MICA: Stratification in COloRectal cancer: from biology to Treatment prediction: S-CORT

Lead Research Organisation: University of Oxford
Department Name: Oncology

Abstract

Colorectal cancer (CRC) is the 3rd most common cancer in the UK, with >40,000 new cases in 2011. While there have been improvements in CRC treatment, it remains a significant killer, with 16,000 deaths in 2011. Research by ourselves/others has revealed that a "one size fits all approach" will not work, as genetic changes in their CRC cells can cause treatments to fail in particular patients. This increased understanding has given rise to the concept of "stratified medicine", where testing a patient's sample prior to treatment can indicate which therapy works in this particular patient. This "stratified" approach also allows patients who will not respond to be spared the often toxic side effects. Recognising the need to provide treatments leading to better survival/Quality of Life (Qol), a group of researchers, clinicians, patient groups and industry have formed a consortium (S-CORT), harnessing its members expertise to develop new approaches to stratify patients to improve outcomes, thus delivering real benefit for CRC patients.

S-CORTs objectives are to:
1. Create a consortium united in the common goal to employ stratified medicine to yield better survival and QoL for CRC patients

2. Build on discoveries by S-CORT researchers to identify particular stratification approaches for patients receiving different therapies for CRC. Three priorities have been established

a. While the drug Oxaliplatin has increased our options for treating CRC, approximately 50% of patients don't respond and develop side effects that can affect their nervous system and reduce their QoL. Being able to decide in advance which patients respond, allows those patients to receive the drug while sparing non-responders the toxic side effects
b. ChemoRadiotherapy (CRT) is used in the treatment of rectal cancer, but 40% of patients with locally advanced disease gain no benefit. A stratification approach may not only indicate which patients to treat, but also allow design of new approaches to make RT more effective
c. In early disease, some patients can have aggressive cancer which invades other parts of the body. Identifying these patients in advance of treatment would allow them to receive more extensive surgery/RT while those with less aggressive disease can be treated with local rectal preserving treatment

3. Establish a more complete understanding of the precise changes that occur in the genes and proteins of CRC cells and use this information to provide novel therapies for patients

4. Develop our best candidates into clinical tests that select patients for the therapies that have the greatest chance of success and/or with the fewest side effects in their particular disease

5. Bring together all our research into a database that will be a vital resource for future research, within and outside this consortium

6. Ensure that the patient is at the centre of all activities in S-CORT, helping with the design of studies, participating in focus groups, meetings and conferences and contributing to the communication of the activities of S-CORT to healthcare and research professionals, patient groups and the public at large

7. Publish our research findings in the best scientific journals and present our results at national and international conferences, thus demonstrating the quality of S-CORT's research

8. Examine how tests that we are developing will perform in the hospital for CRC patients and evaluate the health, economic and societal benefits of this approach

9. Ensure S-CORT's long term sustainability, thus driving implementation of new stratification approaches for CRC patients over the next decade, both in the UK and globally

Delivering these ambitious objectives will allow development of new clinical tests to predict success/ failure of new therapies which, coupled with our increased knowledge of CRC biology will drive a new treatment vision where stratified medicine approaches can significantly benefit our patients.

Technical Summary

Over 40,000 people were diagnosed and 16,000 died from colorectal cancer (CRC) in the UK in 2011. In early disease, 93% are cured by radical surgery, while current therapies have enhanced overall survival for metastatic CRC (mCRC) to ~24 months. Most mCRC patients receive standard chemo- or radiotherapy; however ~50% derive no benefit and develop toxic side-effects. Genomic, immune, and expression approaches have begun to identify distinct subgroups within CRC, refining prognosis and providing some guide in treatment. S-CORT will utilise an unrivalled clinically annotated pathological resource to go beyond the state of the art by: 1. developing new predictive tests, with a particular focus on mCRC/rectal cancer; 2. addressing precise cliniccial questions where stratification will yield practice-changing clinical benefit. FOCUS4, a biologically adaptive randomised clinical trial(RCT) in mCRC, conceived and led by S-CORT researchers is the blueprint for our stratification approach. Promising leads, based on previous work by S-CORT researchers, will be evaluated in samples from selected patients enrolled in RCTs, defining new stratifers to guide therapeutic decisions that address 4 highly relevant clinical questions:
1. Can we predict which patients will respond to oxaliplatin treatment?
2. Can we predict which patients respond to standard or modified radiotherapy (RT) strategies?
3. Does stratification in early rectal/colon cancer predict risk of invasion, thus informing either radical or organ preserving treatment options?
4. Can we develop better biomarkers to predict response to novel molecularly guided approaches in stratified CRC cohorts?
Novel molecular predictors will allow better application of existing treatments, avoid toxicities of ineffective/unnecessary surgery, RT or chemotherapy, drive the evolution and introduction of new therapies, and provide potential for cost savings, thus benefitting both CRC patients and society.

Planned Impact

Stratification for treatment of CRC is both necessary and achievable. S-CORT aims to develop classifiers that predict response to common and emerging CRC treatment strategies, where we can make the greatest impact. The research findings of S-CORT will benefit a range of individuals, including CRC patients (through improved treatment selection), the public (in the national bowel cancer screening programme), the National Health Service(NHS) (through improved resource utilisation), diagnostics companies (through commercialisation of biomarker tests), Pharma/Biotech companies (through more rational drug development/clinical evaluation), researchers and clinicians (through greater understanding of CRC), policy makers (through selection of the right care for the right patients at the right time), as well as the wider UK economy.

In the short-term, researchers will gain biological insights into CRC development, mechanisms of resistance and/or sensitivity to cancer treatments. This will enrich the local research activities of the scientific groups associated with S-CORT, improve international collaboration and research competitiveness. In the short-term, we will also recruit and train scientists, clinicians and allied health care professionals in the research techniques required to examine the phenotype/genotype of the clinical samples and also integrate and interrogate those findings to establish stratification signatures that can be developed into predictive companion diagnostics. In the mid-term, stratification approaches using our successful candidates will enable clinicians to better predict treatment outcome, therefore improving their treatment decision making.

With the introduction of screening, 50% of rectal cancers (8,000 cases per annum) are diagnosed at an early stage, restricted to the rectal wall submucosa. S-CORT will enable selection of up to 2/3 of early rectal cancer for rectum-organ preserving strategies, substantially reducing treatment-associated morbidity and mortality. With an aging population, the need for such improvements can only increase.

In more advanced cases where radiotherapy is used to reduce the size of the tumour to enable R0 resection (clear margins), the biomakers S-CORT will develop will discriminate the sensitive 15% who may be managed without surgery, from the 40% who gain little from current therapy. Understanding the biology of these resistant cases would help guide selection of potential radiosensitisers or a switch away from radiotherapy to alternative strategies.

In the adjuvant setting, about 90% of survivors treated with oxaliplatin and infusional 5-FU (FOLFOX) developed sensory neuropathy. Identification of an oxaliplatin response stratifier is a key early output from S-CORT. Our partner, Almac, have commercialized the DDRD signature and have experience of taking a biomarker to market. S-CORT will provide economic advantage to a UK company and improve patient outcome by identifying patients who benefit from oxaliplatin therapy. In those who do benefit, increased understanding of the DNA damage response may underpin further effective targeting using DNA damage response inhibitors (e.g PARP/ATR inhibitors, in development with our partner AstraZeneca(AZ)) to increase efficacy further. Similarly, discovery of biomarkers to identify patients likely to benefit from expensive modern targeted therapies will aid cost-effective utilisation of new approaches to treatment, benefiting both our Pharma partners AZ and GlaxoSmithKline(GSK) and the healthcare provider (NHS).

The commercialisation of a companion assay and the development of novel molecularly targeted therapies will build commercial partnerships between S-CORT academic institutions and the industrial/biotechnology sector, and lead to IP rights. The products if approved will lead to wealth creation and greater UK economic competitiveness as S-CORT will be at the forefront of these therapeutic advances.

Publications

10 25 50
 
Description CR-UK accelerator award
Amount £4,500,000 (GBP)
Funding ID C309/A21993 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 09/2021
 
Title S:CORT database 
Description WE are building the database to house the multi-omic data, phenotypic and clinical data for the 2000 patients to be analysed in the S:CORT consortium 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact none yet 
 
Description DDRD signature and RNA expression analysis 
Organisation Almac Group
Department Almac Diagnostics
Country United Kingdom 
Sector Private 
PI Contribution Collation of samples and data from clinical trials assessing the benfit of Oxaliplatin chemotherapy, aiming to discover an oxaliplatin response stratifier
Collaborator Contribution ALMAC have used their proprietary technology and DDRD algorithm in 500 samples form the S:CORT consortium in an effort to validate their DDRD signature biomarker for oxaliplatin and or radiotherapy response.
Impact still in development
Start Year 2015
 
Description Centre for Personalised medicine, St Anne's College Oxford, workshop November 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Centre for Personalised Medicine's Personalised Medicine in Practice Seminars at St. Anne's College, Oxford on Monday 28 November. This seminar will focus on Cancer.

1. programme: Each talk is scheduled for 40 minutes which would ideally consist of 35 minutes presentation and 5 minutes for questions and discussion. Please could you send us a confirmed title and short talk abstract by Friday 11 November for inclusion in the programme. If you are concerned about overlap of content with other speakers please feel free to email them directly to liaise or contact Simon Leedham.

Programme
09:00 - 09:30 Registration
09:30 - 09:45 Introduction by Dr Simon Leedham
Predisposition and screening
09:45 - 10:25 Professor Ian Tomlinson, Oxford University, UK
10:25 - 11:05 Professor Rebecca Fitzgerald, Cambridge University, UK
11:05 - 11:30 Coffee
Risk Stratification
11:30 - 12:10 Dr Tjalling Bosse, Leiden University, Netherlands
12:10 - 12:50 Dr James Brenton, Cambridge University, UK
12:50 - 13:50 Lunch
Molecular Heterogeneity
13:50 - 14:30 Dr Louis Vermeulen, Amsterdam Medical Centre, Netherlands
14:30 - 15:10 Dr Marco Gerlinger, Institute of Cancer Research, UK
15:10 - 15:30 Tea
Cancer therapy
15:30 - 16:10 Professor Tim Maughan, Oxford University, UK
16:10 - 16:50 Dr Sergio Quezada, University College London, UK
16:50 - 17:00 Closing remarks by Dr Simon Leedham
Year(s) Of Engagement Activity 2016
 
Description Dr Helen May Russell Lecture Colerectal Cancer - Unity or Infinity? Professor Tim Maughan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Named lecture to general Physicians in the context of the Royal College of Physicians of Edinburgh regional meeting in Wales
Year(s) Of Engagement Activity 2016
 
Description EAPM session on the promise of precision medicine Milan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact collaboration with theological ethics (Hordern), Cystic Fibrosis Trust (Allen) to further discuss the questions around delivery of precision medicine
Year(s) Of Engagement Activity 2018
URL https://eapmmilan2018.com/
 
Description MRC S:CORT symposium Launch 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact public event linked to the consortium launch, attended by consortium members, bowel cancer charity representatatives, public and patient reps. Radio 4 interview on the Today programme the same morning by TSM to publicise launch of the Consortium
Year(s) Of Engagement Activity 2015
 
Description Personalised medicine: for the many or the few? Talk at special session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Special session at European Association of personalised medicine Belfast 2017. I co-hosted this session with Prof Josh Hordern, Associate Professor of Christian Ethics, Univeristy of Oxford
Year(s) Of Engagement Activity 2017
URL http://eapmbelfast2017.com/about-the-congress/
 
Description Public engagement workshop Leeds 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Event held in Leeds to communicate a public understanding of stratified medicine and the contribution of pathology to that exercise.
Year(s) Of Engagement Activity 2016
 
Description Workshop: The hype and the promise of personalised medicine 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 140 people attended the workshop which was held in t he Richard Doll Lecture theatre in Oxford on 9th september 2016. the workshop has been written up and will be published in 2017 as a special edition in the New Bioethics journal.

Convenors
Professor Tim Maughan, Professor of Clinical Oncology, Clinical Director of the CRUK/MRC Oxford Institute for Radiation Oncology within the Department of Oncology, University of Oxford.
Professor Joshua Hordern, Associate Professor of Christian Ethics, Faculty of Theology and Religion, Harris Manchester College, University of Oxford.
Supported by Dr Kezia Gaitskell, Pathology registrar and DPhil student in Population Health, University of Oxford; Dr Therese Feiler, Wellcome Trust postdoctoral researcher, Oxford Healthcare Values Partnership, University of Oxford.
The Healthcare Values Partnership is delighted to be holding this event in association with the Centre for Personalised Medicine and CASMI-Academic.
Funding for this project has been provided by the Wellcome Trust (Wellcome Trust Institutional Strategic Support Fund for Oxford), the British Academy and the Sir Halley Stewart Trust. It is organised by the Oxford Healthcare Values Partnership (OHVP) (more information at www.healthcarevalues.ox.ac.uk/personalised-medicine).


Session 1: 9:15-10.30am The promise and the hype of 'personalised medicine'
In recent years a significant gap has emerged between the promise of progress made by industry, researchers and politicians on the one hand and the reality of biomarker-based personalised medicine in research findings and clinical practice on the other. A variety of problems - commercial, scientific, clinical and public - may arise when the hype meets the reality of slow progress or no progress. This session will explore the dynamics and ethics of hype and promise in relation to personalised medicine.
Questions for discussion include:
• What are the myths around personalised or 'precision' medicine?
• What stories are told about its past and future?
• How good are those involved in personalised medicine at distinguishing between optimism and over-promising (even intentional exaggeration or distortion)?
• What are the arguments for and against hype in the context of such medicine?
• Have population health approaches suffered unduly because of personalised medicine hype?
• Are there good reasons for hype in privately funded research that do not apply to publicly funded research?
• Who bears the risk of hype?
• Where funding for personalised/precision medicine research derives from private and commercial sources, how should such research influence the agenda in public healthcare?
• How should the phenomena of hype and promise be best understood from a historical perspective?
• Are researchers and clinicians more susceptible to imprudent hype around genomic medicine than patients?
• How might scientific, clinical and public expectations be best protected from the effects of unrealistic hype and unfulfilled promises while not extinguishing realistic hope and appropriate ambition?
CHAIR: Joshua Hordern (Associate Professor of Christian Ethics, Healthcare Values Partnership, University of Oxford)
SPEAKERS: Tim Maughan (Professor of Clinical Oncology, University of Oxford), Richard Barker (Centre for the Advancement of Sustainable Medical Innovation, Oxford), Steve Sturdy (Professor of the Sociology of Medical Knowledge, University of Edinburgh)
________________________________________

Session 2: 11am-12.30pm The human person and the communication of risk
It is important to distinguish between different possible meanings of 'personalised medicine' and to situate the experience of personalised medicine by patients and healthcare workers within the practice of healthcare and wider society's expectations. A notion of biological determinism might shape a certain biomedical, genomic understanding of the person in 'personalised medicine'. Preceding the genomic usage but now re-emphasised as an overarching category, another sense of 'personalised medicine' has focussed on relational aspects of care, individual beliefs and values, shared decision-making, risk communication and strategies for individualised compliance. In a related but distinct way, typically emphasised in medical humanities disciplines such as theology, patients are persons who bear both worth and vocation which are not exhausted by genetic data, may become submerged in healthcare systems but are essential to a social vision which can underpin political solidarity in suffering and healthcare. Understanding what communication of risk and value in clinical care involves requires careful navigation of each of these senses of the person.
Questions for discussion include:
• What bridges need to be built between these different senses of 'personalised'?
• How ought 'precision' medicine to pay attention to the patient as person?
• What risks to 'care' are attendant on a focus on biomedical 'cure'?
• Does medical professionalism need to adapt in any way to meet the challenge of genomic medicine?
• What factors affect patient perceptions of value and risk in clinical conversations concerning personalised medicine?
• How can clinicians best communicate with and advise their patients on the risks and benefits of precision medicine in an everyday, meaningful way?
• Is it possible to stratify on the basis of psychological factors as well as biological ones? What outcomes are important to patients in 'precision' medicine?
• How might industry, scientific, clinical and political actors maintain due regard for patients as persons whom they seek to serve in compassion?
• How might other non-healthcare related institutions help in this regard?
CHAIR: Rob Horne (Professor of Behavioural Medicine, UCL School of Pharmacy; CASMI-Academic)
SPEAKERS: Sian Rees (Director, Oxford Health Experiences Institute, Nuffield Department of Primary Care Health Sciences), Joshua Hordern (Associate Professor of Christian Ethics, Healthcare Values Partnership, University of Oxford), Alastair Kent (Genetic Alliance UK)

John Tooke comment before lunch
________________________________________

Session 3: 1.30-2.45pm Data sharing and participation
Participation and data sharing presents a distinct set of problems in relation to personalised medicine. On an important policy level, there are national and international databases which are not interacting sufficiently with each other to make the progress needed. An underlying dimension of this policy matter concerns the motivation for collaboration and participation. The combination of self-interest and compassion for present neighbours and future generations which inspires data sharing is liable to be undermined by fears of data loss and trust violation. This in turn may lead to the worry that well-motivated patient consent to share pearls of data may be trampled underfoot in the pursuit of profit.
Questions for discussion include:
• What can be done to ensure that participation in data sharing, clinical trials and research is meaningful with respect to the values of participants?
• What are public perceptions of and levels of trust in the recipients of big data and the technological advances those recipients pursue?
• Do those perceptions vary across generations?
• What public and clinical educational goals need to be considered?
• How might greater public participation in data sharing and engagement in its use be inspired, in order to enhance the way in which precision medicine can proceed?
• How might relevant institutions be sharing information better?
• What can law achieve in regard to any of these concerns?
CHAIR: Ingrid Slade (Specialist Registrar in Public Health, NHS)
SPEAKERS: Mark Lawler (Prof of Genetics, Queens University Belfast), Anna Middleton (Principal Social Scientist, Wellcome Trust Sanger Institute), Jonathan Montgomery(Professor of Health Care Law, UCL; Chair of Nuffield Council on Bioethics)
________________________________________

Session 4: 3.15-4.30pm Equity and commissioning
There is a pressing practical need to address concepts and mechanisms of justice as pathways to personalised medicine are commissioned in the UK. While there is an intuitive attractiveness to the idea that '4P' medicine will be more cost-effective, there remains questions about affordability, cost-effectiveness, ensuring equality of access, the participatory role of patients and the (re-)alignment of the existing commissioning strategy. There is also a duty of justice towards neighbours, particularly in low- and middle-income countries. A risk attendant on the development of personalised medicine is that of social stratification based on ability to pay which in certain circumstances may lead to corruption. What will the pursuit of value mean when both national and global questions of equity are under consideration?
Questions for discussion include:
• How might precision medicine develop so as to avoid the emergence of greater inequalities?
• What are the relevant inequalities, bearing in mind that the uneven availability of treatment will typically be due to the success of research in specific strata?
• Are threats to a socio-political ethos of risk-pooling inherent to the stratification processes of personalised medicine? If so, can they be adequately addressed?
• What are the policy implications of developments in personalised medicine for commissioners?
• How should the existing emphasis on standardised equitable care for all be connected with the driver towards personalised medicine?
• How might agreement be reached on appropriate levels of funding and outcome measures?
• How can commissioning processes ensure that the precision medicine agenda does not distract from but rather enriches the person-centred-care agenda?
• Who sets the goals (central planners, professionals, pharmaceutical companies, diagnostics companies, patients)?
• Who bears the risks?
• Can personalised medicine really deliver better value?
• Is it a 'Trojan horse' for a neoliberal research agenda?
• Will precision medicine only be available for the rich in many other countries?
• What responsibility, if any, do medical researchers bear for unequal outcomes?
CHAIR: Mark Sheehan (Ethox)
SPEAKERS Muir Gray (Better Value Healthcare, Honorary Professor, Nuffield Department of Primary Care Health Sciences), Richard Sullivan (Chair in Cancer Policy and Global Health, KCL)
________________________________________

4.30pm Closing remarks
Simon Leedham (Director, Centre for Personalised Medicine, University of Oxford), Tim Maughan, Joshua Hordern
Year(s) Of Engagement Activity 2016