NIHRDataInsights/HRCSData huggingface dataset:
Title: Pembrolizumab with carboplatin and paclitaxel or nab-paclitaxel for untreated metastatic squamous non-small-cell lung cancer [ID1306]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of pembrolizumab in combination with carboplatin and paclitaxel or nab-paclitaxel within its marketing authorisation for untreated metastatic squamous non-small-cell lung cancer.

Lay abstract: Lung cancer falls into two main histological categories: around 85–90% are non-small-cell lung cancers (NSCLC) and the remainder are small cell lung cancers. NSCLC can be further classified into 3 histological sub-types of large-cell undifferentiated carcinoma, squamous cell carcinoma and adenocarcinoma. Most lung cancers are diagnosed at an advanced stage, when the cancer has spread to lymph nodes and other organs in the chest (locally advanced disease; stage III) or to other parts of the body (metastatic disease; stage IV). In 2016, around 33,000 people were diagnosed with NSCLC in England.1 Around 12% had stage IIIA, 8% had stage IIIB and 53% had stage IV disease1. The prognosis for people with non-small-cell lung cancer is generally poor. For people with stage III and stage IV disease respectively, around 43% and 16% survive for 1 year or longer.1 For the majority of people with NSCLC, the aims of treatment are to prolong survival and improve quality of life. Treatment choices are influenced by the presence of biological markers (such as mutations in epidermal growth factor receptor-tyrosine kinase (EGFR-TK), anaplastic-lymphoma-kinase (ALK) or PD-L1 status), histology (squamous or non-squamous) and previous treatment experience. NICE clinical guideline 121 (CG121 ‘Lung cancer’) recommends platinumbased chemotherapy (that is, cisplatin or carboplatin and either docetaxel, gemcitabine, paclitaxel, or vinorelbine) as an option for people with previously untreated stage III or IV NSCLC and good performance status. NICE technology appraisal guidance 531 recommends pembrolizumab monotherapy as an option for untreated PD-L1-positive metastatic NSCLC if the tumour expresses PD-L1 with at least 50% tumour proportion score and has no EGFR- or ALK-positive mutations. References 1 National lung cancer audit 2017 (2018). Royal college of Physicians. Accessed May 2018.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Dacomitinib for untreated EGFR-positive non-small-cell lung cancer [ID1346]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of dacomitinib within its marketing authorisation for treating epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer that has not previously been treated.

Lay abstract: Lung cancer falls into two main histological categories: around 85–90% are non-small-cell lung cancers (NSCLC) and the remainder are small-cell lung cancers. NSCLC can be further classified into 3 histological sub-types of large-cell undifferentiated carcinoma, squamous cell carcinoma and adenocarcinoma. The majority of lung cancers are diagnosed at an advanced stage, when the cancer has spread to lymph nodes and other organs in the chest (locally advanced disease; stage III) or to other parts of the body (metastatic disease; stage IV). In 2015, around 33,000 people were estimated to be diagnosed with NSCLC in England.(1),(2) Around 12% have stage IIIA, 9% had stage IIIB and 53% had stage IV disease (1). The prognosis for people with non-small-cell lung cancer is generally poor. Between 2011 and 2015 around 39% of people with lung cancer survived for 1 year or longer and only 15% survived for 5 years or longer.(2) For the majority of people with NSCLC, the aims of therapy are to prolong survival and improve quality of life. Treatment choices may be influenced by the presence of biological markers (such as the checkpoint inhibitor programmed death-ligand 1 [PD-L1] and mutations in epidermal growth factor receptor-tyrosine kinase [EGFR-TK] or anaplastic-lymphoma-kinase [ALK], or), histology (squamous or non-squamous) and previous treatment experience. For people whose locally advanced or metastatic disease tests positive for the activating EGFR-TK mutation and who have not previously had treatment, NICE guidance recommends the tyrosine kinase inhibitors (TKI) afatinib, erlotinib and gefitinib as treatment options (NICE technology appraisal guidance 310, 258 and 192 respectively). References 1 National lung cancer audit 2016 (2017). Royal college of Physicians. Accessed October 2017. 2 Cancer survival in England: adult, stage at diagnosis and childhood-patients followed up to 2016 (2017) Office for National Statistics. Accessed October 2017

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Precision treatment planning for radioembolisation of the liver using radio-labelled microspheres
Funder: Health Education England

Abstract: Radioembolisation is a treatment to deliver radiation to liver tumours via an injection of small radioactive particles. The amount of radioactivity delivered under current practice is based on body surface area; this assumes liver size varies predictably with patient body surface area which it does not. The aim of this study is to develop precision treatment planning on a patient-by-patient basis in order to improve patient outcome. This will be carried out by developing patient imaging and dosimetry methods. In addition to this we will be investigating the potential of incorporating conventional Radiotherapy as a boost dose to tumours.

Lay abstract: Radioembolisation is a treatment to deliver radiation to liver tumours via an injection of small radioactive particles. The amount of radioactivity delivered under current practice is based on body surface area; this assumes liver size varies predictably with patient body surface area which it does not. The aim of this study is to develop precision treatment planning on a patient-by-patient basis in order to improve patient outcome. This will be carried out by developing patient imaging and dosimetry methods. In addition to this we will be investigating the potential of incorporating conventional Radiotherapy as a boost dose to tumours.

Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: LIBOR grant – National Mesothelioma Research Centre
Funder: Department of Health and Social Care

Abstract: Mesothelioma is a cancer of the linings of the lung. It is caused in the great majority of cases by past asbestos exposure. The cancer is aggressive, often producing great pain in the chest wall. It responds poorly to all therapies and the average survival from diagnosis is less than a year. The UK has the highest incidence of mesothelioma in the world. Mesothelioma results in 2,500 deaths a year in the UK, and it is estimated that there will be 60,000 to 75,000 new cases by 2050. Asbestos exposure has an equally high risk of causing lung cancer, leading to a further 2,500 deaths each year. Lung cancer itself is the major cause of cancer death in the UK. The National Centre for Mesothelioma Research (NCMR) was initiated in 2016 with a direct LIBOR grant from the Chancellor of the Exchequer, George Osborne, with additional funding from the British Lung Foundation and the Asmarley Charitable Trust. The NCMR exists as a national and international focus for excellence in research into malignant mesothelioma and lung cancers. Excellence is to be achieved in clinical and basic research. The NCMR represents a collaborative structure based on the National Heart and Lung Institute (NHLI, Imperial College London), The Royal Brompton and Royal Marsden NHS Trusts (RBHT and RMHT), and the Institute for Cancer Research (ICR). The NCMR will extend beyond these institutions to include national and international collaborators.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Integrating biomarkers to stratify adjuvant chemotherapy in pancreatic cancer patients.
Funder: North West Cancer Research

Abstract: The ESPAC-3 trial led by our group via the Liverpool Cancer Trials Unit, demonstrated similar survival benefit for 5-FU or gemcitabine in resected pancreatic cancer patients. We used Tissues Microarrays (TMAs) to show that hENT-1 expression predicted greater benfit form adjuvant gemcitabine. We have further shown that the predictive power of hENT-1 for gemcitabine can be stratified by Ribonucleotide Reductase (RRM1) and Cytosine Deaminase (CDA); and that dihydropyrimidole dehydrogenase (DPD) stratifies 5FU benefit. The ESPAC-4 trial, established the comination of gemcitabine with the 5-FU prodrug G=capecitabine (GemCap) as the standard of care for adjuvant therapy. We now aim to invetsiagte the ability of these biomarkers in stratifying patients treated with GemCap. Aims 1 Confirm that ESPAC-3 predictions apply to GemCap in ESPAC-4; 2 Test candidate biomarkers for GemCap bebefit; 3 Indetify mutations patterns in the Precision-Panc panel associated with protein/transcript biomarkers


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: NCI Health Economics Fellowship 2014: Ms Ethna McFerran
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: To enable Ms Ethna McFerran to undertake a four year PhD programme in health economics in accordance with the following timetable: Module 1 of the York summer course in Health Economics (York, UK) Molecular Prevention Course at the NCI (Bethesda, Maryland, USA) Initial meeting with NCI researchers in the US Six week thesis in a cancer health economics – related topic. Meeting with PhD programme co-ordinator in Northern Ireland. Taught programme in York. PI Workshop with NCI and Northern Ireland/Ireland mentors (Belfast/York). Thesis projects finalised and two year PhD research project under day-to-day supervision of NCI mentor (jointly with the mentor in Northern Ireland/USA – Bethesda or location of NCI Grantee). Third year of PhD research project under day-to-day supervision of mentor in Northern Ireland, jointly with the NCI mentor. PhD thesis submission (Northern Ireland)


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: CANCER AND NEOPLASMS
Title: Opportunity-Led Research Proposal: Movember / Prostate Cancer UK
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Key hypothesis: Hypothesis 1: The underlying gentic/biological basis of high-risk prostate cancer can be used to detect this clinically-significant disease at diagnosis. Hypothesis 2: Understanding the genetic and biological basis of high-risk disease will identify modulators of therapeutic response or resistance to DNA-damage therapeutics (i.e, radiotherapy for localised therapy and use of radionclide and alkylating agents for disseminated disease). Hypothesis 3: The clinical benefit of ionising radiation in localised disease, and radionuclide/alkylating agents in metastatic disease will be enhanced through combination strategies, defined by knowledge of the therapetic mechanism-of-action, and the response of the microenvironment to treatment. Objectives: 1) To improve detection of high-risk CaP and patients at increased risk-of-relapse at diagnosis 2) To improve detection of patients with localised high-risk or metastatic CaP sensitive to treatment with radiotherapy and/or conventional DNA-damage chemotherapeutics, respectively, using tissue and/or liquid biopsy samples 3) To understand the genetic and biological basis of response, resistance and/or toxicity to external beam radiotherapy (EBRT) and brachytherapy treatment for localised CaP, or DNA-damage chemotherapy in metastatis disease 4) To characterise novel biologically-based interventions that enhance therapeutic response to EBRT and brachytherapy for localised high-risk CaP or DNA-damage agents in metastatic disease 5) To understand the bio-physical parameters predicting for relapse in high-risk localised CaP 6) To understand the bio-physical mechanism-of-action of Radium-223 in ologmetastatic and overt metastatic CaP in bone marrow Use patient blood and tissue samples to develop clinically-applicable predictive biomarkers of Radium-223 sensitivity and markers to detect/monitor radionuclide response 8) To catalyse the application of scientific discovery to underpin innovatuve, personalised cancer medicine trials for DNA-damage treatments in high-risk and oligometastatic CaP


Research activity codes: 5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Opportunity Led: Dr Gillian Prue - Movember/GAP4
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Under the Global Action Plan 4 of the Movember Foundation Work Programme, the Movember Board has approved a global prostate cancer exercise and metabolic health study (GAP4 INTERVAL - MCRPC) which has been approved to run in Northern Ireland, recruiting 45 eligible men over a three-year study period. It involves a lifestyle high intensity physical activity intervention and will mainly look at better understanding the biological mechanisms of action and impact of exercise on cancer progression and treatment side effects. Movember funding will cover recruitment and other study-related costs. An exercise physiologist is needed to deliver the intervention, and this resource is not currently available within the HSC. It is therefore proposed that HSC R&D Division provides funding for this post, without which NI would be unable to participate in this global study. In addition, and in order to allow us to maximise the value of the investment in the resource, we have worked with the research team to discuss and refine their ideas around an additional piece of work, which would be a similar but parallel study involving a lower intensity exercise programme that has been developed and tested by researchers at Ulster University. This study would offer an intervention to men ineligible for the main GAP4 study due to the intensity of the GAP4 intervention, and would ensure that the benefits of a lifestyle physical activity intervention in this population are fully assessed for the first time. Any additional physiologist capacity would be utilised within standard care.


Research activity codes: 6.7 PHYSICAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: 2014 Doctoral Fellowship: Do statins improve survival in stage II and III colon cancer and does this effect differ by TP53 or KRAS gene mutation status?
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Background: Statins inhibit the mevalonate pathway, derivatives of which are important in cellular proliferation and survival. The anticancer effects of statins have been identified in-vitro but it is unclear if statins influence prognosis in colon cancer. The mevalonate pathway is up regulated in association with mutant TP53 and statins can reverse the malignant phenotype in mutant but not wild-type TP53 cancer cells in-vitro. Post-translational modification of RAS oncogenes involves the mevalonate pathway therefore KRAS mutant tumours may be more susceptible to statin induced inhibition of RAS signalling. Mutant TP53 and KRAS may therefore represent novel biomarkers that could differentiate statin sensitive tumours. Aim: To analyse the association between statin use, molecular biomarkers and colon cancer survival. Methods: Individual systematic reviews and meta-analyses will be performed examining the association between statin use, TP53 mutations, KRAS mutations, and colon cancer survival. In a primary population-based study, all stage II and III colon cancer patients diagnosed in Northern Ireland (NI) between 2004-2008 will be followed up for at least 5 years using linkage to the NI Cancer Registry and Clinical Oncology Information System. Tumour blocks will be retrieved via the NI Biobank allowing TP53 and KRAS mutation status to be determined. Survival analysis techniques will be utilised to investigate the association between statin use, these potential biomarkers and their interaction, and colon cancer specific survival. Implication: Clarification of the association between statin use, TP53 and KRAS mutation status, and colon cancer progression may assist in the development of targeted colon cancer treatment strategies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: 2014 Doctoral Fellowship: Exploring the role of naturally occurring prostate calcifications as an alternative to surgically implanted fiducial markers for Image guided radiotherapy
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Advanced prostate radiotherapy techniques (e.g. Image guided radiotherapy (IGRT) and Stereotactic) have facilitated the reduction of planning margins and dose escalation studies, which demonstrate a correlation of increased dose with disease free survival. (1-4) Dose escalation is limited by uncertainties in treatment set-up and organ motion which are encompassed by margins added during planning.(5,6) Despite these advances the prostate gland can be difficult to visualise using 2D or 3D IGRT, including Cone Beam Computed Tomography (CBCT).(8) Bones are often used as a surrogate for the position of the prostate gland. However it is widely accepted that the position of the prostate is not fixed in relation to bony landmarks due to variations in bladder/rectal filling and movement of the prostate itself. (9-10). One IGRT strategy involves fiducial markers surgically implanted into the prostate (11) which allow more accurate verification of its position and is widely reported. (12-17) This is an invasive surgical procedure and carries associated risks and costs. It has been reported that 35% of prostate patients treated with radiotherapy have well defined naturally occurring prostate calcifications visible on CBCT images and potentially suitable for IGRT. However data on their potential role in IGRT is limited (20-22). This project will investigate the role of natural prostate calcifications as alternative to surgically implanted fiducial markers in kV CBCT IGRT and define clinical and imaging protocols.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: 2015 Doctoral Fellowship: Identification of Targetable Mediators of Resistance to Neo-Adjuvant Chemotherapy in Oesophageal Adenocarcinoma
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Background: The incidence of oesophageal adenocarcinoma (OAC) in men in the UK has risen 50% in the last 25 years. The five year survival rate is less than 17% and even in early stage loco-regional confined disease this figure lies between 25-35%. There are pressing needs to identify biomarkers capable of predicting response to allow accurate treatment selection and to increase our understanding of the underlying mechanisms of chemotherapy resistance. Materials: We have collected 365 FFPE pre-treatment endoscopic biopsy specimens from early stage OAC patients treated with cisplatin-based neo-adjuvant chemotherapy followed by surgical resection between 2004 and 2012 at 4 centres across the UK (177 NI, 188 GB). Full clinical and response annotation are available for all cases, providing a unique dataset for biology discovery. Methodology: Transcriptional gene expression profiling (Almac Diagnostics Xcel array™) and next generation sequencing data (Ion Torrent Ampliseq™/Whole genome sequencing) are available for this patient cohort. We will discover the underlying biology of a resistance to chemotherapy in early stage OAC and pathway analysis of the microarray data will be carried out using Gene Set Enrichment Analysis (GSEA) and DAVID. We will identify pathways and genes governing both metabolic and histopathological response in early stage OAC to reveal novel drug targets, which will be extensively validated and subjected to mechanistic analysis. Conclusion: Through the application of our unique gene expression and sequencing dataset we will identify targetable mediators of drug resistance in early stage OAC and expand treatment options in this poor prognosis disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: 2016 Doctoral Fellowship: The development of early warning diagnostic and treatment response markers of Non-Uterine Pelvic High Grade Serous Carcinomas (HGSCs)
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: High Grade Serous Carcinomas (HGSCs) constitute the most common type of gynaecological cancer and differ from Low Grade Serous Carcinomas (LGSCs) in underlying pathogenesis, molecular events, behaviour and prognosis. HGSC has a worse prognosis compared to LGSC and is usually detected as stage 3 or 4 metastatic disease. HGSCs strongly associate with defects in the familial breast/ovarian cancer genes BRCA1 and BRCA2 and show an exceedingly high rate of p53 mutations (>95%). There is increasing evidence to suggest that HGSCs actually arise from the distal fallopian tube (FT) with the proposed precursor lesion being serous tubal intraepithelial carcinoma (STIC). We have demonstrated through microarray profiling and unsupervised clustering analyses that highly similar biology exists between STIC and matched HGSCs, compared to matched ovarian surface epithelium samples, confirming this hypothesis. Indeed, methylation arrays performed on the same cases show that there are also methylation events occurring in early disease (STIC) which are maintained or increased in the resultant HGSCs. We believe that early detection of HGSCs would be of great importance in helping to improve the overall treatment of this disease, in particular for high-risk (BRCA1/BRCA2) carriers. Currently BRCA carriers have very limited options for disease management and many elect to undergo prophylactic surgeries upon completion of their families, often in their mid-thirties/early-forties. Using differential genelists from our microarray experiments we have identified and validated (RqPCR both in cell lines and primary tissue and ELISA in sera) a number of secreted protein markers show promising differentials between non-cancer control and HGSC patients. We will further validate secreted protein markers and develop assays to measure methylation of genomic regions, allowing us to also measure differential methylation events occurring in circulating tumour DNA in sera. These combined early warning biomarkers could represent useful tools in the clinical management of HGSC in high-risk women.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS