The Christie School of Oncology: Christie Research Publications Repository
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Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity
No full textType 1 conventional dendritic cells (cDC1s) acquire and cross-present tumor antigens to prime CD8(+) T cells. Whether this selects for specific neoantigens is unclear. DNGR-1 (CLEC9A), a cDC1 receptor for F-actin exposed on dead cells, promotes cross-presentation of cell-associated antigens. Here we show that DNGR-1-deficient mice develop chemically induced tumors more rapidly and at higher incidence, and these are more frequently rejected on transplantation into wild-type recipients. Whole-exome sequencing reveals enrichment of predicted neoantigens derived from mutated F-actin-binding proteins. Consistent with this observation, tethering model antigens to F-actin enhances DNGR-1-dependent cross-presentation. These results suggest that DNGR-1-mediated recognition of F-actin exposed by dead cancer cells favors priming of CD8(+) T cells specific for cytoskeletal neoantigens, which can then drive immune escape of cancer cells lacking or reverting those mutations. Thus, neoantigen cross-presentation by cDC1 can determine the immune visibility of the tumor mutational landscape and sculpt cancer evolution by immunoediting
ESMO-ESTRO consensus statements on the safety of combining radiotherapy with CDK4/6, HER2, PARP, or mTOR inhibitors
No full textBACKGROUND: While combining radiotherapy (RT) with targeted agents or immunotherapy may improve outcomes, it may also increase toxicity. High-quality toxicity data and multidisciplinary, evidence-based guidelines on the combination of these treatment modalities are scarce. DESIGN: The European Society for Medical Oncology (ESMO) and the European SocieTy for Radiotherapy and Oncology (ESTRO) developed a series of systematic reviews with multidisciplinary, tumor-agnostic, evidence-based Delphi consensus statements regarding the safety of combining RT with targeted agents or immunotherapy. The current study addresses the safety of combining RT with CDK4/6 inhibitors, anti-HER2 monoclonal antibodies, PARP inhibitors, or mTOR-inhibitors. During the modified Delphi process, two digital voting rounds were organized with 18 international experts. By systematically evaluating the different drug classes and irradiated areas, 74 clinical scenarios were assessed. Safety statements were formulated for all scenarios, based on the evidence from the systematic literature reviews. RESULTS: A total of 1,341 records were screened during the systematic literature reviews, of which 107 studies were ultimately included in the final reviews and the literature database. After two Delphi voting rounds, agreement was reached on all 74 scenario-specific safety statements. CONCLUSIONS: The expected combined toxicity is often low for anti-HER2 monoclonal antibodies. For most scenarios with CDK4/6, PARP, or mTOR inhibitors, exercising caution is recommended
Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study
No full textBackground: In metastatic hormone-sensitive prostate cancer (mHSPC), phosphatase and tensin homolog (PTEN) deficiency results in phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway activation, providing an independent proliferative drive, which cannot be suppressed by androgen receptor pathway inhibitors (ARPIs), resulting in worse outcomes. Dual inhibition of PI3K/AKT and AR pathways with capivasertib and abiraterone may delay progression and improve disease outcomes. Patients and methods: In CAPItello-281 (NCT04493853), patients with PTEN-deficient mHSPC (diagnostic cut-off: >= 90% viable malignant cells with no specific cytoplasmic PTEN immunohistochemistry staining) received capivasertib or placebo (1 : 1) plus abiraterone, prednisone/prednisolone, and androgen deprivation therapy (ADT). The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS); overall survival (OS) was a key secondary endpoint. Post hoc exploratory subgroups at increasing PTEN cut-off thresholds were also assessed. Results: 25.3% (1519/6003) of patients with valid tumor test results had PTEN-deficient tumors. In the randomized PTEN-deficient population, a statistically significant improvement in rPFS was observed with capivasertib plus abiraterone (n = 507, median 33.2 months) versus placebo plus abiraterone [n = 505, 25.7 months; hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.66-0.98, P = 0.034]. Post hoc rPFS analyses for loss of PTEN cut-offs of >= 95%, >= 99%, and 100% showed that the capivasertib plus abiraterone arm performed consistently across cut-offs, but the placebo plus abiraterone arm performed progressively worse as the cut-off for the degree of PTEN loss was increased, resulting in a numerically improved treatment effect. In the overall population studied, the HR for OS (26.4% maturity) was 0.90, 95% CI 0.71-1.15, P = 0.401. The most common adverse events (AEs) for capivasertib plus abiraterone were diarrhea (51.9%; 8.0% placebo plus abiraterone), hyperglycemia (38.0%; 12.9%), and rash (35.4%; 7.0%). Deaths associated with an AE were reported in 36 (7.2%) and 26 (5.2%) patients in the capivasertib plus abiraterone and placebo plus abiraterone arms, respectively. Conclusions: Capivasertib plus abiraterone improves rPFS versus placebo plus abiraterone in PTEN-deficient mHSPC, on a background of ADT, with a 7.5-month improvement in median rPFS. AE profile was consistent with that of the individual agents. Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone
Concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): final and exploratory analyses of a randomised, open-label, phase 3 trial
No full textBackground The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours. Methods This randomised, open-label, phase 3 study in 137 institutions across Australia, Europe, and North America included participants aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59 center dot 4 Gy in 33 fractions), radiotherapy with concurrent oral temozolomide (75 mg/m(2) per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m(2) temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Participants were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. The eighth amendment of the study protocol (June 27, 2011) incorporated analysis of IDH mutational status into the study. We report the intention-to-treat analysis and the exploratory analysis within the population of participants with astrocytoma with an IDH mutation. As the safety data have been published previously, no safety data are reported. This trial is registered with ClinicalTrials.gov, NCT00626990, and is completed. Findings Between Dec 4, 2007, and Sept 11, 2015, 1407 participants were registered and 751 participants were randomly allocated, 444 of whom were diagnosed with an IDHmt tumour. After a median follow-up for overall survival of 10 center dot 9 years (IQR 9 center dot 5-12 center dot 7), in the intention-to-treat population, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (hazard ratio [HR] 0 center dot 65 [95% CI 0 center dot 54-0 center dot 77]), but concurrent did not compared with no concurrent temozolomide (HR 0 center dot 91 [0 center dot 76-1 center dot 08]). In univariable analysis of the participants with an IDHmt tumour, concurrent temozolomide had no statistically significant effect on overall survival (median 9 center dot 7 years [8 center dot 2-12 center dot 5] vs 7 center dot 2 years [6 center dot 2-9 center dot 4]; HR 0 center dot 81 [0 center dot 63-1 center dot 04]), but median overall survival was 12 center dot 5 years (95% CI 9 center dot 4-15 center dot 0) with adjuvant temozolomide compared with 6 center dot 0 years (5 center dot 1-7 center dot 2) with no adjuvant temozolomide (HR 0 center dot 54 [0 center dot 42-0 center dot 69]). No benefit of temozolomide, neither concurrent nor adjuvant, was observed in participants with IDH wild-type tumours. Methylation-based subtyping and several DNA alterations (eg, amplification of PDGFRA and CDK4, homozygous deletion of CDKN2A, and total copy number variation) were associated with worse outcome, none of which was predictive for benefit to temozolomide. Interpretation Long-term follow-up confirms that radiotherapy followed by 12 cycles of adjuvant temozolomide without concurrent temozolomide during radiotherapy improves survival for individuals with aggressive IDHmt astrocytoma. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies
Establishing a national SABR service: a model for safe and effective clinical implementation
No full textAIMS: Following the successful completion of a registry-based evaluation study of patients with extracranial oligometastatic disease or hepatocellular carcinoma treated with stereotactic ablative body radiotherapy (SABR), National Health Service (NHS) England and NHS Improvement funded an implementation and expansion programme in 2020 to increase SABR provision to 51 radiotherapy centres. This report details the integration of structured mentoring and radiotherapy quality assurance (RT QA) as core components for a safe and effective national SABR implementation programme. MATERIALS AND METHODS: Six members of the UK SABR Consortium developed a framework for effective mentoring that experienced SABR centres could follow to mentor those with limited or no experience. In parallel, the National Radiotherapy Trials Quality Assurance Group delivered an accreditation programme for completion by those centres comprising a facility questionnaire, contouring and planning benchmarks, end-to-end dosimetry audit and individual case review. RESULTS: Sixteen experienced centres mentored thirty-three new SABR sites, covering a range of techniques and equipment. A large multidisciplinary team of 25 individuals, consisting of clinical oncologists, medical physicists and therapeutic radiographers developed and delivered the RT QA programme. As of April 2025, all centres are accredited for lung, bone and nodes; the programme for the remaining anatomical sites is ongoing. Nearly 24,000 patients have been treated since the NHSE 2020 programme commenced. CONCLUSION: This is the first nationally funded programme demonstrating how structured mentorship and RT QA have been beneficial in the safe, effective and timely implementation of SABR services in England. The programme, developed through a multi-professional inter-group collaboration of SABR experts, ensured that radiotherapy centres were trained and supported to deliver consistent, high-quality SABR
Adjuvant immunotherapy in the modern management of resectable melanoma: current status and outlook to 2028 (vol 10, 104295, 2025)
No full textDistant recurrence and margin involvement in invasive breast cancer
No full textThe effect of involved margins after breast cancer surgery on distant recurrence (DR) is unknown. We determined the association between margin width or involvement, DR and cancer deaths. PATIENTS AND METHODS: Greater Manchester (GM) and the National Cancer Registry (NCRAS) cohorts were analysed. Margin status after curative surgery was measured. Cox-proportional hazards investigated factors associated with LR, DR and breast cancer deaths. RESULTS: In GM (2010-2014), 2295 (70.2%) patients had clear margins ( > 2 mm), 302 (9.2%) close (1-2 mm) and 673 (20.6%) involved ( 1 mm. After BCS, in 5246 patients who underwent chemotherapy after BCS, involved margins 1 mm were associated with lower DR and cancer deaths. Guidelines should recommend a minimum margin clearance of 1 mm
Cholangiocarcinoma 2026: status quo, unmet needs and priorities
No full textCholangiocarcinoma (CCA) is a cancer that originates within the bile ducts. Traditionally considered to be a rare neoplasm, increased awareness of CCA alongside advancements in diagnosis and the rising prevalence of certain risk factors have contributed to a global increase in incidence and mortality. CCAs are highly heterogeneous from the clinical, histomorphological and molecular perspectives but commonly share a poor prognosis. These tumours usually develop and progress silently; by the time they are detected, it is often too late for curative surgical intervention. In such cases, current therapeutic approaches offer modest survival improvements and are generally considered palliative. Although well-known risk factors predispose individuals to developing CCA, the majority of cases are considered sporadic, occurring without any identifiable underlying condition. Over the past decade, substantial collaborative efforts have been made to improve our understanding of the aetiopathogenesis of these tumours, aiming to identify novel biomarkers and therapeutic targets to develop more effective treatments. The ultimate goal is to improve patient outcomes and overall well-being. However, there are significant gaps in our understanding of the molecular mechanisms that drive cholangiocarcinogenesis. In this international Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we provide a critical overview of the latest advancements in the field of CCA. We highlight the key aspects of CCA aetiopathogenesis and clinical management and provide insights into promising new treatments. Finally, we provide a set of consensus recommendations and future research priorities for CCA based on a Delphi panel questionnaire involving international experts
Systemic complement protein levels as biomarkers of chemoradiotherapy response in anal squamous cell carcinoma
No full textBackground: Identification of easily measurable biomarkers that are able to predict locoregional failure or disease progression following chemoradiotherapy (CRT) would enable more personalised cancer management. Anal squamous cell cancer (ASCC) is the most common type of anal cancer, accounting for approximately 90% of all cases. While CRT is the standard of care for most locally advanced anal cancers, treatment failure occurs in up to 30% of patients. However, it is currently difficult to predict which patients will fail to respond to treatment, highlighting the need for predictive biomarkers. This study aims to assess whether plasma levels of complement proteins can serve as potential biomarkers of treatment response. Materials and Methods: Serial peripheral blood samples from ASCC patients (n = 40) were collected before, during, and after CRT, alongside 6-month clinical and radiological outcomes. Using multiplex ELISA-based technology, we assessed levels of 14 complement proteins at baseline, during CRT, and 3 months post-CRT. Additionally, the same technology was used to compare levels of complement analytes in ASCC and in age-and sex-matched patients without a cancer diagnosis. Results: Our data indicate that CRT decreases levels of most complement analytes measured, with intact C2, intact C3, intact C5, C3a, C5a, Ba, Bb, SC5b9, Factor D, Factor H, Factor I, and Factor P decreasing 3 months after treatment specifically in those patients achieving complete responses (all p < 0.05). Moreover, the treatment failure group showed changes indicative of persistent alternative complement pathway activation, with a less pronounced decline following CRT compared to responders. Furthermore, intact C2 and intact C5 levels were significantly higher in ASCC patients compared to age-and sex-matched patients without a cancer diagnosis (both p < 0.005). In contrast, C3a and C4a were expressed at higher levels in patients without cancer diagnosis compared to ASCC patients (both p < 0.02). Importantly, patients in the treatment failure group had elevated baseline (pre-treatment) levels of intact C2 and Factor D compared to those achieving complete response (both p < 0.03). Conclusions: These findings suggest that dysregulation of the complement system, particularly involving the alternative pathway, may be more prevalent in patients with a poor treatment response. Intact C2 and Factor D may represent potential markers of treatment failure
SOX2 confers tumour permissiveness in a specific skin progenitor population
No full textThe continuous renewal of the skin relies on stem and progenitor cells, yet their differential susceptibility to oncogenic mutations in cutaneous squamous cell carcinoma (cSCC) remains unclear. Rapid cSCC develops in melanoma patients on BRAF inhibitors due to paradoxical MAPK activation. To model this in mice, we use two complementary approaches: HRASG12V with a BRAF inhibitor to mimic paradoxical MAPK activation, and BRAFV600E, which drives MAPK hyperactivation without further treatment. We target these mutations to the interfollicular stem and differentiation-committed progenitors of the basal epidermis. While stem cells rapidly form tumours, progenitors exhibit long-latency resistance despite retaining mutations and repopulating the basal layer. Ultimately, both populations produce similar tumours, showing a shared transformation process. However, SOX2 is uniquely upregulated in progenitor-derived tumours and is expressed in 20% of human cSCC, indicating it might mark tumours arising from committed progenitors. Here, we show that SOX2 overexpression, along with MAPK activation, in progenitors induces a stem-like state and renders this otherwise resistant population permissive to rapid transformation