British Journal of Cancer最新文献

{"title":"Genomic and transcriptomic landscape of spread through air spaces in stage 1 lung adenocarcinoma.","authors":"Stephanie P L Saw, Mengyuan Pang, Clare Patteri, Angela Takano, Jia Chi Yeo, Ngak Leng Sim, Gillianne G Y Lai, Darren W T Lim, Mei-Kim Ang, Ravindran Kanesvaran, Quan Sing Ng, Amit Jain, Wan Ling Tan, Aaron C Tan, Wei Chong Tan, Amanda O L Seet, Boon-Hean Ong, Tony K H Lim, Anders Jacobsen Skanderup, Daniel S W Tan","doi":"10.1038/s41416-026-03622-8","DOIUrl":"https://doi.org/10.1038/s41416-026-03622-8","url":null,"abstract":"<p><strong>Introduction: </strong>Spread through air spaces (STAS) is an adverse histologic feature in early-stage lung adenocarcinoma (LUAD) incorporated into the ninth edition TNM staging. Despite its clinical significance, the molecular features underlying STAS in stage 1 LUAD remain incompletely characterised.</p><p><strong>Methods: </strong>Patients with stage 1 LUAD and known STAS status were identified. Whole exome and RNA sequencing were performed on tumour samples with matched normal controls. Disease-free survival (DFS) was analysed using the Kaplan-Meier method and Cox regression.</p><p><strong>Results: </strong>Among 378 patients, 54.2% had STAS+ tumours, with similar incidence between EGFR-mutant and EGFR-wildtype LUAD. STAS+ tumours were significantly associated with stage 1B disease, lymphovascular invasion, higher histological grade, micropapillary or solid predominant adenocarcinoma subtype and PD-L1 tumour proportion score ≥1%. STAS+ remained independently associated with inferior DFS after multivariable adjustment (hazard ratio 2.32, 95% CI 1.16-4.63; p = 0.017). At the molecular level, STAS+ tumours were enriched for TP53 co-mutations, whole genome doubling, non-TRU transcriptomic subtypes and upregulation of cell cycle-related pathways, with directionally consistent findings across EGFR-mutant and EGFR-wildtype tumours.</p><p><strong>Conclusions: </strong>STAS+ in stage 1 LUAD is associated with a distinct molecular phenotype characterised by genomic instability and cell cycle dysregulation, consistent with a more aggressive biological phenotype with implications for risk stratification and adjuvant therapy selection.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-adulthood body mass index, mammographic density and post-menopausal breast cancer risk: a mediation analysis.","authors":"Benoit Jauniaux, Michelle N Harvie, Matthew Sperrin, Susan M Astley, Lee Malcomson, D Gareth Evans, Andrew G Renehan","doi":"10.1038/s41416-026-03593-w","DOIUrl":"https://doi.org/10.1038/s41416-026-03593-w","url":null,"abstract":"<p><strong>Background: </strong>To explore potential mechanistic pathways and inform prevention strategies, this study examined whether mammographic density (MD) mediates the inverse association between higher early-adulthood body mass index (BMI) and lower post-menopausal breast cancer risk.</p><p><strong>Methods: </strong>We analysed data from 33,816 post-menopausal women in the UK PROCAS cohort, with self-reported BMI at age 20. MD was measured using full-field digital mammography and assessed using the visual analogue scale (VAS) percentage density and Volpara®-derived fibroglandular volume (FGV). Counterfactual mediation modelling estimated natural direct and indirect effects.</p><p><strong>Results: </strong>Over a median follow-up of 10.44 years, there were 1261 new post-menopausal breast cancers. Higher VAS and FGV were associated with increased breast cancer risk. BMI at age 20 was associated with lower VAS density and reduced breast cancer risk [Hazard Ratio per 5 kg/m²: 0.849 (0.771-0.938)]. The calculated proportion mediated by VAS density was 59.9% (32.6-150), after accounting for intermediate confounding by BMI in later adulthood. FGV was positively associated with higher BMI at cohort entry but not at age 20.</p><p><strong>Conclusions: </strong>Lower VAS density may partially explain the inverse association between early-adulthood BMI and post-menopausal breast cancer risk. The link between FGV and breast cancer risk may represent a different biological pathway.