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

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.

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.

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.