Chirikova E, Ronckers CM, Little MP
… +8 more, Quinn E, Liu B, Hu R, Gillan MT, Frangione B, Benzouak T, Srivastava T, Zablotska LB
Br J Cancer
· 2026 Jun · PMID 42303831
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BACKGROUND: While breast cancer risk from high-dose ionising radiation is known, uncertainties remain about risks at lower doses and risk-modifying factors. We conducted a systematic review and meta-analysis of publicati...BACKGROUND: While breast cancer risk from high-dose ionising radiation is known, uncertainties remain about risks at lower doses and risk-modifying factors. We conducted a systematic review and meta-analysis of publications on radiation-associated risk of breast cancer in women. METHODS: We included studies published in 2005-2022 that assessed breast cancer incidence or mortality in women exposed to ionising radiation. Risk of bias was evaluated. Random-effects meta-analyses estimated excess relative risks per gray (ERR/Gy). RESULTS: Of the 3522 articles screened, 106 met the inclusion criteria; 40 studies provided 44 ERR/Gy estimates. Overall, radiation exposure was associated with increased breast cancer risk (ERR/Gy = 0.56, 95% CI: 0.29-0.83). Between-study heterogeneity (I = 95%) was substantially reduced in subgroup analyses, reaching 5% in low-dose-rate studies. Higher summary ERRs were observed for high dose-rate exposures, moderate (1-5 Gy) doses, childhood exposures, and attained age over 55. Lower but significantly increased risks were estimated for other subgroups and exposure scenarios. CONCLUSIONS: Radiation exposure was associated with a significantly increased risk of breast cancer among women, particularly following high dose-rates, moderate doses, childhood exposures, and older attained age. PROSPERO registration: CRD42021260610.
D'Mellow M, Wang H, Palmer JM
… +39 more, Hemminki K, Cebulla CM, Beasley AB, Bechrakis NE, Pritchard AL, Wadt KW, Johansson PA, Mobuchon L, Barlow S, Brooks K, Beckman T, Olsen CM, Warrier SK, Byrne L, Kalirai H, Mustard C, Ingold N, Försti A, Isaacs T, Jayasinghe GJMSR, Glasson WJ, Williamson G, McGrath LA, Le NQ, Chadha V, Gray ES, Brown KM, Cauchi P, Thomsen H, Connolly J, MacGregor S, Whiteman DC, Kiilgaard JF, Stern MH, Coupland SE, Abdel-Rahman MH, Zeschnigk M, Hayward N, Law MH
Br J Cancer
· 2026 Jun · PMID 42303830
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OBJECTIVE: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy control...OBJECTIVE: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. METHODS: Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM's genetic architecture. RESULTS: We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). CONCLUSIONS: This meta-analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.
Breeze SO, Heaton MJ, Snelling AP
… +3 more, Garioch JJ, Nobes JP, Moncrieff MD
Br J Cancer
· 2026 Jun · PMID 42303829
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BACKGROUND: Sentinel node biopsy (SNB) predicts long-term melanoma outcomes and advises referrals for adjuvant systemic therapy (AST). Concerns regarding the impact of treatment delays on clinical outcomes remain. METHOD...BACKGROUND: Sentinel node biopsy (SNB) predicts long-term melanoma outcomes and advises referrals for adjuvant systemic therapy (AST). Concerns regarding the impact of treatment delays on clinical outcomes remain. METHODS: A UK retrospective cohort study at a supra-regional centre was performed, including 1625 patients listed for SNB between 2010-23. Three parameters were investigated: disease progression, micrometastatic burden, and disease-specific survival. Time-to-SNB was stratified as early (≤90days) or late (>90days), with a subgroup analysis accounting for AST use (2017-23). Sensitivity analyses calculated a wait-time threshold beyond which worsens survival outcomes. RESULTS: Median time-to-SNB was 68 days (IQR = 51-95) and follow-up 75 months (IQR = 35-115). Late surgery correlated with disease progression before surgery (0.34% versus 1.54%; OR = 4.31; p = 0.022); larger micrometastases (1.40 mm vs. 2.95 mm; p = 0.003), and increased high-risk micrometastatic deposits >1 mm (55.2% vs. 69.1%; OR = 2.04; p = 0.014). For patients post-2016, longer wait-times correlated with poorer DSS (HR = 1.01 (1.00-1.02); p = 0.011 for diagnosis-to-SNB; and HR = 1.01 (1.00-1.02); p = 0.016 for primary excision-to-SNB). Sensitivity analyses calculated ≤68-days from diagnosis (HR = 3.17 (1.19-8.46); p = 0.021) and ≤82-days from excision (HR = 2.94 (1.10-7.87); p = 0.032) as optimal treatment thresholds. CONCLUSION: Surgical delays correlated with harm: disease progression, increased tumour burden and worse survival. SNB should occur within 68 days from diagnosis and/or 82 days from excision biopsy.
Zhou H, Liu Q, Ren K
… +5 more, Luo Q, Yang C, Fang T, Chen X, Zou L
Br J Cancer
· 2026 Jun · PMID 42303828
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BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTL) is a rare, aggressive lymphoma in which radioresistance remains a major cause of treatment failure in the relapsed/refractory (R/R) setting. METHODS: We analysed XPO1 exp...BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTL) is a rare, aggressive lymphoma in which radioresistance remains a major cause of treatment failure in the relapsed/refractory (R/R) setting. METHODS: We analysed XPO1 expression in ENKTL and assessed its role in radiosensitization using monoallelic XPO1-knockout models and KPT-330 in vitro and in xenografts. Mechanistic studies focused on the c-Myc-RAD51/CHEK1 axis, and clinical efficacy was evaluated in two R/R patients. RESULTS: Immunohistochemistry showed XPO1 overexpression in primary treatment-naïve ENKTL specimens relative to nasal polyp controls, and high XPO1 expression was associated with inferior overall survival. Monoallelic XPO1 knockout impaired homologous recombination (HR) repair, establishing a DNA repair defect exploitable as a radiosensitizing vulnerability. Pharmacologic inhibition of XPO1 with KPT-330 recapitulated these HR defects and synergised with radiotherapy. Mechanistically, KPT-330 disrupts the XPO1-c-Myc-RAD51/CHEK1 axis by blocking c-Myc nuclear export, reducing c-Myc abundance and promoter occupancy at the RAD51 and CHEK1 loci, thereby impairing HR. In two heavily pretreated R/R ENKTL patients, radiotherapy rechallenge plus low-dose KPT-330 achieved one partial response and one complete response with manageable toxicity. CONCLUSIONS: XPO1 inhibition impairs HR and enhances radiosensitivity by disrupting the c-Myc-RAD51/CHEK1 axis. These findings support prospective evaluation of KPT-330-based radiosensitization in R/R ENKTL.
Sharma D, McNabb E, Geraghty B
… +9 more, Bailey C, Saifuddin M, Yang W, Giles A, Lim C, Albanese P, Stanisz M, Sahgal A, Czarnota GJ
Br J Cancer
· 2026 Jun · PMID 42298002
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BACKGROUND: In recent years, treating solid tumours with focused ultrasound (FUS) has emerged as a novel therapeutic technique because of its noninvasive nature. Recent work has demonstrated the ability of focused ultras...BACKGROUND: In recent years, treating solid tumours with focused ultrasound (FUS) has emerged as a novel therapeutic technique because of its noninvasive nature. Recent work has demonstrated the ability of focused ultrasound-stimulated microbubble (FUS + MB) treatments to enhance radiation effects on tumours significantly. In this study, a rabbit model of brain metastasis was used to evaluate the therapeutic effect of FUS + MB-based therapy and radiation therapy (XRT). METHODS: Experiments were performed with brain-tumour bearing rabbits generated using human prostate cancer xenografts (PC3). Animals were randomized into four groups: control (untreated), FUS + MB alone, XRT alone, and a combined therapy (FUS + MB + XRT). Single treatment regimens and multiple-treatment regimens were evaluated with single-dose and fractionated radiotherapy, respectively. Tumour response was evaluated 24 hours and for up to 1 week after treatment to evaluate longitudinal responses. RESULTS: Tumour cell death and vascular damage was found to be minimal within 24 hour following treatment. However, results obtained following 1 week of multiple treatments demonstrated that combined treated tumour xenografts exhibited a greater extent of cellular and vascular damage confirmed using hematoxylin and eosin (H&E) and factor VIII immunohistochemical staining, respectively. Lesser number of proliferative cells were also observed in the combined treated group as compared to the other groups. Additionally, significant increase in acid sphingomyelinase (ASMase) staining was observed following a combined treatment of FUS + MB and XRT confirming the involvement of ASMase/ceramide pathway in enhanced tumour response. CONCLUSION: These results indicate enhancement of radiation effect to CNS-based tumours through ultrasound-stimulated microbubbles.
Baxter JS, Montiel Equihua C, Molenaar JJ
… +58 more, Aye J, Bisogno G, Blanc P, Breunis W, Chisholm J, Crane J, Daems S, Danielson L, de Wilde B, Durbin AD, Galvez-Cancino F, Gasparini P, Geoerger B, Graham S, Hassan B, Hatley ME, Heenen D, Heske CM, Hettmer S, Hookham E, Houghton P, Kearns P, Keller C, Khan J, Kinnis F, Langenau D, Lass G, Linardic CM, Mascarenhas L, Meister MT, Metts J, Minard-Colin V, Oberoi S, Palacios D, Pannucci A, Patel S, Patel S, Pomella S, Rabbitts T, Rota R, Rudzinski E, Schäfer B, Shern JJ, Straathof K, Venkatramani R, Wachtel M, Wakeling S, Walters Z, Warburton S, Weigel B, Pearson ADJ, Jenkinson D, Shipley J, Casanova M, LifeArc, Innovative Therapies for Children with Cancer (ITCC), Cancer Research UK, Cancer Grand Challenge PROTECT team
Br J Cancer
· 2026 Jun · PMID 42288687
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The third in a series of Paediatric Therapeutic Development Workshops focused on rhabdomyosarcoma. Rhabdomyosarcoma is the most common soft tissue sarcoma in children, with 90% survival for those with the lowest risk dis...The third in a series of Paediatric Therapeutic Development Workshops focused on rhabdomyosarcoma. Rhabdomyosarcoma is the most common soft tissue sarcoma in children, with 90% survival for those with the lowest risk disease, but just 20-30% in children with metastatic disease. An urgent unmet need exists to develop targeted therapeutics for high-risk disease and to reduce the toxicity of treatment. The results of trials of CAR T-cells and ADCs against FGFR4 are awaited with great interest, and developing a FGFR4 degrader is a priority. Directly targeting PAX3::FOXO1 and PAX7::FOXO1 fusion proteins is a high priority. An in vivo study of a MYOD1 degrader approach is required prior to clinical development. Degraders of P300/CBP should be evaluated preclinically with a view to clinical investigation. ROR2 is an interesting target for the L122R mutant MYOD1 rhabdomyosarcoma. Development of a TEAD degrader is a high priority, and this should be evaluated in combination with a Notch inhibitor. Considering targets with existing clinical agents, antibody-drug conjugates targeting cell-surface antigen B7-H3/CD276 are showing preclinical promise in other paediatric cancers and are also deemed a high priority for evaluation in rhabdomyosarcoma. Based on currently available evidence, MEK inhibitors should be evaluated, potentially with BRAF or PI3K inhibitors, in combination with chemotherapy in the maintenance setting. Understanding the mechanism of action underpinning drug combinations, gaining access to therapeutics and optimising clinical trial design will be essential to enable combinatorial testing in patients.
Lange JM, Ahmad I, Dengos IJ
… +7 more, Ryan A, Apostolidou S, Gentry-Maharaj A, Holloway S, Ryser MD, Menon U, Etzioni R
Br J Cancer
· 2026 Jun · PMID 42288686
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BACKGROUND: The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; 2001-2020) showed no reduction in disease mortality in its primary intervention arm using multimodal screening (MMS) with longitudinal Cancer A...BACKGROUND: The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; 2001-2020) showed no reduction in disease mortality in its primary intervention arm using multimodal screening (MMS) with longitudinal Cancer Antigen 125 (CA125) and transvaginal ultrasound. Whether this null result reflects the stop-screen design, screening performance, or ovarian cancer natural history remains unclear. METHODS: Using individual-level screening and diagnosis data from the MMS arm, we estimated ovarian cancer natural history, focusing on high-grade serous ovarian cancer (HGSC), the most common and lethal subtype. We then simulated trial outcomes under (1) continued screening beyond the trial screening interval and (2) high sensitivity for early-stage detection over an extended time period. RESULTS: The estimated window for detecting early-stage HGSC under MMS was <6 months. Continued screening yielded at most a 15% relative mortality reduction. Achieving a ≥20% mortality reduction required extending the detectable early-stage window to 1 year and attaining ≥70% sensitivity during this period. CONCLUSION: Current screening modalities offer a very limited opportunity to intercept HGSC at an early stage. Clinically effective ovarian cancer screening will require first- and second-line tests capable of detecting HGSC substantially earlier in its natural history.