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menopausal hormone therapy and primary liver cancer: long-term follow-up of the women's health initiative randomized trials.","authors":"Margaret S Pichardo, Aaron K Aragaki, JoAnn E Manson, Kathy Pan, Su Yon Jung, Thomas E Rohan, Reed Mszar, Rowan T Chlebowski","doi":"10.1038/s41416-026-03621-9","DOIUrl":"10.1038/s41416-026-03621-9","url":null,"abstract":"<p><strong>Background: </strong>Long-term results on liver cancer incidence and mortality are reported from two Women's Health Initiative randomized trials evaluating menopausal hormone therapy.</p><p><strong>Methods: </strong>16,608 postmenopausal women with a uterus were randomized to conjugated equine estrogen (CEE) 0.625 mg/d plus medroxyprogesterone acetate (MPA) 2.5 mg/d or placebo and 10,739 women with hysterectomy were randomized to 0.625 mg/d of CEE-alone or placebo.</p><p><strong>Results: </strong>After nearly 24 years follow-up and 74 incident liver cancers, neither CEE-alone nor CEE plus MPA influenced liver cancer development (CEE-alone vs placebo (11 vs 15 cancers; hazard ratio [HR] 0.75; 95% CI, 0.34-1.63; CEE plus MPA vs placebo (30 vs 18 cancers; HR 1.63; 95% CI, 0.91-2.92). CEE plus MPA did not significantly influence liver cancer mortality: 27 vs 22 deaths (HR 1.18; 95% CI, 0.67-2.07). In subgroup analyses, CEE plus MPA vs placebo was associated with more liver cancers among women aged 50-59 years (10 vs 0 cancers (P-trend 0.01) and prior oral contraceptive users (HR 4.30, 95% CI, 1.46-12.72; P-interaction 0.01).</p><p><strong>Conclusions: </strong>These findings indicate no overall influence of menopausal hormone therapy on liver cancer incidence or mortality although a possible increased risk with CEE plus MPA in select subgroups warrants further investigation.</p><p><strong>Trial registration: </strong>clinicaltrials.gov Identifier: NCT00000611.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Healthy lifestyle and cancer risk: a pan-cancer analysis in the UK Biobank prospective cohort.","authors":"Jie Ding, Ben Schöttker, Hermann Brenner, Michael Hoffmeister","doi":"10.1038/s41416-026-03613-9","DOIUrl":"https://doi.org/10.1038/s41416-026-03613-9","url":null,"abstract":"<p><strong>Background: </strong>Research on healthy lifestyles across various cancers is limited. We conducted a pan-cancer analysis to evaluate the associations of healthy lifestyle with cancer risk.</p><p><strong>Methods: </strong>Data from 287,745 UK Biobank participants were analysed. A healthy lifestyle score (HLS) was calculated based on smoking, alcohol, diet, physical activity and BMI. Cox models were used to estimate 27 cancer risks, and population attributable fractions (PAFs) were calculated based on incomplete adherence to a healthy lifestyle.</p><p><strong>Results: </strong>During a median 11.5-year follow-up, 12,947 participants developed cancer. Adhering to 4-5 vs 0-1 healthy lifestyle behaviours was associated with decreased risks of 13 of the 27 cancer types: oral, pharyngeal, laryngeal, oesophageal, stomach, colorectal, liver, pancreatic, lung, soft tissue sarcoma, kidney, bladder and postmenopausal breast cancer (HRs from 0.12 to 0.79). Significant PAFs were observed for 14 cancer types in relation to lower HLS. Smoking and overweight were associated with the largest number of cancer types.</p><p><strong>Conclusions: </strong>These findings extend evidence on associations between a healthy lifestyle and lower risks of both common and less-common cancers. Smoking and overweight were associated with more cancer types than the other components, suggesting that smoking cessation and weight control may be cancer prevention strategies to be prioritised.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photodynamic immune stimulation eradicates primary pigmented melanoma and induces long-lasting anti-tumor immunity.","authors":"L Pires, C Calcada, B Cerqueira-Rodrigues, Y Fan, J T George, T McGaha, B C Wilson","doi":"10.1038/s41416-026-03585-w","DOIUrl":"https://doi.org/10.1038/s41416-026-03585-w","url":null,"abstract":"<p><strong>Background: </strong>Melanoma is highly aggressive with limited options in advanced disease. Photodynamic therapy (PDT) has shown poor efficacy in pigmented melanoma due to restricted light penetration and intrinsic ROS resistance. A novel approach is investigated here.</p><p><strong>Methods: </strong>Full-thickness (4 mm) S91 pigmented melanoma grown intradermally in syngeneic immunocompetent (DBA) mice was treated using dual photosensitizers targeting tumor cells and microvasculature, together with a topical optical clearing agent. Anti-tumor immune effects were investigated in multiple functional assays, and the mechanisms-of-action were explored.</p><p><strong>Results: </strong>Primary tumor was eradicated in all mice, with 95% disease-free survival at 90 d, falling to 20% upon CD8 + T-cell depletion pre-treatment. The median survival in nude mice was 21 d. Treated DBA mice also rejected systemic tumor re-challenge at 30 d post treatment. There was delayed growth of untreated contralateral tumors and of tumors co-injected into naïve mice together with splenocytes from treated mice. Biomarker analysis showed rapid tumor infiltration by CD8+ and CD3+ T cells, reduced suppressive myeloid populations, and widespread immune activation. Gene expression profiling revealed enrichment of immune-related pathways and long-lasting memory.</p><p><strong>Conclusions: </strong>Photodynamic immune stimulation treatment can destroy primary pigmented melanoma far beyond the depth of light penetration and has potent anti-tumor systemic efficacy.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking the clock: a systematic review and meta-analysis on optimizing immune checkpoint inhibitor timing for advanced solid tumors.","authors":"Zhao Jin, Jiayi Liu, Baochun Che, Zhonglin Zeng, Yanshuo Cao","doi":"10.1038/s41416-026-03598-5","DOIUrl":"https://doi.org/10.1038/s41416-026-03598-5","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence from observational studies suggests that the time-of-day of immune checkpoint inhibitor (ICI) infusion may influence efficacy. This study sought to quantitatively evaluate the impact of ICI infusion timing on the outcomes of patients with solid tumors through a systematic review and meta-analysis.</p><p><strong>Methods: </strong>We systematically searched Embase, PubMed, and Scopus for articles published before April 1, 2026, that compared the efficacy outcomes between early and late time-of-day ICI administration. The primary endpoints were overall survival and progression-free survival. The secondary outcomes included objective response rates and immune-related adverse events. Hazard and risk ratios were pooled using the random-effects model.</p><p><strong>Results: </strong>Forty-three retrospective cohort studies involving 11,941 patients were included. Pooled analysis revealed a significant association between early time-of-day infusion and improved OS (HR = 0.60, 95% CI: 0.53-0.67) and PFS (HR = 0.65, 95% CI: 0.57-0.73). ORR was also higher (RR = 1.37, 95% CI: 1.21-1.54). No significant differences were observed for any-grade irAEs (RR = 0.98, 95% CI: 0.73-1.32) or grade ≥3 irAEs (RR = 0.95, 95% CI: 0.62-1.46). However, significant publication bias was detected (Egger's test, p < 0.001); after trim-and-fill adjustment, the OS association remained significant (adjusted HR = 0.79, 95% CI: 0.71-0.89), whereas PFS was attenuated and its confidence interval reached the null boundary after rounding (adjusted HR = 0.89, 95% CI: 0.79-1.00).</p><p><strong>Conclusions: </strong>This meta-analysis suggests significant association between early time-of-day ICI administration and improved efficacy outcomes. These findings must be interpreted with caution, as the evidence base is composed entirely of observational studies with inherent risks of bias, and the presence of publication bias may have led to an overestimation of the observed effect size. While current evidence is insufficient to warrant an immediate change in clinical practice, it provides a compelling rationale for the design of future prospective trials to validate these findings.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preferences for the use of Artificial Intelligence (AI) technologies to help detect skin cancer in primary care settings: a UK-wide discrete choice experiment (DCE).","authors":"Owain T Jones, Fiona M Walter, Rubeta N Matin, Natalia Calanzani, Jon Emery, M van der Schaar, Stephen Morris","doi":"10.1038/s41416-026-03611-x","DOIUrl":"10.1038/s41416-026-03611-x","url":null,"abstract":"<p><strong>Background: </strong>AI technologies could help triage suspicious skin lesions. The aim of this study was to examine preferences of general practitioners (GPs), patients, and members of the public for different attributes of AI technologies to help detect skin cancer.</p><p><strong>Methods: </strong>A DCE using online surveys, with choice scenarios based on: false negative and positive rates, cost, location of AI technology, efficacy on different skin tones, and guideline recommendations. Data were analysed using alternative-specific conditional logit regression models.</p><p><strong>Results: </strong>2302 participants completed the survey. All attributes significantly influenced the respondents' preferences. Ranking of attributes by relative importance was the same for GPs, patients, and members of the public: false negative rate was the most important attribute, followed by skin tones on which the technology had been developed and tested. False negative results had a significantly greater negative effect on GP choices than for other groups. Participants preferred AI technologies used by healthcare professionals in a GP surgery over AI technologies patients use at home.</p><p><strong>Conclusions: </strong>Implementation of AI technologies to detect skin cancer should focus on minimising false negative rates. Development and testing of AI technologies using data across all skin tones is essential. Preferences for AI technologies could have significant implications for successful implementation.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmed death ligand 1 (PD-L1) PET/CT imaging to evaluate tumour saturation during atezolizumab treatment.","authors":"Jahlisa S Hooiveld-Noeken, Pim P van de Donk, Laura Kist de Ruijter, Iris C Kok, Claudia A J van Winkel, Danique Giesen, Marjolijn N Lub-de Hooge, Adrienne H Brouwers, Sjoukje F Oosting, Frederike Bensch, Lotte M Smit, Carolien P Schröder, Mathilde Jalving, Sjoerd G Elias, Jourik A Gietema, Regula J Deurloo, Simon P Williams, Alexander Ungewickell, Derk-Jan A de Groot, Elisabeth G E de Vries","doi":"10.1038/s41416-026-03595-8","DOIUrl":"https://doi.org/10.1038/s41416-026-03595-8","url":null,"abstract":"<p><strong>Background: </strong>Little is known regarding tumour target saturation by the programmed death-ligand (PD-L1) antibody atezolizumab. Therefore, tumour saturation by the PD-L1 antibody atezolizumab in patients with advanced solid tumours was assessed using ⁸⁹Zr-atezolizumab PET imaging.</p><p><strong>Methods: </strong>Patients received 10 mg ⁸⁹Zr-atezolizumab after the initial 2 cycles of 1200 mg atezolizumab, followed by PET/CT scans. Tracer uptake was calculated as tumour standardized uptake value (SUV)_max, normal tissues SUV_mean, and tumour-to-background ratio SUV_max/SUV_max tumour. Tumour biopsies were obtained around day 7 of both cycles for autoradiography and PD-L1 immunohistochemistry. Findings were compared with previously reported pretreatment ⁸⁹Zr-atezolizumab PET/CT data.</p><p><strong>Results: </strong>Geometric mean tumour SUV_max day 7 was similar between cycle 1 (5.5, 95% CI, 4.4-6.9) and 2 (5.4, 95% CI, 4.3-6.8, N = 13, P = 0.88). Geometric mean tumour-to-background ratio was 1.67 (95% CI, 1.15-2.41) and 1.53 (N = 11, 95% CI, 1.05-2.21, P = 0.32), respectively. Higher tumour-to-background ratios showed a positive trend with best overall response p_trend 0.069. Autoradiography signal was present in tumour biopsies. On-treatment uptake was lower in the lesions and spleen, with a higher blood pool SUV_mean than pre-treatment.</p><p><strong>Conclusions: </strong>Compared to earlier reported pre-treatment ⁸⁹Zr-atezolizumab PET/CT results, ⁸⁹Zr-atezolizumab tumour uptake during treatment is lower, suggesting partial PD-L1 tumour saturation during atezolizumab treatment.</p><p><strong>Clinicaltrials: </strong>GOV: NCT02453984, NCT02478099.