S:CORT is a UK-wide multi-disciplinary consortium of clinicians, healthcare professionals, academics and scientists looking to apply cutting edge molecular diagnostic technologies to enable tailored treatment of patients colorectal (bowel) cancer (CRC).
More than 41,500 people are diagnosed with CRC each year in the UK and treatment varies based on the type and size of the tumour, whether the disease has started to spread (metastasise), and on the health and fitness of each patient. Our programme of research will identify and use new ways to predict the patient’s response to treatment based on the molecular make-up of their tumour, as well as helping doctors decide how to treat patients more effectively.
Lead by Prof. Tim Maughan (University of Oxford) the consortium draws together researchers across eight universities and hospitals.
The approach of the consortium is to correlate the molecular phenotype from over 2000 samples from CRC patients (on standard of care and clinical trials), with clinical outcome. Cohorts were selected to ensure patients treated with a range of chemotherapeutic, surgical and radiotherapy regimes will be included. The result will be a unique dataset that will help us understand CRC in more detail, and develop novel diagnostic strategies for ensuring patients receive the treatment granting them greatest chance of response.
The S:CORT analytical pipeline (overseen by Prof Tomlinson, University of Birmingham) is summarised below. Samples are processed in a central laboratory (University of Leeds) and analysed for genetic mutations (Sanger Institute), DNA methylation (University of Birmingham), RNA levels (Queen’s University Belfast) and immunohistochemistry. High level summaries of the analytical platforms patient cohorts and clinical questions can be found below.
S:CORT Molecular Analysis Platforms
Below is a high level summary of the analytical platforms that CRC patient tissue have been analysed with.
- Mutation Analysis. Mutations in 116 cancer driver genes and copy number variation across 51 sites is assessed using the Illumina HiSeq2000 platform at the Sanger Institute under the direction of Prof. Peter Campbell.
- DNA Methylation. DNA methylation at over 800,000 genomic locations is assessed by Infinium HD assay and the Illumina iScan platform at Birmingham University.
- RNA Profiling. Genome wide mRNA levels are assessed using the Affymetrix Almac Xcel Array platform at Queen’s University Belfast.
- H&E and Immunohistochemistry. Assessment of a range of standard and immunological markers are assessed using standard immune-histochemistry assays at Leeds and Queens University.
Data from the above assays is integrated with clinical and outcome data and is available for bio-informatic and statistical analysis through the S:CORT eLab housed at Oxford University.
The above molecular analysis is housed with harmonised clinical data for the below cohorts:
- Cohort 1. 500 patients from the FOCUS and FOXTROT clinical trials have been selected on basis of understanding the molecular basis of patient response to Oxaliplatin treatment.
- Cohort 2. 350 patients from the TREC and RITS clincal trials, as well as standard of care, have been selected on the basis of understanding the molecular basis of of patient response to radiation therapy.
- Cohort 3. 400 patients have been selected to identify the molecular basis of the efficacy of surgery in treating CRC
- Cohort 4. 120 patients form the NewEPOC clinical trial have been selected to further our understanding of the molecular basis of patient response to anti-EGF receptor (Cetuximab) therapy.
S:CORT Clinical Questions
Below is a summary of the clinical questions S:CORT seeks to tackle:
- Can we predict which patients will respond to oxaliplatin treatment? Addition of oxaliplatin to 5-Fluorouracil (5-FU)-based therapies represented a significant improvement in CRC management. However, while this combination approach can be effective, chronic peripheral neuropathy occurs in 50% of patients exposed to oxaliplatin. Currently, no reliable clinically-validated test is available to predict response to oxaliplatin–based chemotherapy; thus, a sizeable group of patients may receive minimal therapeutic benefit but endure distressing side-effects from oxaliplatin-containing regimens, impairing their quality of life. A clinically-validated molecular predictor would underpin decision making, identifying patients who respond to treatment, while sparing non-responders the debilitating long term neurotoxicity.
- Can we predict which patients respond to standard or modified radiotherapy (RT) strategies? For patients with low rectal cancer, current standard of care involves pre-operative chemoradiotherapy (CRT) followed by surgery and a permanent stoma. In locally advanced disease, 40% of patients gain no benefit from current RT/CRT protocols. We aim to find stratifiers that identify (i) patients responding to the current standard of care, (ii) those failing due to early metastatic CRC in whom primary chemotherapy would be indicated and (iii) candidate pathways (e.g. hypoxia) for modification to improve radio-sensitivity (RS) and thereby local control.
- Does stratification in early rectal/colon cancer predict risk of invasion, thus informing either radical or organ preserving treatment options? Defining particular molecular subtypes in early disease may identify candidate signatures for further evaluation as stratifiers of treatment response and selection. Developing molecular stratifiers that predict whether rectal cancer patients require radical surgery or local organ preserving treatment will deliver significant therapeutic and quality of life benefits and may also yield health economic savings. Over 8,000 patients in the UK are diagnosed with early rectal cancer; the combined outputs from the RT stratifier and early disease stratification could lead to 80% of rectal cancer patients being stratified for local excision + RT as an organ conserving strategy. To achieve this goal we are examining the biological characteristics of early colon and rectal cancer and assessing these traits as drivers of early invasion/metastasis.
- Can we develop better biomarkers to predict response to novel molecularly guided approaches in stratified CRC cohorts? The NewEPOC trial is the exemplar approach on which we are building our molecular stratification strategy for EGF targeted therapies.
Below is a summary of the senior members of the S:CORT Consortium Management Group
- Prof. Tim Maughan, Prof. Simon Leadham, Prof Chris Holmes, Prof. Francesca Buffa (University of Oxford)
- Prof Dian Morton, Prof. Ian Tomlinson, Prof Andy Beggs (University of Birmingham)
- Dr. Lou Brown, Prof. Rick Kaplan (University College London)
- Prof. Peter Campbell (Sanger Institute)
- Prof. Phil Quirke (University of Leeds)
- Prof. Richard Wilson, Prof. Manuel Salto-Tellez, Prof Mark Lawler, Dr. Steve Walker (Queen’s University Belfast & Almac)
- Prof Graeme Murray (Aberdeen University)
- Prof. Simon Gollins (North Wales Cancer Treatment Centre)