NIHRDataInsights/HRCSData huggingface dataset:
Title: Integration of 2 week Ki67 with IHC4 in the POETIC trial
Funder: Cancer Research UK

Abstract: Background: By January 2013 we will have recruited the targeted 4,000 patients with primary ER+ breast cancer to POETIC (PeriOperative Endocrine Treatment for Individualised Care). The primary biomarker analysis is to compare the prognostic value of Ki67 measured at diagnosis (before treatment) with that at surgery (after 2 weeks' aromatase inhibitor) in the two-thirds of patients in the AI-treatment arm. Since starting the trial we have found that the integration of pretreatment Ki67 with measures of ER, PgR and HER2 into the IHC4 provides prognostic information similar to that by the expensive OncotypeDx 21 gene recurrence score. In POETIC, plasma has been collected before surgery (x2) and at first follow-up that could allow cell-free tumour DNA (cftDNA) to be assessed as a potential marker of residual disease. The value of these samples would be markedly enhanced by the availability of a sample collected later in follow-up. Aims: (a) To determine the added prognostic information from measuring Ki67 after 2 weeks' AI versus baseline Ki67 after integration into IHC4. (b) To collect one plasma sample from each patient during continued follow-up of POETIC. Methods: (a) Pretreatment ER,and PgR will be measured in the c.2,600 patients in the AI-treament arm by methods used for creating the original IHC4. HER2 status will be collected from the CRFs. A new algorithm using on-treatment Ki67 and pretreatment ER, PgR and HER2 will be developed and tested within POETIC using the same statistical methods as used for deriving the IHC4. (b) Plasma samples will be collected and stored at -80C in an identical manner to those collected already for future potential measurement of cftDNA. Use of results: (a) If the integration of 2-week Ki67 into IHC4 substantially enhances the prognostic information derived beyond that from the original IHC4 score presurgical treatment with an AI, measurement of Ki67 is likely to become the new standard of care and prognostic evaluation of the very large numbers of primary breast cancer patients with ER+ disease. (b) The plasma samples will be used when sufficiently well-validated methods for assessing cftDNA have become available. If the results indicate that there is a strong relationship between the presence of ctfDNA and recurrence monitoring of cftDNA is likely to become widespread practise and delivery of adjuvant therapy managed by reference to cftDNA.


Research activity codes: 4.4 POPULATION SCREENING;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/13/017: A randomized phase II trial of Hippocampal Sparing versus Conventional Whole Brain Radiotherapy after surgical resection or radiosurgery in favourable prognosis patients with 1-4 brain metastases (jointly funded with The Brain Tumour Charity)
Funder: Cancer Research UK

Abstract: Background: Brain metastases are usually treated palliatively with steroids and/or whole brain radiotherapy (WBRT), with survival typically 2-6 months. For patients with Karnofsky Performance Status (KPS) of at least 70, adding surgical excision or stereotactic radiosurgery (SRS) of brain metastases to WBRT improves overall survival in the case of a solitary metastasis, while patients with 2-3 metastases maintain their performance status longer and have reduced steroid requirements. However, it is debated whether, after localised treatment, patients should have WBRT or be observed and treated on progression. While WBRT reduces intracranial relapse and improves progression free survival, it does not increase overall survival or duration of functional independence, and it may impair neurocognitive function (NCF), which can reduce quality of life. On the other hand, maintaining intracranial control is important in preserving NCF. Modern radiotherapy techniques now allow the rest of the brain to be irradiated while minimising dose to the hippocampi, which appear to be particularly radiosensitive and important in new memory formation. Aims: To determine in a randomized Phase II trial whether hippocampal sparing WBRT (HS-WBRT) reduces decline in NCF compared to standard WBRT in patients with 1-4 brain metastases after neurosurgery or SRS and to assess the feasibility of a Phase III randomised trial of HS-WBRT. Secondary aims are to assess treatment toxicity, steroid and anti-epileptic drug requirements, quality of life, duration of functional independence, local and intracranial control and overall survival. Blood samples will be collected for future translational research to explain individual variation in NCF decline. Methods: Eighty-four adults with KPS at least 70, and 1-4 brain metastases, each treated by surgery or SRS in line with UK commissioning criteria, will be randomized to WBRT or HS-WBRT. Patients will be assessed at baseline and followed up for 2 years with toxicity scoring, steroid and anti-epileptic drug recording, quality of life questionnaires, NCF tests and MRI brain imaging. The primary endpoint will be total recall by the revised Hopkins Verbal Learning Test at 4 months. How the results of this research will be used: A Phase III trial to determine whether HS-WBRT should become the standard of care after SRS or neurosurgery of brain metastases will be considered if the Phase II trial shows that HS-WBRT reduces NCF decline, and it appears feasible in terms of patient recruitment to conduct an adequately powered Phase III trial.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: Beta adrenergic receptor expression and beta-blocker use: association with breast cancer survival and prognosis
Funder: Cancer Research UK