Chin JH, Kim D, Lee HS
… +7 more, Jeon S, Lee JA, Lee YJ, Bae SY, Park WC, Song JH, Yoon CI
Br J Cancer
· 2026 Jun · PMID 42286233
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BACKGROUND: Adjuvant radiotherapy (RT) is standard for breast cancer, but its impact on skin cancer risk, especially in Asian populations, remains unclear despite advanced techniques. This study aimed to assess skin canc...BACKGROUND: Adjuvant radiotherapy (RT) is standard for breast cancer, but its impact on skin cancer risk, especially in Asian populations, remains unclear despite advanced techniques. This study aimed to assess skin cancer incidence following RT in a large South Korean cohort. METHODS: This retrospective cohort study, using South Korean Health Insurance Review and Assessment Service data (2009-2012), included 37,957 patients aged ≥20 with invasive breast cancer or ductal carcinoma in situ who underwent curative surgery. Prior malignancies or oncological treatment were excluded. Incidence of malignant melanoma and non-melanoma skin cancers were assessed. 1:1 propensity score matching was performed to balance confounders, resulting in 19,856 matched patients (9928 per group). Multivariable Cox proportional hazards models identified risk factors. RESULTS: Post-matching, skin cancer incidence was comparable between RT and non-RT (NRT) groups (0.97% vs. 1.02%; p = 0.720). RT showed no significant association with overall skin cancer (p = 0.604), malignant melanoma (p = 0.094) or non-melanoma skin cancer (p = 0.196). Increased risk was associated with older age, mole presence (HR 5.254), pre-malignant skin lesions (HR 12.905), and lymphedema (HR 1.978). CONCLUSION: Adjuvant RT did not increase skin cancer risk after breast cancer surgery. Dermatologic factors and lymphedema were principal predictors, emphasising vigilant follow-up in at-risk patients.
Byrd DA, Zouiouich S, Wahl D
… +18 more, Pardini B, Gomez Morales MF, Tarallo S, Bulfamante S, Francavilla A, Francescato G, Hogue SR, Armaroli P, Bellisario C, Ferrante G, Vogtmann E, Wan Y, Hua X, Shi J, Gunter M, Naccarati A, Senore C, Sinha R
Br J Cancer
· 2026 Jun · PMID 42286232
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BACKGROUND: Large, prospective cohorts are needed to research the gut microbiome's role in colorectal cancer (CRC) risk. We evaluated the gut microbiome leveraging residual fecal immunochemical tests (FIT) from a CRC scr...BACKGROUND: Large, prospective cohorts are needed to research the gut microbiome's role in colorectal cancer (CRC) risk. We evaluated the gut microbiome leveraging residual fecal immunochemical tests (FIT) from a CRC screening program in Turin, Italy, and conducted one of the largest population-based case-control studies across the adenoma-carcinoma sequence to date. METHODS: We extracted DNA from residual FIT stool, used whole-genome shotgun sequencing, and included those with CRC (N = 44), advanced adenomas (N = 269), early adenomas (N = 134), and FIT-negative controls (N = 478). Alpha diversity, beta diversity, and species, gene, and pathway relative abundances were estimated. Multivariable logistic regression models were used to estimate associations of these metrics with colorectal neoplasms. RESULTS: Alpha diversity was mostly inversely associated with colorectal neoplasms, particularly early adenomas (OR: 0.45, 95% CI: 0.25-0.80; P = 0.01). Presence of oral pathogens, including Parvimonas micra, was associated with higher odds of CRC. Furthermore, Escherichia coli and Bacteroides fragilis were strongly associated with higher odds of all colorectal neoplasms. Several genes and pathways were associated with colorectal neoplasms. CONCLUSIONS: Our findings align with smaller studies of the gut microbiome and colorectal neoplasms, supporting that CRC screening programs provide opportunities to prospectively study the gut microbiome's association with cancer risk in large populations.
Lee SH, Aktas BK, Kim A
… +3 more, Deshpande V, Vyas M, Yilmaz O
Br J Cancer
· 2026 Jun · PMID 42286231
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BACKGROUND: Tumour deposits (TDs) are established adverse prognostic features in colorectal carcinoma, yet their biologic significance and integration into current nodal staging systems remain controversial. Although TD...BACKGROUND: Tumour deposits (TDs) are established adverse prognostic features in colorectal carcinoma, yet their biologic significance and integration into current nodal staging systems remain controversial. Although TD burden has been associated with adverse prognosis beyond lymph node metastasis, its incremental staging relevance and the immune microenvironmental features of the primary tumour that may underlie the aggressive behaviour of TD-positive tumours remain incompletely defined. METHODS: We evaluated 845 consecutive colorectal carcinomas resected at a single institution between 2007 and 2015. Clinicopathologic features, TD burden and disease-specific survival (DSS) were analysed. Immune profiling was performed on tissue microarrays using immunohistochemistry for CD8, CD163, FoxP3, LAG3, PD-L1, HLA class I, HLA class II, and beta-2-microglobulin (B2M), with automated quantitative image analysis. RESULTS: Among 825 patients with available data, TDs were identified in 106 cases (12.8%) and were significantly associated with adverse clinicopathologic features, including advanced T stage, lymph node metastasis, extramural venous invasion, perineural invasion, and distant metastasis. TD-positive tumours demonstrated significantly worse 5-year DSS compared with TD-negative tumours (45.8 vs. 81.0%, p < 0.001). Increasing TD burden conferred a dose-dependent adverse impact on DSS (p < 0.001), including within lymph node-positive disease. Within stage III tumours, TD burden stratified outcome beyond conventional nodal categories with pN1 tumours lacking TDs approximating stage II survival and pN2 tumours with TDs approaching stage IV outcomes. In this context, TD-positive tumours showed reduced intratumoral CD8+ T-cell infiltration, decreased tumour cell B2M expression and increased tumour cell PD-L1 expression, consistent with an immune-evasive phenotype. CONCLUSIONS: TDs are associated with adverse clinicopathologic features, immune-evasive tumour microenvironments and poor disease-specific survival in colorectal carcinoma. Quantitative TD burden provides additional prognostic information beyond nodal status, supporting the incorporation of TD burden into future staging paradigms.
Armstrong A, Heng YJ, Sardella BR
… +4 more, Ratcliffe M, Rosner B, Tamimi RM, Yaghjyan L
Br J Cancer
· 2026 Jun · PMID 42277287
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BACKGROUND: We explored the associations of alcohol consumption with expression of α-Smooth Muscle Actin (α-SMA), Tenascin-C (TNC), Fibroblast Activation Protein (FAP), Matrix Metalloproteinase-14 (MMP14), and Calcyclin...BACKGROUND: We explored the associations of alcohol consumption with expression of α-Smooth Muscle Actin (α-SMA), Tenascin-C (TNC), Fibroblast Activation Protein (FAP), Matrix Metalloproteinase-14 (MMP14), and Calcyclin (s100a6) stromal markers in benign breast biopsy samples. METHODS: The study included 683 cancer-free women from the Nurses' Health Study II who had biopsy-confirmed benign breast disease (BBD). Alcohol consumption was assessed with semi-quantitative Food Frequency Questionnaires. The data on breast cancer (BCa) risk factors were obtained from biennial questionnaires. Immunofluorescence for stromal markers was performed on tissue microarrays. For each core, the % positivity was quantified by inForm v2.6.0. Generalised linear regression was used to examine associations between alcohol consumption (recent [at biopsy date] and cumulative average from all available questionnaires before the biopsy date) and log-transformed expression of each marker, adjusting for BCa risk factors and BBD subtype. RESULTS: In multivariate analysis, we observed a suggestive positive association of cumulative average alcohol with TNC (β per 11 g/day = 0.59, 95% CI -0.03,1.22, p = 0.06). Alcohol consumption was not associated with α-SMA, FAP, s100a6, and MMP14. CONCLUSION: Alcohol consumption may be associated with an increased normal stromal fibroblast activation as measured by TNC expression in histologically normal breast tissue. Future studies are warranted to confirm our findings.
Slawinski CGV, Malcomson L, Barriuso J
… +8 more, Guo H, Emsley R, Riley RD, Harkin A, Iveson T, Glynne-Jones R, van de Velde CJH, Renehan AG
Br J Cancer
· 2026 Jun · PMID 42265335
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INTRODUCTION: We aimed to disentangle whether elevated body mass index (BMI) is directly associated with adverse survival in primary colorectal cancer (CRC), or indirectly through treatment-related mechanisms, e.g., dose...INTRODUCTION: We aimed to disentangle whether elevated body mass index (BMI) is directly associated with adverse survival in primary colorectal cancer (CRC), or indirectly through treatment-related mechanisms, e.g., dose-capping adjuvant chemotherapy (ACT) and toxicity, using individual participant data meta-analysis (IPD-MA) and causal inference approaches. METHODS: Using BMI from four CRC-ACT randomised trials [OCTOPUS], and two ACT adherence measures (average cumulative relative dose [ACRD]; average relative dose intensity [ARDI]), we performed two-stage random effects IPD-MA, assessing total (TE) and direct effects (DE) (excluding and including mediators, respectively) of pre-defined causal paths, with overall survival (OS) as primary outcome. FINDINGS: In 7264 patients, the TE of 5 kg/m BMI increments was a significant ACRD reduction (-1.15% [95% CI -1.92, -0.38]), and ACRD 5% increments were associated with improved OS (HR 0.94 [0.91, 0.96]), implying possible adverse indirect effects; though not large enough to induce an adverse TE of BMI on OS (HR 0.98 [0.90, 1.07]). BMI-ARDI relationships were similar (TE -1.08% [-1.44, -0.72]), but ARDI-OS relationships were inverted (HR 1.05 [1.01, 1.09]). BMI showed no association with grade 3+ toxicity (OR 1.01 (0.91, 1.14)). However, toxicity was associated with worse OS (TE HR 1.37 [1.17, 1.61]), which attenuated on adjusting for ACRD (DE HR 1.20 [1.02, 1.41]), suggesting partial mediation via a significant toxicity-ACRD relationship (-10.37% [-11.77, -8.97]). CONCLUSION: Our study establishes possible adverse indirect effects of obesity on CRC survival, through treatment-selection, supporting full BSA-based ACT dosing.
Hektoen HH, Tsuruda KM, Mæhlen MT
… +2 more, Helland Å, Andreassen BK
Br J Cancer
· 2026 Jun · PMID 42259946
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BACKGROUND: Comorbidities are common in advanced non-small cell lung cancer (NSCLC) patients, yet their impact on systemic anti-cancer treatment (SACT) and survival in the era of immune checkpoint inhibitors (ICIs) remai...BACKGROUND: Comorbidities are common in advanced non-small cell lung cancer (NSCLC) patients, yet their impact on systemic anti-cancer treatment (SACT) and survival in the era of immune checkpoint inhibitors (ICIs) remains unclear due to limited representation in clinical trials. METHODS: This nationwide registry-based study included 9178 patients with stage IIIB-IV NSCLC diagnosed before and after ICI introduction. Kaplan-Meier and multivariable Cox models were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Common comorbidities included chronic obstructive pulmonary disease (COPD: 22%), cardiovascular disease (CVD: 21%), type 2 diabetes (T2D: 10%), and rheumatic and musculoskeletal diseases (RMD: 6%). Patients with comorbidities were less likely to receive SACT. Following ICI introduction, SACT use increased across all comorbidity groups and 2-year OS improved up to threefold. CVD patients had better 2-year OS when treated with ICI alone than ICI plus chemotherapy (38 vs 22%). Patients with CVD, T2D and RMD had higher risk of death when treated with ICI plus chemotherapy compared to patients without these comorbidities (HR = 1.36 (1.07-1.73), HR = 1.33 (0.99-1.78) and HR = 1.38 (0.97-1.95), respectively). CONCLUSIONS: Survival among patients with comorbidities improved following ICI introduction, however the benefit varied by comorbidity and treatment modality, supporting more individualised treatment strategies.
Chen YW, Shiah SG, Yuan SS
… +16 more, Wang YY, Tsai FY, Chen IC, Lin CM, Chung TT, Lee JJ, Chen MK, Liu YT, Yang SF, Wang WL, Wang CC, Hsieh YP, Yen CY, Liu TW, Jiang SS, Liu KJ
Br J Cancer
· 2026 Jun · PMID 42251141
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BACKGROUND: Oral potentially malignant disorders (OPMDs) are precursor lesions with variable risk of progressing to oral squamous cell carcinoma (OSCC). Reliable biomarkers to predict malignant transformation (MT) risk a...BACKGROUND: Oral potentially malignant disorders (OPMDs) are precursor lesions with variable risk of progressing to oral squamous cell carcinoma (OSCC). Reliable biomarkers to predict malignant transformation (MT) risk are urgently needed. METHODS: RNA sequencing and pathway analyses were performed on 18 progressive and 22 non-progressive OPMDs. A prospective, multicenter cohort study (TWOPMD) analysed 1313 saliva samples from eight Taiwan healthcare centers: 356 healthy controls, 860 OPMD patients and 97 OSCC patients. Eight inflammation-related cytokines were quantified using Bio-Plex immunoassay. Cox regression models evaluated 749 OPMD cases with longitudinal follow-up to identify cytokine predictors of malignant transformation. RESULTS: Interferon (IFN) signalling was significantly enriched in progressive OPMDs, with IFN signatures correlating strongly with inflammation-related cytokine expression. IL-1β, IL-6, IL-8, TNF-α and IL-10 were significantly dysregulated across the OPMD, OSCC and control groups. Cox regression identified IL-6, IL-6/IL-1Ra ratio, and composite index (IL-6×IL-8)/IL-1Ra as significant MT predictors. Kaplan-Meier analyses confirmed elevated cytokine biomarkers were associated with significantly higher cancer risk (p = 0.02, p = 0.00001, p = 0.002). Incorporation of betel nut chewing status into the cytokine-based models further improved prognostic performance. DISCUSSION: Salivary cytokines, particularly IL-6/IL-1Ra ratio, are promising noninvasive biomarkers for predicting oral cancer risk in OPMD patients.
Evans TRJ, Cook N, El-Khoueiry A
… +11 more, Pinato DJ, Tran NH, Hsiehchen D, Mena E, Meyer T, Wu J, Pathak SM, Paoletti C, Dutta L, Okpara CE, Lopez JS
Br J Cancer
· 2026 Jun · PMID 42243349
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BACKGROUND: We present data from the Phase 1 open-label Study 101 of E7386, an oral protein-protein interaction inhibitor reported to block the CBP/β-catenin interaction, in patients with solid tumours. METHODS: Eligible...BACKGROUND: We present data from the Phase 1 open-label Study 101 of E7386, an oral protein-protein interaction inhibitor reported to block the CBP/β-catenin interaction, in patients with solid tumours. METHODS: Eligible patients (across the UK and US) aged ≥18 years had advanced/recurrent solid tumours (dose-escalation) or CTNNB1-mutated hepatocellular carcinoma (dose-expansion). Primary objectives were to assess safety/tolerability and determine the recommended Phase 2 dose (RP2D) of E7386. RESULTS: Thirty-eight patients received study drug (dose-escalation: n = 32; expansion: n = 6; dose-range: 5-120 mg twice daily [BID]); 60.5% received ≥3 prior anticancer medications. Dose-limiting toxicities (grade-2 lethargy and grade-2 decreased appetite) occurred in 1 patient (20 mg BID cohort). The RP2D was determined as 120 mg BID. Most (94.7%) patients experienced treatment-related adverse events (TRAEs), most frequently nausea (65.8%) and vomiting (60.5%), which were primarily grade 1/2 and well-managed with antiemetics. No grade 4/5 TRAEs were noted. Pharmacokinetic exposure increased with increasing dose, although large intersubject variability was observed. No objective responses were noted; stable disease (SD) was observed in 36.8% of patients, including SD ≥ 23 weeks in 18.8% of patients (dose-escalation). CONCLUSIONS: E7386 demonstrated a manageable safety profile, a dose-dependent pharmacokinetic profile, and some disease stabilisation in heavily pretreated patients with advanced solid tumours. TRIAL REGISTRATION: NCT03264664 https://clinicaltrials.gov/study/NCT03264664 .
Br J Cancer
· 2026 Jun · PMID 42237021
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Traditional models used to study lymphoid malignancies, such as 2D cell cultures and murine systems, have significantly advanced our understanding of tumour biology and drug development. However, their limited capacity t...Traditional models used to study lymphoid malignancies, such as 2D cell cultures and murine systems, have significantly advanced our understanding of tumour biology and drug development. However, their limited capacity to recapitulate the tumour microenvironment and 3D anatomical structure restricts their translational relevance. In response to these challenges, three-dimensional (3D) culture systems have recently emerged as promising platforms to more accurately replicate the architecture and biological complexity of lymphoid tissues. A variety of 3D models have been developed, ranging from simple spheroids to advanced organ-on-chip technologies that allow for continuous perfusion and precise modulation of microenvironmental parameters. Current optimisation efforts aim to enhance these systems' ability to sustain lymphoma cell viability and mimic key in vivo features such as stromal integration, spatial organisation, and biomechanical cues. This review provides an overview of the current 3D models used to investigate mature lymphoid malignancies, with a particular focus on chronic lymphocytic leukaemia and lymphomas. We discuss their relevance, strengths, and limitations, especially in the context of therapeutic screening and the advancement of personalised treatment approaches.
Richards AR, Gomez MF, Dowling BI
… +12 more, Bulka CM, Gigic B, Figueiredo JC, Li CI, Shibata D, Toriola AT, Byrd DA, Ulrich CM, Teng M, Stewart PA, Siegel EM, Kresovich JK
Br J Cancer
· 2026 Jun · PMID 42237020
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BACKGROUND: Cancer immunology research has traditionally focused on tumor-infiltrating leukocytes, but the role of the peripheral leukocytes remains understudied. Since tumor-infiltrating leukocytes are recruited from th...BACKGROUND: Cancer immunology research has traditionally focused on tumor-infiltrating leukocytes, but the role of the peripheral leukocytes remains understudied. Since tumor-infiltrating leukocytes are recruited from the blood, circulating immune profiles may provide prognostic insights obtainable before surgery, reflecting overall immune competence. METHODS: We analyzed treatment-naïve blood samples from 134 stage I-III colorectal cancer (CRC) patients using a nested case-control design (33 recurrences, 45 deaths; median follow-up: 7.4 years). Circulating leukocyte subsets were estimated using methylation cytometry applied to genome-wide methylation profiles. Cox regression models estimated associations between leukocyte metrics and disease-free and overall survival, adjusting for clinical factors. RESULTS: Higher counts of circulating neutrophils and T-regulatory cells were associated with worse disease-free and overall survival (neutrophil, disease-free HR: 1.32, 95% CI: 1.01, 1.72, P = 0.04; overall HR: 1.39, 95% CI: 1.00, 1.94, P = 0.05; T regulatory, disease-free HR: 1.32, 95% CI: 1.00, 1.74, P = 0.05; overall HR: 1.38, 95% CI: 1.00, 1.90, P = 0.05). Memory B cells were associated with worse disease-free survival (HR: 1.56, 95% CI: 1.31, 1.86, P < 0.0001), particularly in those diagnosed with rectal cancer. Higher basophil counts and proportions were associated with worse overall survival (count HR: 1.44, 95% CI: 1.05, 1.99, P = 0.02; proportion HR: 1.47, 95% CI: 1.06, 2.03, P = 0.02), with stronger associations in those diagnosed at earlier stages or with rectal tumors. CONCLUSIONS: Peripheral immune cell composition identifies CRC patients at higher risk for recurrence and death, providing insights into systemic immune contributions to CRC survival.