS) and progression-free survival (PFS) and antibiotic or steroid use before and during the study. RESULTS: Of 693 patients, 80 used steroids and 52 used antibiotics prior to the study, while 360 and 331, respectively, used them concomitantly. Lack of prior antibiotic use was associated with longer OS (No vs. Yes: HR 0.552, 95%-CI 0.370-0.822, p = 0.0035) and PFS (No vs. Yes: HR 0.703, 95%-CI 0.485-1.019, p = 0.0625), whereas concomitant antibiotic use had no such effect. Patients with concomitant steroid use demonstrated longer PFS (No vs. Yes: HR 1.359, 95%-CI 1.091-1.693, p = 0.0061). DISCUSSION: Our study confirmed associations between antibiotic and steroid use and ICI efficacy in cancer. Prior, but not concomitant, antibiotic use was linked to reduced OS, supporting the role of microbiome diversity in tumour response. Concomitant steroid use was associated with improved PFS, potentially reflecting its link to irAE occurrence.
She H, Xiang T, Wang J
… +12 more, Lin Z, Huang W, Wu H, Xu Y, Wang Q, Wu X, Chen H, Chen Z, Liang L, Bian X, Li X, Zhang Q
Br J Cancer
· 2026 May · PMID 42156979
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BACKGROUND: Lymph node metastasis (LNM) is an important prognostic factor but is often underdiagnosed due to limitations in conventional assessment methods. We aimed to develop a deep learning (DL) model to predict LNM s...BACKGROUND: Lymph node metastasis (LNM) is an important prognostic factor but is often underdiagnosed due to limitations in conventional assessment methods. We aimed to develop a deep learning (DL) model to predict LNM status from primary gastric cancer (GC) whole-slide images. METHODS: This retrospective study included 929 patients with GC from three independent cohorts across two centers. A DL model based on Clustering-constrained Attention Multiple Instance Learning was trained and validated to predict LNM from whole-slide images of primary tumors. The ability of the model to predict occult tumor cells (OTCs) in patients initially staged as pN0 and its prognostic value in patients with GC were examined. RESULTS: The model demonstrated robust LNM predictive performance. Notably, it also predicted OTCs in patients initially staged as pN0. Patients staged as pN0 with OTCs had significantly worse survival outcomes than those staged as pN0 without OTCs (P = 0.003). The score generated by the model was an independent prognostic factor for patients with GC. CONCLUSIONS: Our DL-based model enables accurate prediction of LNM and OTCs from primary GC slides, serving as a valuable tool for guiding personalized clinical strategies and as a novel biomarker for prognostic evaluation in patients with GC.
Barraud S, Roussel-Simonin C, Pautier P
… +8 more, Italiano A, Massard C, Hollebecque A, Michels J, Blanc-Durand F, Ouali K, Rouleau E, Leary A
Br J Cancer
· 2026 May · PMID 42151561
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BACKGROUND: Immune checkpoint inhibitors (ICI) are approved for metastatic cervical cancer (mCC) after platinum failure, but only a minority of patients derive durable benefit. We aimed to compare long-term responders (L...BACKGROUND: Immune checkpoint inhibitors (ICI) are approved for metastatic cervical cancer (mCC) after platinum failure, but only a minority of patients derive durable benefit. We aimed to compare long-term responders (LTR) and non-long-term responders (NLTR) to ICI and to identify clinical and molecular predictors of long-term response. METHODS: We retrospectively reviewed patients with mCC treated with ICI at Gustave Roussy. LTR were defined as patients achieving complete or partial response or stable disease lasting >12 months, while NLTR progressed within 12 months. Logistic regression analyses were performed to identify factors associated with LTR. Genomic analyses were available for a subset of patients using large-panel next-generation sequencing. RESULTS: Between January 2015 and September 2023, 106 patients received ICI; 20 (19%) were classified as LTR and 86 (81%) as NLTR. After a median follow-up of 42 months, median progression-free survival was not reached in LTR versus 3.5 months in NLTR. Eleven LTR maintained a sustained response after ICI discontinuation. In multivariate analysis, oligometastatic disease, lymph node-only metastases, and progression outside prior radiation fields were independently associated with LTR. Tumour mutational burden and mismatch repair status were not predictive. PIK3CA mutations were significantly more frequent in LTR, while STK11 alterations were enriched in NLTR. CONCLUSION: Durable responses to ICI in mCC, although uncommon, are associated with prolonged disease control and may persist after treatment discontinuation. Specific clinical and molecular features are strongly associated with long-term benefit and may help refine patient selection for immunotherapy.
Kahounová Z, Hrušková M, Drápela S
… +8 more, Naar O, Víchová R, Navrátil J, Fabian P, Kokáš FZ, Hampl A, Bouchal J, Souček K
Br J Cancer
· 2026 May · PMID 42151560
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BACKGROUND: Circulating tumour cells (CTCs) are mediators of cancer dissemination and the formation of metastasis, which is the leading cause of cancer-related deaths. Experimental models derived from CTCs contribute to...BACKGROUND: Circulating tumour cells (CTCs) are mediators of cancer dissemination and the formation of metastasis, which is the leading cause of cancer-related deaths. Experimental models derived from CTCs contribute to understanding the biology of CTCs, their role in dissemination, and the discovery of potential drugs targeting CTCs. METHODS: A xenograft was derived from CTCs isolated from a patient diagnosed with metastatic invasive ductal carcinoma of the breast. The characterisation of the CTCs-derived xenograft (CDX) was conducted through in vivo experimental metastatic assays, RNA-Seq, spectral flow cytometry, and drug sensitivity tests. RESULTS: The CTCs-enriched fraction formed a CDX within 6 months, and its metastatic potential was confirmed. CDX cells were propagated in vitro, where the enrichment of CD44/CD24 breast cancer stem cells was confirmed. An RNA-Seq-based comparison of CDX with the primary tumour from the same patient unravelled substantial changes in genes related to cell growth, metabolism, and extracellular signalling. CDX and in vitro cell culture showed sensitivity to carboplatin. A partial response was also observed for vandetanib, which was selected through in silico analysis of transcriptomic data. CONCLUSIONS: We present and characterise a novel model derived from CTCs for understanding the plasticity and behaviour of CTCs and advanced breast cancer. CDX_IBP_01 was established from the CTC-enriched fraction obtained from the patient with progressing breast cancer. Once stably re-transplanted and growing in vivo, the transcriptomes of CDX and archived primary BCa1 samples were compared. 2D and 3D in vitro cell cultures were established from sorted human cancer cells from an in vivo xenograft. Phenotypes of established models and their stability were characterised using spectral flow cytometry. The metastatic potential of CDX was evaluated in an in vivo assay. Finally, the applicability of the established model for in vivo and in vitro drug screening was evaluated. Created in https://BioRender.com .
Zhang L, Liu Z, Ding Y
… +13 more, Sun J, Wu Y, Shi J, Su X, Jin K, Zeng H, Chang Y, Xu L, Zhang W, Wang Z, Liu H, Zhu Y, Xu J
Br J Cancer
· 2026 May · PMID 42141154
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BACKGROUND: The MYC proto-oncogene is frequently overexpressed (OE) and orchestrates key programs in urothelial carcinoma (UC). However, its impact on clinical outcomes, biological behaviors, and tumor microenvironment (...BACKGROUND: The MYC proto-oncogene is frequently overexpressed (OE) and orchestrates key programs in urothelial carcinoma (UC). However, its impact on clinical outcomes, biological behaviors, and tumor microenvironment (TME) in UC patients remains unclear. METHODS: This study included 250 UC patients with matched clinical annotations from two in-house cohorts (ZSHS and FUSCC cohorts). The MYC status was determined by immunohistochemical analysis and targeted sequencing. We investigated the associations between MYC status and clinical outcomes, tumor biological behaviors, and TME features. Additionally, 1603 UC patients from three external datasets were used for validations. RESULTS: MYC OE was detected in 25.2% of UC patients, and was associated with advanced tumor stage, higher histological grade, and the presence of lymphovascular invasion in the ZSHS cohort. Patients with MYC OE or MYC amplification delineated the worst prognosis and exhibited resistance to platinum-based chemotherapy and PD-(L)1 blockade, independent of classical basal/luminal status. Mechanistically, MYC-OE UC displayed a hybrid/partial EMT phenotype characterized by high-grade tumor budding. This unique cellular state co-occurs with TGFB1-related fibrogenesis and immunosuppression. CONCLUSIONS: MYC OE defines a lethal subtype with aggressive behaviors and therapeutic resistance in UC patients. Our findings highlight the need for tailored therapeutic strategies for this refractory subtype of UC.
Br J Cancer
· 2026 May · PMID 42129338
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BACKGROUND: The NHS Breast Screening Programme invites eligible women using either a timed appointment letter (option to change), or an open invitation to make an appointment. Non-attenders receive a 'Timed' or 'Open' se...BACKGROUND: The NHS Breast Screening Programme invites eligible women using either a timed appointment letter (option to change), or an open invitation to make an appointment. Non-attenders receive a 'Timed' or 'Open' second invitation. NHS England commissioned a service evaluation to determine the effect of different combinations of timed and open invitations. METHODS: Seven services, selected to ensure adequate representation of diverse socio-economic, ethnic, urban/rural, and current uptake groups, participated. Women were individually quasi-randomised to four combinations of Open/Timed invitations. The primary outcome was 90-day attendance. RESULTS: 17,965 women (mean age 58 years, IQR: 47-69) invited from April-October 2023 were included. Attendance overall increased from 49.1% (95%CI 47.7-50.6%) for Open/Open to 67.9% (66.5-69.2%) for Timed/Timed. Attendance following Open/Timed or Timed/Open invitations was 60.0% (58.6-61.4%) and 64.7% (63.3-66.1%) respectively. The same pattern was observed across all deprivation quintiles. Attendance amongst the most deprived increased from 41.1% (38.2-44.1%; Open/Open) to 63.3% (60.6-66.2%; Timed/Timed), compared with 61.4% (57.6-65.2%) to 78.0% (74.5-81.4%) for the least deprived quintile. CONCLUSION: Sending timed appointment invitations increases attendance at breast screening. This might have a larger impact in the most deprived areas. Findings informed NHS England on the most effective invitation methodologies from April 2025.
Waldron NR, Silva D, Westaby D
… +3 more, Jiménez-Vacas J, Taylor J, Sharp A
Br J Cancer
· 2026 Jul · PMID 42129337
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Full text
Advanced prostate cancer remains a major healthcare problem and cause of death in the United Kingdom. In contrast to many other cancer types, with the exception of poly (ADP-ribose) polymerase inhibition in DNA repair de...Advanced prostate cancer remains a major healthcare problem and cause of death in the United Kingdom. In contrast to many other cancer types, with the exception of poly (ADP-ribose) polymerase inhibition in DNA repair defective cancers, clinically actionable molecular subtypes are lacking. There are a number of studies that suggest the RAF-MEK-ERK-RSK cascade, a major oncogenic pathway, is activated in prostate cancer and this increases as the disease progresses. Mechanisms of activation are not dominated by pathogenic mutations in pathway proteins and include paracrine and autocrine mechanisms. There is strong evidence linking pathway activation with enhancing key proliferative signalling programmes and promoting cell survival in prostate cancer. Whilst inhibitors of the RAF-MEK-ERK-RSK pathway have demonstrated clinical utility in other cancers this has not been realised in prostate cancer. The reasons for this include a lack of predictive biomarkers for, and the unique landscape of pathway activation. Future studies need to identify robust predictive biomarkers, and improve the understanding of the fundamental biology of RAF-MEK-ERK-RSK activated prostate cancers if we are to successfully target this important sub-group.