Abstract: BACKGROUND: Breast cancer is the most common neoplasm in UK women and the second most common cause of cancer death. Mortality remains high despite advances in surgery, imaging and systemic therapy, underlining the need to identify additional therapeutic strategies that impact upon survival. Increased stimulation of beta adrenergic receptors (ß-AR) can lead to the activation of signalling pathways that promote breast cancer progression, with potentially worse prognosis amongst high ß-AR expressors. ß-AR antagonist drugs (ß-blockers), operate by blocking the stimulation of ß-AR receptors and may therefore favourably impact upon cancer survival. However, studies to date that have examined ß-blocker use and breast cancer progression have been relatively small and have shown inconsistent results with respect to the selectivity of ß-blockers. Only one study has thus far examined ß-AR expression in relation to clinicopathological features and breast cancer specific survival but did not examine ß-blocker use. AIM: The aim of the proposed research is to investigate the prognostic significance of tumour ß-AR expression and post-diagnostic ß-blocker use with breast cancer specific survival and prognosis. METHODS: A retrospective, nested case-control study will be utilised to identify all breast cancer patients diagnosed between 1st January 2009 and the 31st December 2014. Patients who have died from breast cancer over this period (cases) will be subsequently matched on age and tumour stage to breast cancer patients who are alive at the cases’ time of death (controls), using incidence density sampling. Amongst patients who have undergone surgical resection (90%), tumour blocks will be retrieved and used to construct tissue microarrays for characterisation of ß-AR expression (via immunohistochemistry on an automatic staining system using an optimised monoclonal adenoceptor antibody). Staining intensity from each tissue section will be assessed by two independent observers blinded to case-control status. Conditional logistic regression analyses will be used to compare the risk of cancer-specific death by 1) ß-AR expression and 2) ß-blocker use generating odds ratios (OR) and 95% confidence intervals (CI) adjusting for various potential confounders. HOW THE RESULTS OF THIS RESEARCH WILL BE USED: By using linked cancer records, drug data and tumour samples of breast cancer patients in Northern Ireland, this unique study will offer robust information on the potential for therapy with ß-blockers in these patients with a view to future randomized trials, as well as providing molecular insights into those tumours most at risk of progressing.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Quality and outcomes of care for chronic conditions in older patients diagnosed with breast, colorectal, or prostate cancer compared to non-cancer controls: An observational study using the clinical practice research datalink (CPRD)
Funder: Cancer Research UK

Abstract: Background As cancer survival rates continue to improve, more of those diagnosed with cancer will die from other causes - up to half according to a recent study. Increasingly, therefore, overall survival in cancer will depend on prevention and high quality care of other conditions throughout the continuum of cancer care, especially in older patients with multiple conditions. Aims The specific aims of this study are to assess the quality and outcomes of care for underlying chronic conditions in older patients diagnosed with breast, colorectal, or prostate cancer, and to compare quality and outcomes in cancer patients to a matched cohort of non-cancer controls. Methods Data source and patients The source of data will be the Clinical Practice Research Datalink (CPRD), which now includes linkages to the National Cancer Intelligence Network, Office for National Statistics, and Hospital Episode Statistics. Using CPRD, we will identify cohorts of patients with breast, colorectal, or prostate cancer, aged = 50 at diagnosis, who had at least one chronic condition prior to cancer diagnosis, e.g. hypertension, diabetes, coronary heart disease, heart failure, peripheral arterial disease, stroke, or transient ischaemic attack. We also will identify a matched non-cancer control group. Cancer patients and controls will be followed from not less than 24 months before diagnosis (matched sham date for controls) up to 60 months after diagnosis, death, or the end of the data (presently 31/10/2011). Outcome measures Quality of care will be assessed based on whether patients meet blood pressure, cholesterol, and HbA1c (diabetes) thresholds, receive appropriate medications and tests, and have influenza immunisation according to the Quality and Outcomes Framework (QOF). Outcomes will be assessed based on the rates of inpatient and outpatient hospital episodes pertaining to the conditions, incidence of new medical conditions, or complications of current conditions, e.g. diabetic retinopathy and mortality. Analysis Analyses will compare adjusted rates of compliance with the QOF indicators, hospital episodes, new conditions, and condition-specific (“competing risk”) mortality between cancer patients and controls. Comparisons will be stratified by type of cancer, stage, and type(s) of conditions at cancer diagnosis. How Results Will Be Used The findings will serve as the basis and benchmark for informing changes to practice management to improve quality of care and outcomes of chronic conditions in cancer. To our knowledge, this will be the first population-based study in the UK assessing the quality of care for chronic conditions from the diagnosis of cancer forward.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: The effect of manipulating tumour metabolism and the microenvironment on 3D radiosensitivity.
Funder: Cancer Research UK

