The Christie School of Oncology: Christie Research Publications Repository
Not a member yet
16373 research outputs found
Sort by
European standard clinical practice recommendations for newly diagnosed ependymoma of childhood and adolescence (vol 5, 100227, 2025)
No full textCirculating Tumor DNA as a Prognostic Biomarker for Selecting Participants to Early Phase Clinical Trials
No full textINTRODUCTION: Patients with advanced solid tumors may be considered for early phase clinical trials investigating the safety, tolerability, and dosing of experimental therapies. Optimizing participant selection is critical to maximize clinical benefit and meet trial endpoints with fewer participants. One in six participants does not meet routine life expectancy requirements (>3 months), highlighting the need for improved prognostication. Variant allele frequency (VAF) in circulating tumor DNA (ctDNA) correlates with overall survival (OS) in advanced solid tumors. We aimed to derive an optimal VAF threshold as a prognostic biomarker to enhance participant selection. METHODS: ctDNA testing was performed as part of the TARGET (NIHR Clinical Research Network CPMS ID 39172) and TARGET National (NCT04723316) prospective cohort studies, in patients with advanced solid tumors referred for early phase clinical trials. Maximum (maxVAF) and mean VAF (meanVAF) were compared in their association with OS and ability to delineate favorable and poor outcomes at set threshold points using hazard ratios (HRs). Optimal thresholds of VAF were explored using receiver operating characteristic curve analysis to predict 3-month landmark OS. Univariable and multivariable analysis was performed to determine whether VAF was an independent prognostic marker. RESULTS: Of 631 patients, 587 had evaluable ctDNA results. MeanVAF and maxVAF exhibited similar correlation with OS (r(s) = -0.32 vs -0.35, respectively) and similar prognostic utility at matched threshold points. A maxVAF value of 4% was selected as optimal for prognostic subgrouping (area under curve 0.77). OS was 5.9 versus 12.1 months (p < 0.0001) for patients with more than 4% and 4% or less maxVAF, respectively. Multivariable analysis confirmed more than 4% maxVAF as independently associated with reduced 3-month landmark OS (HR 2.17 [1.76-2.70], p < 0.001). CONCLUSION: VAF is an independent prognostic marker in patients with advanced solid tumors, with 4% maxVAF deemed optimal for delineating favorable and poorer prognostic subgroups in this patient cohort. Further validation and integration into existing prognostic scores are warranted
UpSMART: five years of digital innovation in cancer clinical research-achievements, challenges, and recommendations
No full textUpSMART, a research programme involving 24 European cancer centres, aimed to promote digital innovation in early-phase clinical research addressing challenges in recruitment, data collection and analysis. Several open-source digital healthcare products (DHPs) were developed through UpSMART, including eTARGET and trialFinder for trial matching, and PROACT 2.0 for patient-reported data. Lessons learned highlight the importance of multidisciplinary teams, sustainable funding and deployment, and engagement with the research community to maximise impact
Mastering CT-based radiomic research in lung cancer: a practical guide from study design to critical appraisal
No full textRadiomics is a health technology that has the potential to extract clinically meaningful biomarkers from standard of care imaging. Despite a wealth of exploratory analysis performed on scans acquired from patients with lung cancer and existing guidelines describing some of the key steps, no radiomic-based biomarker has been widely accepted. This is primarily due to limitations with methodology, data analysis, and interpretation of the available studies. There is currently a lack of guidance relating to the entire radiomic workflow from study design to critical appraisal. This guide, written with early career lung cancer researchers, describes a more complete radiomic workflow. Lung cancer image analysis is the focus due to some of the unique challenges encountered such as patient movement from breathing. The guide will focus on CT imaging as these are the most common scans performed on patients with lung cancer. The aim of this article is to support the production of high-quality research that has the potential to positively impact outcome of patients with lung cancer
Unlocking the potential of highly conformal external beam radiotherapy planning for locally advanced cervical cancer: results from EMBRACE-II
No full textA role for frailty assessments in frail and older adults diagnosed with Acute Myeloid Leukaemia
No full textPhase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer
No full textBACKGROUND: Although endocrine therapies, alone or in combination with CDK4/6 inhibitors, have led to notable improvements in the treatment of estrogen receptor-positive (ER+) breast cancer, progression is inevitable for most patients. We report dose escalation and expansion data from a trial of H3B-6545 (a novel selective ER covalent antagonist that inactivates wild-type and mutant ERα) in women with locally advanced/metastatic ER+, HER2-negative breast cancer (BC). METHODS: This study was a multicenter, open-label, phase 1/2 trial. Women ≥ 18 years of age with ER+, HER2 − BC whose disease progressed on their most recent therapy were eligible. Prior therapy must have included at least 2 hormonal therapies (HTs), or 1 HT and 1 chemotherapy, or 1 HT and a CDK4/6 inhibitor. In phase 1, H3B-6545 was administered orally once daily at doses of 100–600 mg. In phase 2, the efficacy of the recommended phase 2 dose (RP2D) determined in phase 1 was examined in additional patients, including those with/without ERα mutation. The primary endpoints were RP2D determination (phase 1) and objective response rate (ORR) (phase 2, investigator-assessed per RECIST v1.1). Additional primary endpoints (phase 2) included progression-free survival (PFS) and overall survival (OS), per Kaplan-Meier estimates. RESULTS: 151 Patients were treated across phases. During phase 1, 2 DLTs (drug eruption and fatigue, both grade 3) were observed at the 600 mg dose, and 450 mg was deemed the RP2D. In the total population (phases 1 and 2), all patients experienced ≥ 1 treatment-emergent adverse event (TEAE), and 50.3% had grade 3–4 TEAEs, with no grade 5 TEAEs observed. In phase 1, the overall ORR was 7.5% (95% CI 1.6–20.4). The ORR in all response-evaluable patients treated at 450 mg (n = 94) was 20.2% (95% CI 12.6–29.8). Patients with clonal ESR1 Y537S mutation had an ORR of 32.1% (95% CI 15.9–52.4). For all patients who received H3B-6545 450 mg, median PFS was 4.6 months (95% CI 3.5–6.7) and median OS was 21.5 months (95% CI 16.6–25.5). CONCLUSIONS: Results suggest that H3B-6545 may be further investigated as an endocrine therapy option for patients with previously treated metastatic ER + BC. TRIAL REGISTRATION: NCT03250676. Registered August 11, 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-025-02069-8
SRSF2 mutation-induced CHD8 exon skipping represents a novel pathogenic mediator and therapeutic dependence in chronic myelomonocytic leukemia (CMML)
No full text
Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer
No full textMolecular subtypes of small cell lung cancer (SCLC) have been described based on differential expression of the transcription factors (TFs) ASCL1, NEUROD1, and POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC circulating tumor cell-derived explant (CDX) model biobank. Here, we show that ATOH1 protein is detected in 7 of 81 preclinical models and 16 of 102 clinical samples of SCLC. In CDX models, ATOH1 directly regulates neurogenesis and differentiation programs, consistent with roles in normal tissues. In ex vivo cultures of ATOH1+ CDXs, ATOH1 is required for cell survival. In vivo, ATOH1 depletion slows tumor growth and suppresses liver metastasis. Our data validate ATOH1 as a bona fide lineage-defining TF of SCLC with cell survival and pro-metastatic functions. Further investigation exploring ATOH1-driven vulnerabilities for targeted treatment with predictive biomarkers is warranted