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant triplet chemotherapy enables radiotherapy avoidance in human papillomavirus-associated oropharyngeal cancer: a multicentre Phase II trial.","authors":"Tomoya Yokota, Toyonori Tsuzuki, Tetsuro Onitsuka, Akira Iizuka, Yohei Ouchi, Terushige Mori, Kiyoaki Tsukahara, Kenji Hanyu, Takashi Mukaigawa, Torahiko Nakashima, Hideoki Uryu, Go Omura, Hiromu Nakamura, Hirokazu Uemura, Daisuke Nishikawa, Satoshi Kano, Yasuto Akiyama, Tsuyoshi Onoe, Shunsuke Oyamada, Takuhiro Yamaguchi","doi":"10.1038/s41416-026-03610-y","DOIUrl":"https://doi.org/10.1038/s41416-026-03610-y","url":null,"abstract":"<p><strong>Background: </strong>This prospective Phase 2 trial assessed a novel de-escalation strategy for upfront neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (NAC-TPF) to avoid postoperative radiotherapy (PORT) and chemoradiotherapy (POCRT) for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC).</p><p><strong>Methods: </strong>Patients with HPV-associated resectable OPSCC were enrolled. Invasive surgery or PORT/POCRT was an inclusion criterion if upfront surgery was performed. Treatment started with three cycles of NAC-TPF, followed by surgery. The primary endpoint was the centrally reviewed pathological complete response (pCR) rate after NAC-TPF. Levels of high-risk HPV RNA in tumor specimens and plasma circulating tumor (ct) HPV DNA, and quality of life (QOL) scores were assessed.</p><p><strong>Results: </strong>Of 32 eligible patients, 30 patients underwent transoral surgery after NAC-TPF. R0 resection was confirmed in 31 patients. pCR and virological complete response rate at both the primary site and lymph nodes were 65.6% and 64.5%, respectively. No PORT/POCRT was performed in 91%. All QOL scores recovered to baseline values or improved within 1 year. Twenty-three patients showed undetectable ctHPV DNA levels after NAC-TPF.</p><p><strong>Conclusion: </strong>Although the primary endpoint was not met, NAC-TPF in HPV-associated resectable OPSCC achieved clinically meaningful pCR, enabling avoidance of PORT/POCRT in the majority of patients. (Clinical trial registration numbers: jRCT1041220029).</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational modelling challenges receptor‑occupancy‑based dosing of PD‑1 inhibitors like pembrolizumab.","authors":"Judith D J Verdonk, Leila-Sophie Otten, Ghazal Montaseri, Michel M van den Heuvel, Ruben L Smeets, Hans J P M Koenen, Rob Ter Heine","doi":"10.1038/s41416-026-03612-w","DOIUrl":"https://doi.org/10.1038/s41416-026-03612-w","url":null,"abstract":"<p><strong>Background: </strong>Optimal dosing of the programmed death-1 (PD-1) inhibitor pembrolizumab remains poorly defined. Dosing has been guided by achieving complete peripheral receptor occupancy, which may not reflect immune activation. We investigated relationships between dose, systemic and intratumoural pharmacokinetics, receptor occupancy, and immune activation in non-small cell lung cancer.</p><p><strong>Methods: </strong>A physiological pharmacokinetic model describing plasma and intratumoural kinetics was extended with receptor occupancy and interleukin-2 (IL-2) induction parameters derived from ex vivo experiments. Simulations compared three approved regimens-2 mg/kg Q3W, 200 mg Q3W, and 400 mg Q6W.</p><p><strong>Results: </strong>All regimens produced near-complete PD-1 receptor occupancy in both compartments. Despite this, IL-2 concentrations were predicted to change throughout the dosing interval, tracking pembrolizumab concentration rather than receptor occupancy. The 400 mg Q6W regimen yielded the highest IL-2 levels. Changes in intratumoural IL-2 concentration were less pronounced than in plasma.</p><p><strong>Conclusion: </strong>Receptor occupancy did not predict immune activation, suggesting it's an inadequate pharmacodynamic surrogate for pembrolizumab. These findings challenge current PD-1 inhibitor dose selection strategies and highlight the need for robust pharmacodynamic markers and clearer definition of the immune activation required for optimal efficacy.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}