Experimental Cancer Medicine Centre Research Articles

Modeling the relative influence of socio-demographic variables on post-acute COVID-19 quality of life.

Post-acute sequelae of SARS-CoV-2, referred to as "long COVID", are a globally pervasive threat. While their many clinical determinants are commonly considered, their plausible social correlates are often overlooked. To compare social and clinical predictors of differences in quality of life (QoL) with long COVID. Additionally, to measure how much adjusted associations between social factors and long COVID-associated quality of life are unexplained by important clinical intermediates. Data from the ISARIC long COVID multi-country prospective cohort study. Subjects from Norway, the United Kingdom (UK), and Russia, aged 16 and above, with confirmed acute SARS-CoV-2 infection reporting >= 1 long COVID-associated symptoms 1+ month following infection. The social exposures considered were educational attainment (Norway), employment status (UK and Russia), and female vs male sex (all countries). Quality of life-adjusted days, or QALDs, with long COVID. This cohort study included a total of 3891 participants. In all three countries, educational attainment, employment status, and female sex were important predictors of long COVID QALDs. Furthermore, a majority of the estimated relationships between each of these social correlates and long COVID QALDs could not be attributed to key long COVID-predicting comorbidities. In Norway, 90% (95% CI: 77%, 100%) of the adjusted association between the top two quintiles of educational attainment and long COVID QALDs was not explained by clinical intermediates. The same was true for 86% (73%, 100%) and 93% (80%,100%) of the adjusted associations between full-time employment and long COVID QALDs in the United Kingdom (UK) and Russia. Additionally, 77% (46%,100%) and 73% (52%, 94%) of the adjusted associations between female sex and long COVID QALDs in Norway and the UK were unexplained by the clinical mediators. This study highlights the role of socio-economic status indicators and female sex, in line with or beyond commonly cited clinical conditions, as predictors of long COVID-associated QoL, and further reveal that other (non-clinical) mechanisms likely drive their observed relationships. Our findings point to the importance of COVID interventions which go further than an exclusive focus on comorbidity management in order to help redress inequalities in experiences with this chronic disease.

Social determinants of health inequalities in early phase clinical trials in Northern England

BackgroundEarly phase clinical trials in Oncology represent a subspecialised area where UK patient selection is influenced by access to Experimental Cancer Medicine Centres (ECMCs). Equity of access with respect to social determinants of health (SDoH) were explored for two major ECMCs.MethodsA retrospective cohort study including all referrals to Newcastle and Manchester ECMCs in 2021 was completed. Consent to screening or pre-screening was stratified against SDoH characteristics, including: Index of Multiple Deprivation (IMD) decile, ethnicity and distance to centre.Results1243 patients were referred for trials. IMD quintile 1 (most deprived) patients had reduced likelihood of referral compared to expected population models (OR, 0.67; 95% CI: 0.55 to 0.80, p = <0.0001). IMD quintile 5 (least deprived) had increased likelihood of referral (OR, 1.46; 95% CI: 1.17 to 1.82, p = 0.0007). Living beyond median distance from Manchester reduced the likelihood of consenting to trials (OR, 0.72; 95% CI: 0.55 to 0.94, p = 0.015). Ethnicity data represented a White British propensity.ConclusionsInequalities in socioeconomic and geographic factors influence referral and enrolment to early phase clinical trials in Northern England. This has implications for equity of access and generalisability of trial results internationally and warrants further study.

Hospital Factors Influencing the Mobility of Patients for Systemic Therapies in Breast and Bowel Cancer in the Metastatic Setting: A National Population-based Evaluation

AimsThis national study investigated hospital quality and patient factors associated with treatment location for systemic anticancer treatment (SACT) in patients with metastatic cancers. Materials and methodsUsing linked administrative datasets from the English NHS, we identified all patients diagnosed with metastatic breast and bowel cancer between 1 January 2016 and 31 December 2018, who subsequently received SACT within 4 months from diagnosis. The extent to which patients bypassed their nearest hospital was investigated using a geographic information system (ArcGIS). Conditional logistic regression models were used to estimate the impact of travel time, hospital quality and patient characteristics on where patients underwent SACT. Results541 of 2,364 women (22.9%) diagnosed with metastatic breast cancer, and 2,809 of 10,050 (28.0%) patients diagnosed with metastatic bowel cancer bypassed their nearest hospital providing SACT. There was a strong preference for receiving treatment at hospitals near where patients lived (p < 0.001). However, patients who were younger (p = 0.043 for breast cancer; p < 0.001 for bowel cancer) or from rural areas (p = 0.001 for breast cancer; p < 0.001 for bowel cancer) were more likely to travel to more distant hospitals. Patients diagnosed with rectal cancer were more likely to travel further for SACT than patients with colon cancer (p = 0.002). Patients were more likely to travel to comprehensive cancer centres (p = 0.019 for bowel cancer) and designated Experimental Cancer Medicine Centres (ECMCs) although the latter association was not significant. Patients were less likely to receive SACT in hospitals with the highest readmission rates (p = 0.046 for bowel cancer). ConclusionPatients with metastatic cancer receiving primary SACT are prepared to travel to alternative more distant hospitals for treatment with a preference for larger comprehensive centres providing multimodal care or hospitals which offer early phase cancer clinical trials.

Prevalence of mutations in common tumour types in Northern England and comparable utility of national and international Trial Finders

PurposeTumour genomic profiling is of increasing importance in early phase trials to match patients to targeted therapeutics. Mutations vary by demographic group; however, regional differences are not characterised. This was investigated by comparing mutation prevalence for common cancers presenting to Newcastle Experimental Cancer Medicine Centre (ECMC) to The Cancer Genome Atlas (TCGA) and utility of trial matching modalities.MethodsDetailed clinicogenomic data were obtained for patients presenting September 2017–December 2020. Prevalence of mutations in lung, colorectal, breast and prostate cancer was compared to TCGA GDC Data Portal. Experimental Cancer (EC) Trial Finder utility in matching trials was compared to a Molecular Tumour Board (MTB) and commercial sequencing reports.ResultsOf 311 patients with advanced cancer, this consisted of lung (n = 131, 42.1%), colorectal (n = 44, 14.1%), breast (n = 36, 11.6%) and prostate (n = 18, 5.6%). More than one mutation was identified in the majority (n = 260, 84%). Significant prevalence differences compared to TCGA were identified, including a high prevalence of EGFR in lung (P = 0.001); RB1 in breast (P = 0.0002); and multiple mutations in prostate cancer. EC Trial Finder demonstrated significantly different utility than sequencing reports in identifying trials (P = 0.007).ConclusionsRegional differences in mutations may exist with advanced stage accounting for prevalence of specific mutations. A national Trial Finder shows utility in finding targeted trials whilst commercial sequencing reports may over-report ‘actionable’ mutations. Understanding local prevalence and trial availability could increase enrolment onto matched early phase trials.

A phase I/II study of the CXCR2 inhibitor, AZD5069, in combination with durvalumab, in patients (pts) with advanced hepatocellular carcinoma (HCC).

TPS631 Background: HCC is increasing rapidly in incidence worldwide driven by a rise in chronic liver disease including non-alcoholic steato-hepatitis (NASH). Most pts are not suitable for curative or loco-regional treatments and may be candidates for systemic therapies. Immune checkpoint inhibitors combined with VEGF inhibition is a standard of care in HCC. However, a meta-analysis of 3 phase III randomised trials of PD-1 or PDL-1 inhibitors (n &gt; 1,600 pts) with HCC suggests that pts with NASH-related HCC treated with PD-1/PDL-1 inhibitors had reduced overall survival compared with other aetiologies. Neutrophils expressing the chemokine receptor CXCR2, crucial to neutrophil recruitment in acute-injury, are highly represented in NASH-HCC. In NASH-HCC murine models, lacking response to immune-checkpoint inhibitors, AZD5069 (CXCR2 inhibitor) in combination with anti-PDL-1 suppressed tumor burden and extended survival, accompanied by an increase in tumor-associated neutrophils which switched from a pro-tumor to anti-tumor progenitor-like neutrophil phenotype. We propose that inhibition of CXCR2 may potentiate the efficacy of anti-PDL-1 inhibition in pts with HCC. Methods: In this multi-centre (n = 10) study, pts with biopsy-confirmed HCC, PS ECOG &lt; 1, Child-Pugh A, &lt; 1 prior systemic therapies, receive 1 of escalating doses of AZD5069 (bid, po daily) with Durvalumab (1.5 gm iv on day 1) in 28-day cycles for up to 2 years to determine the recommended phase II dose using a Keyboard design, followed by an additional cohort of pts to determine the anti-tumor efficacy of this combination using a Simon’s two-stage design (min 18, max 35 pts; target objective response rate &gt; 30%; unacceptable response rate &lt; 10%). Dose limiting toxicities (DLTs) are assessed during cycle 1. Disease assessments are performed 8-weekly (12-weekly after 1 year). The 1st dose cohort has been completed with no DLTs. The 2nd dose cohort opened to recruitment in September 2022. Exploratory studies (blood; pre- &amp; on-treatment tumor and non-malignant liver biopsies) include biomarkers of CXCR2 inhibition (blood); proof-of-mechanism (tumor: expression of CXCR2, PD-L1, PD-1, CD8, CD4, CD66b, CD69); proof-of-mechanism (blood: ctDNA); drug-induced changes of mRNA expression, CXCR2 ligands &amp; signalling pathway genes, T-cell and myeloid cell pathways, neutrophil-associated genes; predictive biomarkers (blood and tumour) include biomarkers of the CXCR2/PD-L1 immune axis; aberrant CXCR2 signalling pathways; proliferation biomarkers and CD10 (neutrophils), CD68 (macrophages), CD103 (T-regs); tumour mutational status. This study is funded by a grant from Cancer Research UK (A29287) and is co-sponsored by University of Glasgow and NHS Greater Glasgow &amp; Clyde. Study sites are supported by the Experimental Cancer Medicine Centre Network. AZD5069 and Durvalumab are provided by Astra Zeneca. Clinical trial information: 2020-003346-36 .

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination.

Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p<0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p<0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p<0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p=0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R=0.05, p=0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript.

An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients.

Whilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings. Here, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. Our analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61-0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population. Although clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome. Bronner P. Gonçalves, Peter Horby, Gail Carson, Piero L. Olliaro, Valeria Balan, Barbara Wanjiru Citarella, and research costs were supported by the UK Foreign, Commonwealth and Development Office (FCDO) and Wellcome [215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z]; and Janice Caoili and Madiha Hashmi were supported by the UK FCDO and Wellcome [222048/Z/20/Z]. Peter Horby, Gail Carson, Piero L. Olliaro, Kalynn Kennon and Joaquin Baruch were supported by the Bill & Melinda Gates Foundation [OPP1209135]; Laura Merson was supported by University of Oxford's COVID-19 Research Response Fund - with thanks to its donors for their philanthropic support. Matthew Hall was supported by a Li Ka Shing Foundation award to Christophe Fraser. Moritz U.G. Kraemer was supported by the Branco Weiss Fellowship, Google.org, the Oxford Martin School, the Rockefeller Foundation, and the European Union Horizon 2020 project MOOD (#874850). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. Contributions from Srinivas Murthy, Asgar Rishu, Rob Fowler, James Joshua Douglas, François Martin Carrier were supported by CIHR Coronavirus Rapid Research Funding Opportunity OV2170359 and coordinated out of Sunnybrook Research Institute. Contributions from Evert-Jan Wils and David S.Y. Ong were supported by a grant from foundation Bevordering Onderzoek Franciscus; and Andrea Angheben by the Italian Ministry of Health "Fondi Ricerca corrente-L1P6" to IRCCS Ospedale Sacro Cuore-Don Calabria. The data contributions of J.Kenneth Baillie, Malcolm G. Semple, and Ewen M. Harrison were supported by grants from the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059), and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE) (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award IS-BRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support. All funders of the ISARIC Clinical Characterisation Group are listed in the appendix.

Evaluation of an automated artificial intelligence (AI)/ natural language processing (NLP) engine to match patients (pts) with advanced solid cancers to biomarker-driven early phase (EP) clinical trials.

e13513 Background: The increasing complexity of precision medicine in oncology creates significant challenges in identification of pts for biomarker-driven clinical trials. Worldwide expansion of genomic testing will identify more pts with potentially actionable alterations, but the manual task of matching pts to clinical trials requires laborious interpretation of fragmented medical information and knowledge of suitable trial eligibility criteria. Inspirata’s Trial Navigator (TN) solution uses AI and NLP to automatically extract relevant information from both patient medical records and trial protocols to identify appropriate trials. We conducted a retrospective study to evaluate the ability of TN to match pts referred to the Guy’s Hospital EP trials unit. Methods: Anonymised referral letters and genomic reports for pts referred from Jan 2019 to Dec 2020 were used. A subset was used to train TN to extract relevant variables for matching against eligibility criteria for all UK Experimental Cancer Medicine Centre (ECMC) Network trials open within 160 km of Guy’s Hospital at the time of referral, favouring biomarker-matched studies. Finally, TN was tasked with finding 5 ECMC trial matches for 40 referred pts. Matches were scored for eligibility and tumour and/ or biomarker suitability using a quality index (QI): 0, ineligible; 1, generic match; 2, tumour match; 3, biomarker match; 4, tumour and biomarker match. Results: Of 40 pts, most common tumour groups included gastrointestinal (55%), HNSCC (20%) and gynae (10%). TN was able to correctly identify at least 1 suitable trial (median = 4) for 39/40 pts (97%). Selection biomarkers were available for 27 pts, of whom 21 (78%) were matched to at least one appropriate biomarker-directed trial, 5 (12%) were matched to biomarker-agnostic trials and one was not correctly matched due to exclusion for progressive CNS metastases. Of 13 pts without biomarker information, 11 (84%) were matched to at least 1 tumour-appropriate trial and 2 to tumour-agnostic trials. Of all 200 trial matches, 134 (67%) were appropriately matched, of which 80 (59%) were external to Guy’s Cancer centre. Conclusions: TN successfully matched 90% of these preselected cancer pts to an appropriate biomarker- or tumour-directed trial, indicating potential to improve access and recruitment to early phase cancer trials, including those external to the primary treating site with which referrers may not be familiar. A prospective multicentre evaluation of TN is warranted to further define improvements in trial recruitment and efficiency.[Table: see text]

TARGET National: A U.K.-wide liquid-based molecular profiling program to enhance recruitment to early-phase trials.

TPS3163 Background: Precision medicine programs have largely focused on tissue-based assays to screen patients for genomic variants amenable to experimental targeted therapies. Challenges faced in such studies include time taken to acquire archival biopsies and limitation in capturing tumor heterogeneity and clonal evolution. The TARGET study (Rothwell, Nature Medicine 2019) previously demonstrated feasibility of using ctDNA to match patients to early phase trials with the benefit of rapid turnaround of results. With an ever-increasing number of novel therapies in development targeting rare genomic alterations across different tumor types, ctDNA holds great promise in enhancing recruitment to studies with rapid and efficient comprehensive genomic profiling assays covering a broad range of variants. There is need to perform profiling at scale to identify rare alterations and to utilise networks for identification of suitable clinical trials across the country. ctDNA is not detectable in all patients (owing to differences across disease types/ burden), thus tissue analysis still plays an important role. Methods: TARGET National is an investigator-initiated multi-centre molecular profiling study. The primary endpoints are to establish a national framework to offer profiling from blood samples (or tissue if appropriate) for patients being considered for early phase clinical trials across the UK Experimental Cancer Medicine Centre (ECMC) Network, and to measure the number of patients receiving matched therapy (MT). Secondary endpoints include curating the genomic landscape of the early phase population in the UK, and outcomes for patients receiving MT versus unmatched. Enrolment began in July 2021 and &gt;250 patients have been recruited across 9 ECMCs with plans to expand to 20 centres by Q3 2022. Planned enrolment is 6000 patients over 5 years. Patients must be ≥ 16 years old, provide written consent, have histologically confirmed advanced solid cancer, progressing disease and be considered fit enough to receive an experimental therapy. ctDNA is analysed with Foundation Medicine Liquid CDx with option for other providers. A multi-disciplinary national Molecular Tumor Board enables interpretation of genomic reports and identifies suitable clinical trials, supported by eTARGET; a bespoke clinical-genomic data capture solution including trial finding software. The study provides broad access to genomic profiling throughout the UK, increasing experience with ctDNA assays, and will improve opportunities for patients to participate in early phase research. The UK database will provide means for identification of rare genomic patient groups for new first-in-human studies, and the program provides a national infrastructure to collect additional samples for translational research and pre-clinical models to progress understanding of biological predictors of response and resistance. Clinical trial information: NCT04723316.

47P Prevalence of mutations in common tumour types in Northern England and utility of Experimental Cancer Medicine Centre (ECMC) CRUK Trial Finder

Genomic profiling of tumours has expanded rapidly, and is of increasing importance in early phase trial units in matching patients to targeted clinical trials. It is recognised that mutational signatures vary by demographic group, however, regional differences are not yet characterised. This was investigated by comparing relative prevalence of mutations for common cancers presenting to Newcastle ECMC to The Cancer Genome Atlas (TCGA) and comparative utility of trial matching modalities within and outside the UK.

The UpSMART Accelerator: driving digital innovation to change the conduct of early phase cancer medicine trials

Digitalizing clinical trials provide an opportunity to address challenges faced in the Phase I trial settings, where near real-time data capture and data interpretation are prerequisites for iterative decision-making to rapidly adapt trial designs based on emerging insights. Although digital technologies have driven significant improvements in many businesses and organizations, the adoption of digital technologies in clinical trials has been slow. In recognition of this lag, the UpSMART consortium, a 5-year funded program (2020-2024), has been established in Europe between the UK, Spain, and Italy to embrace digital technologies and drive benefits to patients. The consortium, led by the Cancer Research UK Manchester Institute Cancer Biomarker Centre, aims to ’digitalize’ Experimental Cancer Medicine Centres in the UK and Early Drug Development Units in Spain and Italy by open-sourcing and sharing digital healthcare products between participating centers across the consortium. The goal is to optimize data capture and interpretation thus accelerating Phase I clinical research to ultimately benefit patients by allowing faster access to tomorrow’s medicines.

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Targeting cancer associated fibroblasts to enhance immunotherapy: emerging strategies and future perspectives.

Cancer associated fibroblasts are a prominent component of the tumour microenvironment in most solid cancers. This heterogeneous population of cells are known to play an important role in tumour progression and recent studies have demonstrated that CAFs may confer resistance to checkpoint immunotherapy, suggesting that targeting these cells could improve response rates. However, effective clinical strategies for CAF targeting have yet to be identified. In this editorial, we highlight current limitations in our understanding of CAF heterogeneity, and discuss the potential and possible approaches for CAF-directed therapy.

The Utility of a Methylation Panel in the Assessment of Clinical Response to Radiofrequency Ablation for Barrett's Esophagus

Background: Radiofrequency ablation (RFA) is an effective treatment for dysplastic Barrett’s esophagus (BE), but recurrence can occur after initial response. Currently there is uncertainty about how to best define histological remission. A DNA methylation panel on esophageal samples was previously shown to have high diagnostic accuracy for BE. We aimed to investigate this biomarker panel in the assessment of response to RFA treatment. Methods: We retrospectively analyzed esophageal and gastroesophageal junction (GEJ) biopsies from patients with BE before and after RFA treatment. We quantified the extent of intestinal metaplasia (IM) based on number of glands with goblet cells (IM-Score) and expression of the intestinal factor trefoil factor-3 (TFF3-Score). Promoter methylation of 3 genes (ZNF345, TFP12, ZNF569) was measured by methylight (Meth-Score) throughout the RFA treatment pathway. Findings: We included 45 patients (11 non-dysplastic BE, 14 low-grade dysplasia, 20 high-grade dysplasia/intramucosal cancer). Meth-Scores were significantly higher in BE with and without dysplasia and GEJ with IM compared to GEJ without IM (P <·001). Meth-scores significantly correlated with the extent of IM at the GEJ measured both with IM-Scores (rho=66·0%, P<·001), and TFF3-Scores (rho=75·6%, P<·001). In patients with residual IM at the GEJ, RFA re-treatment brought about a 7·6-fold reduction in the methylation levels. The Meth-score had an area under the ROC curve of 95·1% (95%CI 91·1% - 99·1%) differentiating BE from normal GEJ. Interpretation: A DNA methylation panel can discriminate between the extent of histological IM in esophageal and junctional biopsies and could be used to objectively quantify residual disease following RFA. Funding Statement: This study was funded by a Medical Research Council core grant to RCF. WJ was funded by a Cancer Research UK multidisciplinary award (C47594/A21202). We would like to acknowledge clinical research infrastructure support from the Experimental Cancer Medicine Centre and the Cambridge Biomedical Research Centre. The funding bodies had no role in study design, patient recruitment, data collection, data analysis, data interpretation, writing of the manuscript or any other aspect pertinent to the study. Declaration of Interests: All of the authors disclose no conflict of interest. Ethics Approval Statement: The study was approved by the ethics committee at the local institution (LREC01/149). Informed consent for biomarker analysis was obtained from each patient before endoscopic treatment.

Aneuploidy in Targeted Endoscopic Biopsies Outperforms Other Tissue Biomarkers in the Prediction of Histologic Progression of Barrett's Oesophagus: A Multi-Centre Prospective Cohort Study

Introduction: The cancer risk in Barrett’s oesophagus (BO) is difficult to estimate. Confirmed histologic dysplasia has strong predictive power, but can be missed by random biopsies, while other clinical parameters have limited utility for risk stratification. We aimed to assess the utility of a large panel of molecular biomarkers on targeted biopsies to predict neoplastic progression of BO. Methods: In a prospective study in three tertiary centres, 203 patients with BO were tested for 9 biomarkers (p53 and cyclin A expression; aneuploidy and tetraploidy; CDKN2A (encoding for p16), RUNX3 and HPP1 hypermethylation; 9p and 17p loss of heterozygosity) on autofluorescence-targeted biopsies taken at index endoscopy and followed-up as per clinical standard. Data comparing progressors to non-progressors were evaluated by univariate and multivariate analyses using survival curves, Cox-proportional hazards and logistic regression models. Findings: 127 patients with no high-grade dysplasia (HGD) or early oesophageal adenocarcinoma (OAC) were included, of which 42 had evidence of any histologic progression over time. Aneuploidy was the only predictor of progression from non-dysplastic BO (NDBO) to any grade of neoplasia (p=0.013) and HGD/OAC (p=0.002). Aberrant p53 expression correlated with the risk of short-term progression within 12 months, with an odds ratio for histologically missed dysplasia of 6.0 (95% CI: 3.1-11.2). A biomarker panel comprising aneuploidy and p53 had an area under the ROC curve of 0.68 (95% CI: 0.59-0.77) for prediction of any histologic progression. Interpretation: In our study, aneuploidy is the only biomarker that predicts neoplastic progression of NDBO. Aberrant p53 expression suggests prevalent dysplasia, which might have been missed by random biopsies, and warrants early follow up. Funding Statement: This study was funded by a Medical Research Council Program Grant to RCF and by a Lister Institute for Preventive Medicine prize to RCF, with additional clinical research infrastructure support from the Experimental Cancer Medicine Centre and the Cambridge Biomedical Research Centre. Declaration of Interests: KR reports grants, personal fees and non-financial support from Olympus, outside the submitted work. JJGHMB reports grants from Olympus Endoscopy, outside the submitted work. Other authors declare no conflicts of interest. Ethics Approval Statement: This was a prospective study approved by the Cambridgeshire 2 Research Ethics Committee (09/H0308/118) and the Amsterdam University Medical Centre (AUMC) Medical Ethics Committee (MEC 09/073). This was a National Institute of Health research (NIHR) portfolio study (UKCRN ID 7561).

Histological Subtypes and Response to PD-1/PD-L1 Blockade in Advanced Urothelial Cancer: A Retrospective Study.

Urinary tract cancer can be pure urothelial carcinoma, pure nonurothelial carcinoma or variant urothelial carcinoma (defined here as mixed urothelial carcinoma). Little is known regarding outcomes for patients with variant urothelial carcinoma receiving immune checkpoint inhibitors. We hypothesized that variant urothelial carcinoma does not compromise immune checkpoint inhibitor efficacy in patients with advanced urothelial carcinoma. We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathological, treatment and outcomes data were collected for patients with advanced urothelial carcinoma who received immune checkpoint inhibitors. Patients were divided into pure vs variant urothelial carcinoma subgroups, with variant urothelial carcinoma further divided by type of variant (ie squamous, neuroendocrine etc). We compared overall response rate using univariate and multivariate logistic regression and progression-free survival and overall survival using Kaplan-Meier and univariate and multivariate Cox proportional hazards. Overall 519 patients were identified, with 395, 406 and 403 included in overall response rate, overall survival and progression-free survival analyses, respectively. Overall response rate to immune checkpoint inhibitors between patients with pure vs variant urothelial carcinoma was comparable (28% vs 29%, p=0.90) without significant differences for individual subtypes vs pure urothelial carcinoma. Median overall survival for patients with pure urothelial carcinoma was 11.0 months vs 10.1 months for variant urothelial carcinoma (p=0.60), but only 4.6 months for patients with neuroendocrine features (9 patients, HR 2.75, 95% CI 1.40-5.40 vs pure urothelial carcinoma, p=0.003). Median progression-free survival was 4.1 months for pure vs 5.2 months for variant urothelial carcinoma (p=0.43) and 3.7 months for neuroendocrine features (HR 1.87, 95% CI 0.92-3.79 vs pure urothelial carcinoma, p=0.09). Overall response rate to immune checkpoint inhibitors was comparable across histological types. However, overall survival was worse for patients with tumors containing neuroendocrine features. Variant urothelial carcinoma should not exclude patients from receiving immune checkpoint inhibitors.

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Using single cell data to validate the cellular origins of a clonal expression biomarker in lung cancer

Abstract Background Molecular biomarkers aim to stratify cancer patients into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumour stage. Transcriptomic intra-tumour heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types. Methods Here, we analyse multi-region whole-exome and RNA sequencing data for 156 tumour regions from 48 TRACERx patients to explore and control for RNA-ITH in non-small cell lung cancer (NSCLC). Results We find that chromosomal instability (CIN) is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumour sampling bias. To address this, we identify genes expressed homogeneously within individual tumours that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumour evolution. Leveraging single-cell data, we examine the origins of the expression signals, and relate our findings to published biological and clinical gene expression signatures. Conclusions Clonal transcriptomic biomarkers overcome tumour sampling bias, associate with survival independently of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types. Clinical trial identification NCT0188860. Legal entity responsible for the study University College London (UCL/12/0279) and has been approved by an independent Research Ethics Committee (13/LO/1546). Funding Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202), and the Wellcome Trust (FC001169, FC001202). The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), ERC Advanced Grant (PROTEUS) has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 835297), Chromavision – this project has received funding from the European’s Union Horizon 2020 research and innovation programme (grant agreement No. 665233). Disclosure D. Biswas: Non-remunerated activity/ies, patent co-inventor: CRUK; Studentship: Jean Shanks Foundation MBPhD; Funding (self): MBPhD programme at University College London; Funding (institution): the NIHR BRC at University College London Hospitals. N.J. Birkbak: Non-remunerated activity/ies, patent co-inventor: CRUK; Fellow: Lundbeck Foundation; Funding (self): the Aarhus University Research Foundation; Funding (institution): Danish Cancer Society. N. McGranahan: Non-remunerated activity/ies, patent co-inventor: CRUK. Fellow: Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z); Funding (institution): CRUK, Rosetrees, the NIHR BRC at University College London Hospitals. C. Swanton: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Ventana; Advisory / Consultancy: Novartis; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Illumina; Advisory / Consultancy: Genentech; Advisory / Consultancy, Shareholder / Stockholder / Stock options: GRAIL; Advisory / Consultancy: Medicxi; Advisory / Consultancy: Sarah Cannon Research Institute; Advisory / Consultancy: Dynamo Therapeutics; Shareholder / Stockholder / Stock options: ApoGen Biotechnologies; Shareholder / Stockholder / Stock options: Epic Bioscience; Shareholder / Stockholder / Stock options: Achilles Therapeutics. Funding (institution) Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation (BCRF), National Institute for Health Research, the University College London Hospitals Biomedical Research Centre, and the Cancer Research UK University College London Experimental Cancer Medicine Centre.

LBA73 - SELPAC: A 3 arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel (PT) in metastatic uveal melanoma (UM)

LBA73 - SELPAC: A 3 arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel (PT) in metastatic uveal melanoma (UM)

1834P - Filling the gaps in informed consent for advanced cancer patients considering phase I oncology trials: An in-depth qualitative study of key stakeholders at a large United Kingdom phase I unit

BackgroundExtensive research has demonstrated that patients considering early phase oncology trials do not appreciate the design or purpose of these trials and also harbour unrealistic expectations of the personal benefit they can expect from the trial. There have been few interventional studies examining the informed consent process in this setting and they have shown limited effectiveness. We aimed to use a qualitative methodology to understand the perspectives of key stakeholders and identify the areas of need and the potential opportunities for an intervention to improve our informed consent processes. MethodsWe used an experience-based co-design framework which consisted of a semi-structured interview script of ten key questions. Two trained interviewers performed interviews of three consultant medical oncologists, nine clinical fellows, two study managers, two clinical nurse specialists, two focus groups with four patients each and two regulatory officers. We also interviewed four members of our investigator-initiated sponsor team to obtain an understanding of the sponsor perspective. All audio interviews were transcribed, and thematic analysis was performed on the narrative text to extract core themes. ResultsConsistent themes raised by participants included 1. The core elements that participants need to comprehend prior to consenting are that trials are experiments and not treatment, the low prospect of benefit, potential toxicity and the significant time commitment. 2. Participant information sheets (PIS) are too long, too complex and the information is not provided in a patient centred manner. Sponsors were in strong support of shorter and more accessible PIS. 3. Digital media would be acceptable and useful but to be mindful of subgroups of patients who are not as comfortable with digital media. ConclusionsThere is widespread understanding that improvement is required in the length, design and style of participant information sheets for phase 1 oncology trials. Furthermore, digital media would be acceptable to all stakeholders but its development will require ongoing stakeholder engagement to ensure user acceptability. Legal entity responsible for the studyDrug Development Unit - Royal Marsden Hospital, Sutton. FundingCancer Research UK (CRUK), Experimental Cancer Medicine Centres (ECMC), National Institute of Health Research (NIHR) Royal Marsden Biomedical Research Centre. DisclosureJ. Lopez: Advisory / Consultancy: Genmab; Advisory / Consultancy: Novartis; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Basilea; Travel / Accommodation / Expenses: Basilea; Travel / Accommodation / Expenses: Roche/Genentech. All other authors have declared no conflicts of interest.