Abstract: Hypoxia, which occurs where the delivery of oxygen is insufficient to meet the metabolic demands of a tissue, is a hallmark of the cancer microenvironment. It correlates with a poor clinical outcome, metastatic phenotype and resistance to therapeutic intervention. Radiotherapy, which is used to treat nearly half of all cancer patients, is particularly affected by hypoxia as normal levels of oxygen are essential to potentiate the effects of radiation. The aim of our work is to reduce tumour hypoxia in order to improve response to radiotherapy. To study the formation, development and manipulation of hypoxia requires a 3D environment where gradients of oxygen can form. Whilst in vivo models such as rodents offer this, they are a relatively closed system, which is difficult to accurately manipulate externally. Instead we use clusters of cancer cells, known as multicellular tumour spheroids, which naturally form regions of hypoxia, mimicking the microenvironment seen in small tumours. Spheroids are straightforward to culture in high volumes, easily manipulable, and highly desirable from an ethical perspective as no animals are required. We have shown that it is possible to reduce hypoxia in spheroids using inhibitors of the PI3K pathway, which is overactive in the majority of cancers. The mechanism by which these inhibitors effect this change is via a reduction in cellular respiration, i.e. oxygen consumption. Hypoxia is a problem of supply vs. demand, so by reducing individual cells’ demand for oxygen, there is more oxygen available in the microenvironment. The next phase of this research is to demonstrate that changes in hypoxia, obtained via manipulation of cellular respiration, translate to an improvement in radiosensitivity. Thus the aim of the outlined research proposal is to gain a practical understanding of how multicellular tumour spheroids can be used to assess oxygen-dependent radiosensitivity. To achieve this, I propose undertaking a training visit to the University of Pennsylvania, in Philadelphia, to work with one of the pioneers in this field, Professor Cameron Koch. During the proposed visit, I will learn how to (i) accurately quantify hypoxia in spheroids using the hypoxia biomarker EF5; (ii) measure oxygen-dependent radiation-induced damage using image analysis techniques. To understand how the above are affected by oxygen consumption, we will treat spheroids with a standard respiratory inhibitor (myxathiazol). The overall goal of this project is to bring these necessary skills back to Oxford and apply them to our existing research into the manipulation of tumour hypoxia.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Development of hyperpolarised carbon-13 MRI as a novel clinical imaging tool in oncology
Funder: Cancer Research UK

Abstract: Background Magnetic resonance imaging (MRI) is a powerful clinical tool for non-invasively probing tissue metabolism in cancer, but its main limitation is lack of sensitivity. Cambridge has been developing a new technique to increase the sensitivity of MRI by more than 10,000-fold, which is termed hyperpolarized carbon-13 imaging or Dynamic Nuclear Polarization (DNP). This method allows carbon metabolism to be studied non-invasively. A device has now been developed which will allow this technique to be used on patients. Aims • To translate DNP into patient imaging using two probes: hyperpolarized pyruvate as a marker of tumour glycolysis and fumarate as a marker of tumour necrosis. • To understand the relationship between the signal generated with DNP and the biophysical environment by comparing to histology. • To use ovarian cancer as a model system for this new technique. • Ultimately to find applications of this technology in the field of oncology that will benefit patients. Methods Up to 40 patients with ovarian cancer will be imaged with hyperpolarized pyruvate and 40 with hyperpolarized fumarate. Tissue will be surgically removed and compared to the imaging findings using standard histopathology and immunohistochemical techniques. In addition, the imaging will be compared to biochemical measures of the metabolites, transporters and enzymes that are involved in the metabolism of the two substrates. Images will also be compared to RNA expression profiling as an exploratory element of the trial. How the results of the research will be used Development of new functional and molecular imaging techniques is essential to improve patient care in the current era of molecular medicine and personalised treatment. DNP offers the possibility of a new imaging technique, which does not involve ionising radiation and utilises endogenous molecules as probes of fundamental metabolic pathways in cancer. There is increasing evidence from pre-clinical models that it could be used as an early and specific marker of successful treatment response to cancer therapies as well as improving tumour characterization and staging. This study will form one of the earliest clinical trials of the technique.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Harnessing transposons for drug resistance gene discovery in cancer.
Funder: Cancer Research UK

