NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/14/032 IDRIS: Phase III randomised trial of immunomodulatory therapy in high risk solitary bone plasmacytoma
Funder: Cancer Research UK

Abstract: Solitary bone plasmacytoma (SBP) is a condition characterised by a localised proliferation of malignant plasma cells in the absence of evidence of the disease elsewhere in the body. The standard of care is involved field radical radiotherapy with curative intent. Outright cure is possible with radiotherapy, but despite radical doses approximately 50% of patients with SBP develop myeloma at a median of 21 months. SBP has a risk of progression risk to myeloma of 65–84% at 10 years and 65–100% at 15 years. Few formal studies have been carried out to assess the effectiveness of adjuvant therapy in SBP. Smouldering myeloma offers a useful parallel, as a condition with a similarly low burden of neoplastic plasma cells. A recent study by Mateos et al has shown that Lenalidomide and dexamethasone significantly increases progression-free survival in patients with high-risk smouldering myeloma compared to the standard watch and wait approach. A similar approach is proposed in this study, namely to assess the effectiveness of Lenalidomide and dexamethasone in patients with high-risk SBP, as defined by an abnormal serum free light chain ratio and aberrant plasma cell phenotype by multiparametric flow cytometry. Patients who are low risk (normal SFLC ratio at baseline and without aberrant plasma cell phenotype) will be followed up regularly but receive no further treatment. Patients who are high risk (abnormal SFLC ratio and/or aberrant plasma cell phenotype) will be randomised to receive either no further treatment or lenalidomide + dexamethasone


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/046: ROSCO - Response to Optimal Selection of neo-adjuvant Chemotherapy in Operable breast cancer
Funder: Cancer Research UK

Abstract: Background: Chemotherapy as neoadjuvant treatment facilitates less aggressive surgery. Pathological complete response (pCR) is widely used as an outcome parameter in neoadjuvant studies. The NEAT study demonstrated a 30% improvement in survival with inclusion of epirubicin as adjuvant therapy. Retrospective analysis of tumour blocks has demonstrated benefit from anthracyclines is restricted to tumours with duplication of CEP17 rather than TopoII or HER-2 amplification. Docetaxel is now routinely used for the treatment of high risk early breast cancer. Potential molecular signatures for taxane sensitivity have been inconsistent and require more evidence. Docetaxel at fully active doses is myelosuppressive and has significant other toxicities. Nanoparticle albumin bound paclitaxel (nab-paclitaxel) is used for advanced breast cancer and has the potential to outperform docetaxel both in efficacy and tolerability in early breast cancer management. The utility of a negative post neoadjuvant chemotherapy sentinel lymph node biopsy (SLNB) in women with prior biopsy proven nodal involvement has not been established. Aims: This study aims to establish the clinical utility of determining chemotherapy selection through testing for CEP17 duplication. It will also determine if nab-paclitaxel is superior to and better tolerated than docetaxel. It will also establish if post neoadjuvant chemotherapy SLNB is an accurate staging procedure in women with pre chemotherapy FNA/biopsy evidence of nodal involvement. pCR will be used as primary outcome measure. Methods: This trial will enrol women with non-luminal A cancers, that are greater than or = to 2cm or are node positive, centrally test and stratify for CEP17 duplication then randomise patients to neoadjuvant FEC or taxane/cyclophosphamide based chemotherapy. A second randomisation to taxane (docetaxel 3 weekly or nab-paclitaxel weekly) will also be performed. Surgery will be performed after 4 cycles of chemotherapy and women who do not achieve a pCR will receive an additional 4 cycles of treatment with the alternative treatment arm. Both SLNB and axillary clearance will be performed on women where node involvement was identified by fine needle aspiration or core biopsy prior to treatment. 1200 patients will be required to answer the marker directed and taxane questions. Results: The published results will inform clinicians if marker directed chemotherapy selection can improve overall pCR. Comparative data on taxanes will determine if nab-paclitaxel should replace docetaxel as the neoadjuvant taxane of choice. Data on accuracy of SNLB will determine if this is a safe form of staging post neoadjuvant chemotherapy and is thus suitable for routine practice.


Research activity codes: 6.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Cancer risk tools and their influence on clinical judgement
Funder: Cancer Research UK

Abstract: Background Cancer risk tools are algorithms that calculate the probability of a patient being diagnosed with cancer within a specific timeframe. Integrated with the electronic health record, they are operationalised in every patient consultation by generating an alert when the risk exceeds a certain threshold. There is evidence however that GPs override these alerts or notice them after they have made a management decision. Given the renewed emphasis on the earlier diagnosis of cancer, it is likely that General Practitioners will need to incorporate explicit risk estimates of cancer into their decision making. Aim To explore influences of risk scores on clinical judgements and decisions and investigate ways to optimise the presentation of risk scores. The research findings will inform future applications of risk scores, both in association with an existing diagnostic decision support system and in a generalisable way across other support systems. Methods The proposed programme of work comprises three studies. In all the studies, GPs will respond to clinical cases online. - Study 1 aims to gauge the extent to which GPs’ intuitive estimates of cancer risk differ from estimates based on a risk tool (algorithm); investigate whether GPs update their risk estimates and referral decisions after seeing the algorithm, and whether this is related to the difference between the algorithm’s estimate and their own estimate. - Study 2 aims to determine the best way for presenting the result of an algorithm, in order to increase GP commitment to its future use. - Study 3 aims to explore GPs’ gist of risk, i.e., their subjective interpretation of numerical estimates, and other gists that may influence referral decisions, e.g., their gist about risks and benefits of urgent referral to the patient and to themselves, in cases of lung and colorectal cancer. Studies 1 and 2 will also measure GPs' disposition towards the algorithm having compared it with their own intuitive estimates. Impact The research will increase understanding of how risk scores interact with human judgement, when they are likely to be used, and how they should best be presented. Future research could investigate their integration within a Learning Health System, and include the patient perspective, e.g., the patients’ understanding of their cancer risk.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: A Comparison of cervico-vaginal self –samples and clinician taken routine cervical screening samples in terms of HPV positivity rate, referral rates after triage and CIN2+ detection rates using current and novel triage strategies - Predictors 5.2
Funder: Cancer Research UK

Abstract: BACKGROUND Screening is moving towards primary hrHPV based testing programmes requiring a vaginal sample and not one taken directly from the cervix. HrHPV self-sampling is a major innovation. The ability to perform screening at home would revolutionise screening. Initial results from studies show high sensitivity of the self-sample, comparable to a clinician sample, but lower specificity. Our recent work indicates that adding DNA methylation testing could more accurately identify those infections associated with pathologic precursor lesions. We will undertake a direct comparison of self-samples taken at the time of routine screening and individually matched with the immediate clinical sample. Many hrHPV positive women do not harbour lesions likely to progress to cancer, and more work is needed to determine which women need to be referred to colposcopy. This study will allow for an evaluation of the difference between a clinician and a self-sample in making this determination, and permit a direct comparison of the value of different HPV DNA and methylation cut-off levels. AIMS • To directly compare hrHPV positivity on self vs clinician samples both overall and in those with CIN2+ when both samples are taken from a screening population at the same visit. • To compare the sensitivity for CIN2+ and specificity for CIN2 of the self vs clinician sampls at different HPV thresholds for the self-sample and the value of DNA methylation, HPV genotyping and viral load for improving the specificity. METHODS We aim to recruit 2000 women aged 25-65years attending for routine screening. Their involvement requires they take a self-sample using Copan FLOQswab and their cervical screener takes a second research sample after their routine NHS screening sample. They will be managed in the routine way from their NHS sample. Participating GP practices will identify eligible women and forward study information for them to consider joining the study. They will be asked for written consent during their routine screening appointment. HOW THE RESULTS OF THIS RESEARCH WILL BE USED This study will provide data to inform an implementation study to determine practical and detailed plans for routine use of a self-sample. Data will also be used to explore personalised screening management strategies, using mathematical modelling depending on self-sampling results in combination with vaccine status, age, HPV genotype and viral load.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Backfill for Professor Charlie Swanton
Funder: Cancer Research UK

Abstract: The CRUK Lung Cancer Centre of Excellence at Manchester and UCL brings together a unique range of internationally renowned scientists and clinicians within the field of lung cancer research. By building on this existing foundation, we will create an environment that catalyses imaginative and innovative lung cancer research. The Centre combines expertise in basic, translational and clinical research, which is focused around eight complementary and interacting themes: Basic Science, Immunology, Drug Discovery, Early Detection and Pre-Invasive Disease, Tumour Evolution and Heterogeneity, Biomarkers, Clinical Trials and Radiation Biology/Radiotherapy Trials


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cell Migration and Chemotaxis
Funder: Cancer Research UK

Abstract: Background: We will focus on two fundamental questions about how cells direct their movement. Both are fundamentally important, both to normal physiology and development, and to the process of cancer cell metastasis. Aims: First, we aim to understand self-generated chemotactic gradients, in which cells create their own gradients by locally breaking down an abundant attractant. Self-generated gradients are highly relevant to cancer, because they steer individual cells away from areas of high cell density such as tumours. We aim to understand both their scope - which cancer types are they important for, and what are the attractants? - and the mechanisms - how do self-generated gradients work? Second, we aim to understand how cells move. This question is fundamental to a proper understanding of chemotaxis, and more generally of metastasis. Methods: We will measure self-generated chemotaxis in different cancers, identify the most important attractants and the enzymes used to break them down, and assess their importance in metastasis. We will similarly examine which types of immune cells are steered by self-generated gradients, and whether this is relevant to immune behaviour. We will analyze self-generated gradients in the developmental migration of melanoblasts. And we will develop techniques to measure self-generated gradients in assays, intact tissues and in samples from cancer patients. We will study the regulation of movement by the SCAR/WAVE complex and WASP. We will use a newly-developed cell line with no plasma membrane Arp2/3 activators to assess the function of a range of different SCAR mutants whose functional role has previously not been testable. We have shown that cytoplasmic SCAR and WASP are held in refractory states that cannot be activated by known pathways; we will work out the mechanisms that hold them refractory and release them. And we will investigate two novel physiological roles for WASP, in regulating Rac levels and stabilising damage to cell membranes. How the results will be used: Our work on self-generated gradients includes potential prognostic tests - if we know when such gradients are important to metastasis we can design tests to see if they are present. More generally, these two studies will illuminate the control of cell migration at different levels of organisation, to understand how it is normally controlled and how it goes wrong during cancer metastasis. Understanding what goes wrong is fundamental to trying to fix it.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Integrative Cancer Biology
Funder: Cancer Research UK

Abstract: 300 years ago a new quantitative technology was introduced in medicine: the thermometer. Many doctors were afraid that Daniel Fahrenheit's innovation would replace them with numerical values. Instead, over time, doctors who used the thermometer replaced doctors who did not. The next shift in medical practice will come from the key quantitative technologies of today: predictive modelling by machine learning and artificial intelligence. My group and I are creating novel measurement and prediction systems for integrated cancer biology. In this report, I give a broad overview of my group's achievements and our future research agenda. Over the last five years, we have focussed on three areas --cancer evolution, genomics in a tissue context, interaction networks-- and built a strong track record in developing methods and deriving biological insights. In the next five years, we will capitalise on these strengths in translational projects on three frontiers: 1- Revealing the mutational processes acting on cancer genomes, measuring their impact on patient phenotypes, and using them for personalised therapy decisions; 2- Improved patient stratification, early detection, and prognosis by predictive modelling of tumour imaging and genomics data; 3- Predicting strategies to overcome resistance and reduce toxicity by comparative network analysis of transcriptional responses to combinatorial CRISPR perturbations in single cells. Our work is closely aligned with the strategic direction of the Cambridge Institute and its focus on the evolution and ecology of cancer. Our computational approaches and the close collaborations we have built with other groups place us at a central position to integrate cancer biology, gain insight into key cancer mechanisms and exploit their weaknesses for patient benefit. Predictive modelling will not replace doctors, but doctors using quantitative technologies will replace doctors who do not.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Cancer Immunology – Hedgehog signalling in T cells
Funder: Cancer Research UK

Abstract: The de la Roche lab is a newly established cancer immunology group. We are interested in the differentiation, migration and function of CD8 T cells during the adaptive anti-tumour response. Tumour-specific naïve CD8 T cells are activated in the lymph node, expand, and develop into cytotoxic T lymphocytes (CTLs). These CTLs then home to the tumour and specifically kill tumour cells by targeted secretion of lytic granules containing cytotoxic granzymes and perforin. Our lab investigates the Hedgehog (Hh) signalling pathway that we have previously shown is required for CTL killing in vitro (de la Roche et al, Science Dec 2013). We want to understand how Hh signalling functions in CD8 T cells and uncover its role throughout the CD8 anti-tumour response using genetic models as well as molecular and imaging approaches. Our long-term goal is to modulate Hh signalling pharmacologically to improve the CD8 response in tumour patients


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: ANTICIPATE- Artificial Intelligence to improve Classification and Predict Malignant Transformation of Oral Epithelial Dysplasia
Funder: Cancer Research UK

Abstract: BACKGROUND Oral epithelial dysplasia (OED) encompasses premalignant and precancerous changes in the oral mucosa. It is the precursor to oral squamous cell carcinoma (OSCC) which is amongst the top ten cancers in the world with increasing frequency and mortality. Early and accurate diagnosis of OED is therefore crucial to predict cancer development and improve prognosis. Histopathological analysis of a biopsy sample is the gold standard for diagnosis. However, the precise grading of OED is a diagnostic challenge as conventional grading is subjective, considering a wide range of features with wide inter-observer variability even amongst experienced pathologists. Correct grade is vital in early oral cancer detection by informing treatment decisions, enabling a surgeon to determine whether a lesion is to be clinically monitored or surgically excised. Machine learning and Artificial Intelligence (AI) can aid tissue diagnostics by removing subjectivity, using automation and quantification to guide diagnosis and treatment. However, a role for AI in grading and risk prediction of OED has not been investigated to date. AIMS The principal aim is to determine if AI can accurately, objectively and consistently grade oral epithelial dysplasia (OED) and predict malignant progression to OSCC. METHODS Archived OED tissue samples will be used (n). H&E-stained tissue slides will be scanned to obtain digital whole slide images (WSI). The cases will include a training cohort on which AI algorithms will be trained (for conventional and novel features) and optimised followed by validation on an unseen cohort. Five-year followup, and clinical history will be obtained to allow training for malignant risk prediction. Statistical correlation will be carried out using ML classifiers (random forest) and survival analysis. HOW THE RESULTS OF THIS RESEARCH WILL BE USED The results of this research have the potential to revolutionize OED diagnosis and management by removing subjectivity and ensuring accuracy, consistency and objectivity. Risk prediction will facilitate early oral cancer detection and guide treatment decisions allowing prevention of a large number of avoidable cancers. The proposed algorithms have a strong translational angle and can be rapidly employed as an aid to clinical and diagnostic practice. The methodology also has the potential to be modified for use in a range of other dysplasias (i.e. larynx, GI, prostate, bladder, breast etc.). The findings from the study will be shared and disseminated widely for continual evolution and to benefit patient treatment for any interested researchers and clinicians worldwide.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: PROTECTOR (Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal) study
Funder: Barts Charity

Abstract: Ovarian cancer (OC) remains the leading cause of deaths from women?s cancers. OC is predicted to rise by 37% by 2035. Removal of tubes and ovaries prevents this lethal disease in high risk women. However, this causes early menopause in younger women. Early menopause adversely impacts bone, heart, sexual and neurological health. Majority of OC arise from the tube (not ovary). Removal of tubes alone (Early Salpingectomy) can prevent OC while avoiding harmful consequences of early menopause. This study (Phase1) enables high risk women in East London and UK to undergo Early Salpingectomy to prevent OC. It will inform on logistics, satisfaction, impact on sexual function, menopause, quality of life and psychological health. This has UK wide support from health professionals and patient groups. Results will enable grant submission for a larger national trial (Phase2) for this new strategy.


Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: CRUK/19/012 EsPhALL 2017/COG AALL1631 International Phase 3 trial in Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) testing imatinib in combination with two different cytotoxic chemotherapy backbones
Funder: Cancer Research UK

Abstract: 1. BackgroundAcute lymphoblastic leukaemia (ALL) is an uncommon cancer that is usually seen in children, teenagers and young adults. Some of these have the Philadelphia chromosome (Ph+ ALL), which is associated with a poor prognosis. These particular patients are treated with induction, consolidation, intensification and maintenance chemotherapy (multiple drugs) and a tyrosine kinase inhibitor. 2. Aims:After Ph+ ALL patients finish their initial induction and consolidation therapy, they have a bone marrow sample taken to measure minimal residual disease (MRD), which is used to classify them as standard risk (MRD less than 5x 10-4) or high risk (MRD at least 5x 10-4). In standard risk patients, the aim is to de-intensify the backbone chemotherapy given alongside imatinib, in order to reduce the incidence of serious side effects such as infections, and reduce hospitalisations for treatment-related toxicities. High risk patients undergo allogeneic hematopoietic stem cell transplant (HSCT) after induction and consolidation chemotherapy/imatinib. The aim here is to examine whether they benefit from imatinib as monotherapy after HSCT. 3. Methods: Standard risk patients will be randomised in a non-inferiority trial to current dose chemotherapy or low intensity chemotherapy (less dose of several drugs) when combined with imatinib. The primary endpoint is disease-free survival, with a non-inferiority margin of 10%. 475 patients are planned. High risk patients will be offered maintenance imatinib after completing HSCT, in a single arm study. The main endpoint is the proportion who can receive at least 75% of the intended doses of imatinib. 90-120 patients are planned. Other endpoints in all patients include short and long term toxicities and grade; overall survival; and adherence to different drugs. This a major international randomised trial for paediatric Ph+ ALL patients. It has two sponsors (Children’s Oncology Group in the US, and the University of Milano-Bicocca for Europe), and multiple collaborative groups. The protocol has been approved by both sponsors, and sites activated in several countries. 50-60 patients are planned for the UK. 4. How the results of this research will be used. If reduced intensity chemotherapy is non-inferior to the currently used chemotherapy regimens in standard risk patients, it would become the standard of care and also the backbone therapy for future treatment trials. If high risk patients can tolerate imatinib after HSCT and with improved relapse rates, this would standardise clinical practice. Either of the above would be used to revise national and international guidelines on treating paediatric leukaemia.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS