The Christie School of Oncology: Christie Research Publications Repository
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A Scoping Review of Global Enablers and Barriers to Training the Next Generation of Radiation Oncology Physician Scientists
No full textMulticentre adaptive randomised trial of GvHD prophylaxis following unrelated donor stem cell transplantation comparing thymoglobulin versus calcineurin inhibitor-based or sirolimus-based post-transplant cyclophosphamide (methods of T cell depletion, MoTD trial)
No full textINTRODUCTION: Graft-versus-host disease (GvHD) remains a major complication of allogeneic stem cell transplantation (allo-SCT), affecting 30-70% of patients (representing 800 new patients per year in the UK). The risk is higher in patients undergoing unrelated allo-SCT. About 1 in 10 patients die as a result of GvHD or through complications of its treatment. In patients who survive GvHD and or the complications of treatment, about 1 in 3 patients develop chronic GvHD which has a negative impact on quality of life (QoL). Many transplant protocols use alemtuzumab or anti-thymocyte globulin (ATG) in combination with a calcineurin inhibitor (CNI) and mycophenolate mofetil as GvHD prophylaxis; however, the outcomes of these treatments are complicated by high rates of infection and therefore the development of improved GvHD prophylaxis strategies represents a major unmet need. METHODS AND ANALYSIS: The Methods of T-Cell Depletion trial is a prospective, multicentre, adaptive randomised trial in patients undergoing reduced intensity-conditioned unrelated donor allo-SCT. The trial will compare the novel GvHD prophylaxis regimens post-transplant cyclophosphamide (PTCy) in combination with a CNI or sirolimus (PTCy-CNI or PTCy-sirolimus, respectively) to a current standard-of-care GvHD prophylaxis involving the use of Thymoglobulin (a specific brand of ATG containing rabbit polyclonal antibodies). The primary outcome measure is GvHD-free, relapse-free survival at 1 year. Secondary outcomes include cumulative incidence of acute grade II-IV GvHD at 1 year, cumulative incidence of moderate and severe chronic GvHD at 1 year, overall survival at 1 year and cumulative incidence of non-relapse mortality at 1 year. ETHICS AND DISSEMINATION: The protocol was approved by the West Midlands, Edgbaston Research Ethics Committee (20/WM/0195); initial approval was received on 11 September 2020, current protocol version (V.4.0) approval on 25 July 2023. The Medicines and Healthcare products Regulatory Authority also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: EudraCT Number: 2019-002419-24.ISRCTN Number: 50290131
TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors
No full textMany patients with cancer do not benefit from currently approved immune checkpoint inhibitors (ICIs), suggesting that additional immunomodulation of the immunosuppressive tumor microenvironment (TME) is required. MTL-CCAAT enhancer-binding protein alpha (CEBPA) specifically upregulates the expression of the master myeloid transcription factor, CEBPA, relieving myeloid-driven immunosuppression. Here, we report the safety, tolerability, pharmacokinetics, and efficacy of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumors that typically show ICI resistance. Multimodal exploratory analyses of paired patient biopsies demonstrate biological changes associated with the combination treatment of MTL-CEBPA and pembrolizumab, including increased infiltration of T cell and antigen-presenting cells supporting conversion from an immune-desert toward a more immune-inflamed TME. Patients with disease stabilization demonstrate reductions in immunosuppressive myeloid cells post treatment. Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335)
Impact of platinum-based chemotherapy (CT) on acquired resistance (AR) to first-line immunecheckpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC): individual patient data metanalysis
No full textA revised prognostic model for patients with acute myeloid leukemia and first relapse
No full textMost patients with acute myeloid leukemia (AML) may obtain remission upon induction chemotherapy, but relapse is frequent and associated with poor survival. Previous prognostic models for outcomes after relapse lacked analysis of comprehensive molecular data. A validated prognostic model integrating clinical, cytogenetic, and molecular variables may support treatment decisions. We studied 943 patients with AML who relapsed after intensive induction treatment in a development cohort (HOVON-SAKK). A random survival forest algorithm was used to evaluate the association of clinical parameters, cytogenetic abnormalities, and molecular variables at diagnosis with overall survival (OS). Relapsing patients (n = 377) who were enrolled in the NCRI-AML18 trial were used for validation. In the development cohort, the median age at relapse was 58 years, and patients were classified as 2022 European LeukemiaNet favorable (22%), intermediate (31%), and adverse risk (48%). One-third underwent allogeneic transplantation in the first complete remission. Variable selection yielded 9 variables associated with 1-year OS, including relapse-free interval, age, white blood cell count, mutated TP53, FLT3 internal tandem duplication, core-binding factor abnormalities, t(v;11q23)/KMT2A rearrangement, and complex/monosomal karyotype, which were assigned points according to their estimated hazard ratios. Three prognostic groups were defined with distinct 1-year OS in both development (favorable, 51% ± 3%; intermediate, 29% ± 3%; and poor, 14% ± 2%, respectively) and validation cohorts (51% ± 4%, 26% ± 5%, and 14% ± 3%, respectively). Validation confirmed the improved accuracy in predicting outcomes for patients with AML in first relapse. The revised AML relapse model improved on previous prognostic models for outcomes after first relapse. It provides stratification that might support tailoring second line treatment
The evolution of targeted intra operative radiotherapy in early breast cancer
No full textTargeted intraoperative radiotherapy (IORT) delivers a single dose of radiation to a fresh tumour bed immediately after lumpectomy, commonly used to treat early breast cancer (EBC). It is delivered during the same sitting, with improved patient compliance and better sparing of adjacent healthy tissue, compared to conventional adjuvant radiotherapy to the whole breast. The recently published 12-year results (median follow up of 8.6 years) of the TARGIT-A trial offers reliable conclusions, of comparable oncological outcomes with a reduced toxicity profile supporting IORT as a replacement for whole breast external beam radiotherapy (EBRT) for suitable patients with EBC. Reduced need of multiple hospital visits is an added logistic advantage which makes IORT a cost-effective, less painful and cosmetically favourable alternative to standard EBRT, now included in several international guidelines with growing popularity among clinicians worldwide
APOBEC affects tumor evolution and age at onset of lung cancer in smokers
No full textMost solid tumors harbor somatic mutations attributed to off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes affect tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, multi-omics profiling of 309 lung cancers from smokers identifies two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations; HAS for A3A-like mutagenesis and TP53 mutations. Compared to LAS, HAS have older age at onset and high proportions of newly generated progenitor-like cells likely due to the combined tobacco smoking- and APOBEC3A-associated DNA damage and apoptosis. Consistently, HAS exhibit high expression of pulmonary healing signaling pathway, stemness markers, distal cell-of-origin, more neoantigens, slower clonal expansion, but no smoking-associated genomic/epigenomic changes. With validation in 184 lung tumor samples, these findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development
Prevalence and breakdown of KRAS driver mutations in a large UK non-small cell lung cancer cohort
No full textKirsten rat sarcoma viral oncogene (KRAS) is a frequently mutated oncogene in lung cancer, now amenable to targeted therapy with allele-specific G12C inhibitors. Non-small cell lung cancer (NSCLC) driver mutations show geographical variability and therefore the KRAS mutation breakdown, co-occurring oncogenic mutation rate and associated PD-L1 expression were studied in a large UK cohort. We interrogated archival clinical next-generation sequencing (NGS) data over 5 years. 3283 NSCLC samples were included, referred from 38 centres over 4 years. Somatic mutation hotspots in cancer-associated genes were analysed using ampliseq/ion-torrent based NGS assays. In a subset of the cohort, PD-L1 scores were also collated. 1118 KRAS variants were detected. Class I mutations occurred most frequently (86.94%), with KRAS G12C, G12V and G12D being most prevalent. Class II (7.96%), III (4.65%) and IV (0.45%) mutations were also detected and mutations in PIK3CA and BRAF were the most frequently observed co-mutations. No significant difference in PD-L1 expression was found between KRAS wild-type and mutant tumours
Trifluridine/tipiracil (FTD/TPI) in advanced gastric cancer-a retrospective cohort study providing real-world survival and safety data from the United Kingdom
No full textBackground: In advanced gastric adenocarcinoma (aGC), the TAGS study demonstrated a survival advantage of trifluridine/tipiracil (FTD/TPI) over placebo in >= 3rd line setting. This led to approval in the United Kingdom (UK). Clinical trial and real-world patients often differ in age, fitness and comorbidity, which has implications for safety and survival. Real-world data can inform clinical practice. This study sought to define the UK patient population who have received FTD/TPI and compare outcomes to TAGS. Methods: This was a retrospective study. Patients with aGC commenced on FTD/TPI prior to 1st February 2024 were eligible. Patients were identified from electronic health records. Data on baseline demographics and cancer outcome, including survival and toxicity, were collected. Results: Data was collected for 58 patients from 12 centres in England, Scotland and Northern Ireland. Median age was 68.5 (range, 40-85) years, 44 (75.9%) were male and 10 (17.2%), 35 (60.3%) and 13 (22.4%) were Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, and >= 2, respectively. Most primary tumours were gastroesophageal junctional (70.7%) and 24.1% were human epidermal growth factor receptor 2 (HER2) positive. FTD/TPI was given in 3rd line for 44 (75.9%) patients, 48 (82.8%) were commenced on full dose and on progression 6 (10.3%) received subsequent therapy. Median number of cycles received was 3 (range, 1-11). Median overall survival (mOS) in the whole population was 4.0 months [95% confidence interval (CI): 3.5-5.4], with mOS 5.9 vs. 4.0 vs. 2.5 months for ECOG PS 0, 1, and >= 2 respectively. On cox-regression analysis, with age, sex, ECOG PS, HER2 status, primary site and albumin as variables, ECOG PS >= 2 [hazard ratio (HR) =3.00; 95% CI: 1.07-8.35; P=0.04] and albumin >= 35 g/L (HR =0.47; 95% CI: 0.25-0.89; P=0.02) were prognostic; 29 (50%) and 16 (27.6%) patients required dose delay and reduction respectively, most commonly due to neutropenia. Grade >= 3 toxicity, attributed to FTD/TPI, was observed in 17 (29.3%) patients; 14 (82.4%) due to neutropenia and 3 (17.6%) anaemia. One (1.7%) patient stopped due to toxicity. Conclusions: We present UK real-world data regarding use of FTD/TPI for aGC. Compared to TAGS, the patient population differed and mOS was lower than the reported 5.7 months, but long-term survivors are observed. Pre-treatment ECOG PS and albumin appear prognostic. Toxicity is in line with that reported previously. Our data support the use of FTD/TPI in selected populations with aGC
Medullary carcinoma of the colon: not as favourable as previously thought?
No full textINTRODUCTION: Medullary carcinoma of the colon (MCC) is a rare, evolving subtype of colorectal cancer that is histologically and clinically distinct from poorly differentiated and undifferentiated adenocarcinoma. Comprehensive meta-analyses show that MCCs predominantly have a mismatch repair-deficient (MMRd) phenotype, which typically predicts a more favourable prognosis. CASE PRESENTATION: We present a unique case involving a male patient with an aggressive presentation of colon cancer. Histopathology supported a diagnosis of MCC, initially staged as T3N0M0. Shortly after resection, the patient presented with rapidly progressing metastatic disease involving brain and subcutaneous metastases and subsequent mortality. CONCLUSION: MCC is an understudied subpopulation of colon cancers. Historically, the presence of MMRd in early-stage colon cancer predicts a favourable prognosis and also a lack of benefit from adjuvant chemotherapy. Whether this also extrapolates to MCCs remains unclear, and as such, the case presented highlights the uncertainty in the current evidence base. Further research is warranted to help inform robust clinical management