Abstract: As we embark on a systematic programme of whole genome sequencing of human cancers it is likely that we will identify signatures of genomic alterations that predict for drug sensitivity across many cancer types. Indeed, there is already compelling evidence that the likelihood of any patient’s cancer responding to treatment can be strongly influenced by alterations in the cancer genome. Notable recent examples of correlations between drug response and tumour genotypes include melanoma (BRAF mutation), lung cancer (EGFR mutations &amp; EML4-ALK translocation), GIST (KIT mutations) and CML (BCR-ABL translocation). However, despite advances in how we will stratify and treat cancer patients in the future, clinical experience dictates that almost all responses are inevitably followed by the emergence of drug resistance disease. Whether this is the result of clonal expansion of intrinsically-resistant subclones or cross-talk activation of alternate signalling pathways in sensitive cells is the focus of intense investigation. Nowhere has drug resistance been seen more dramatically than in BRAF mutant melanoma, where initial response rates of 70% have been followed by rapid relapse with drug-resistant disease. Significant efforts worldwide are focused on the use of next-generation sequencing technologies to determine the likely resistance mechanisms and the means to overcome them. There is therefore a critical need for systematic models to predict likely resistance mechanisms in the context of preclinical and clinical cancer drugs and that can be used to develop in vitro models to overcome drug resistance. We have previously generated drug-resistant cell lines in the setting of EML4-ALK lung cancer and BRAF mutant melanoma through serial drug exposure and have characterized these using a combination of next-generation sequencing and high-throughput drug screens. While in some cases we have successfully identified clinically relevant mutations underpinning the drug resistance as well as second-line therapies to overcome this, in other cases we have been faced with a large number of acquired mutations and changes in drug sensitivity patterns do not aid in highlighting the resistance genes. This points to the need for a model whereby, genome-wide, barcoded gain-of-function genetic events can be engineered into cancer cells and used to specifically identify those that are responsible for the resistance phenotype. We propose to use transposon-based mutagenesis in the setting of immortalised melanoma cancer cell lines as well as early passage cultures to generate complete catalogs of all drug resistance genes and to confirm their validity in the MelResist clinical trial.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Edinburgh Cancer Research UK Centre (Bridging Funding)
Funder: Cancer Research UK

Abstract: The Edinburgh Cancer Research UK Centre brings together scientists, doctors and nurses from across the city. It harnesses the breadth of research expertise in Edinburgh, developing new ideas from the laboratory into improvements in treatment that will benefit patients in the city and beyond. The Centre is a partnership between Cancer Research UK, the University of Edinburgh and NHS Lothian, which links state-of-the-art cancer research to the best possible patient care. Researchers at the Edinburgh Cancer Research UK Centre focus on bowel, breast and ovarian cancers, but will also develop new research programs into other common cancers. They study the genetics and biology of cancer, as well as researching and devising new ways to treat the disease. Scientists at the Centre are particularly interested in understanding how cancer spreads and becomes resistant to drugs. They aim to develop new imaging techniques to monitor cancer spread and, crucially, to find ways to slow or stop the process. This research will help to improve treatment for patients with advanced cancer. Researchers in Edinburgh are also uncovering the genetic changes involved in bowel cancer, making it possible to identify those people at greatest risk of the disease and offer them tailored advice, screening and treatment. Scientists and doctors will work in partnership to identify biomarkers that can be used to predict an individual’s cancer risk or determine the best treatment. And unique imaging approaches will underpin efforts to detect cancer earlier and to monitor the effects of treatment.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Targeting aberrant fibroblast growth factor receptor signalling in cancer
Funder: Cancer Research UK

Abstract: Activation of the fibroblast growth factor receptors (FGFR) is one of the most common oncogenic events in cancer, yet little is known about what defines a cancer that is likely to be respond to FGFR inhibitors, and the likely mechanisms of resistance. This proposal is directed at providing a strong scientific basis to understanding the factors that define dependence on FGFR signalling, with the aim of substantially enhancing the clinical development of strategies targeting FGF signalling. This proposal has two distinct but interrelated aims interrelated aims, focusing on cancers with amplification of FGFR1, but also extend this work to examine autocrine FGF2 signalling in breast cancer.<br/><br/>FGFR1 amplification is one of the most common focal amplifications of cancer, and represents a major therapeutic opportunity across multiple cancer types. We will identify the determinants of sensitivity to FGFR inhibitors in FGFR1 amplified breast and lung cancer cell lines, using RNA interference screens and in vitro derived resistant cell lines, and validate these findings in vivo. <br/><br/>We will seek to understand how autocrine FGF signalling in basal-like breast cancer can be exploited for therapeutic benefit with combination drug screens, RNA interference screens, and examination of signalling responses to FGFR inhibition. Through this approach we will identify the key alternative survival pathways that promote the growth of basal-like breast cancer cell lines in the presence of FGFR inhibitors and assess potential combinations with FGFR inhibitors in vivo. <br/><br/>Through this research we will identify rational combination therapeutic approaches to take forward to clinical trial, and establish how best to select patients for clinical trials of FGFR inhibitors.<br/>


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS