Title: Novel blood test to personalise Early Stage Colorectal Cancer treatment
Funder: Medical Research Council

Abstract: This study will assess the use of a new blood test to precisely guide who should be offered chemotherapy after surgery for bowel cancer. By the end of the study we will know whether use of this new test allows some people to avoid chemotherapy and whether this can be used in the NHS. _x000D_ _x000D_ Bowel cancer is the 3rd most common cancer (men and women), with more than 40,000 people diagnosed each year in the UK. Most patients have an operation to remove the tumour. Unfortunately, the cancer returns in up to 1 of 2 patients and chemotherapy is generally offered to reduce the chance of cancer coming back._x000D_ _x000D_ Chemotherapy works by killing off remaining microscopic size cancer cells left behind after surgery. Untreated, this microscopic disease will cause the cancer to return, often within 3 years. Understandably, many patients choose to receive chemotherapy hoping to improve their chances of cure. However, 1 in 2 patients do not have microscopic disease. They are cured by the surgery alone and chemotherapy is unnecessary for them. _x000D_ _x000D_ To date, it has not been possible to detect which patients have microscopic cancer cells left after surgery and which patients do not. This has prevented doctors from being able to precisely advise each patient on whether they are likely to benefit from chemotherapy. Therefore, these patients are currently offered chemotherapy._x000D_ _x000D_ Unfortunately, chemotherapy produces side-effects that can include mouth ulcers, loss of appetite, diarrhoea, sore hands and feet, brittle hair and nails. More serious and troublesome side-effects include: damage to the nerves in the hands and feet, life threatening infections, cardiac chest pain, and blood clots. Although side effects can be temporary, they are sometimes life-long and patients report them to be debilitating, cause anxiety, impact close relationships and impair their ability to work. _x000D_ _x000D_ A new test has been developed that now allows the accurate detection and measurement of microscopic cancer through analysis of blood samples. This measures DNA shed from microscopic size cancer cells into the bloodstream. Several small studies have shown that a positive DNA blood test after surgery accurately predicted those patients in whom the cancer returned. The next step is to use each patient’s DNA blood test after surgery to precisely guide recommendations for chemotherapy treatment for each individual patient. _x000D_ _x000D_ We have an established network of UK hospitals that are recruiting patients undergoing surgery for bowel cancer to a national study. We are currently collecting blood samples from them and monitoring for relapse of their cancer. We now propose to modify this study so that for some of these patients, their blood samples (taken shortly after surgery) are used to help precisely guide whether they should receive chemotherapy and the type of chemotherapy treatment they receive. _x000D_ _x000D_ This study has been designed with patients who have lived experience of bowel cancer and chemotherapy. Lay people will continue to play an important role in the delivery of this research, representing the patient perspective, protecting the public interest and supporting our communication to lay audiences. Assuming that this study shows that the blood test helps us precisely guide chemotherapy, we will use our connections and influence amongst those who commission and provide services to ensure practice is changed. Reducing the use of unnecessary chemotherapy after bowel surgery through our proposed precise approach would benefit patients, but could also significantly save NHS resources. This could revolutionise treatment for operable bowel cancer within 5-8 years.

Lay abstract: Research question: Is circulating tumour DNA (ctDNA) guided chemotherapy following surgery for colorectal cancer (CRC) a better strategy for clinical and health economic outcomes in comparison to the current ‘one-size fits all’ standard of care approach?_x000D_ _x000D_ Background: There are 42,000 new cases of CRC, a top four cancer, diagnosed in the UK each year. Approximately half of these cases are curable and include stage II (n=9600/year) and III (n=10,500/year). Currently patients with stage II disease (node negative) with high risk pathological features (~25%) and stage III (node positive) disease are standardly offered post-operative chemotherapy for 3-6 months with one or two drugs in a ‘one size fits all’ approach to reduce risk of relapse. However, >50% (stage III) and >80% (high risk stage II) of patients are already cured by surgery alone and are being exposed to unnecessary chemotherapy with short- and long-term side effects. There is significant unmet need to spare appropriate patients from futile treatment. ctDNA identifies minimal residual disease (MRD) after surgery in many cancers including CRC. Detected by sequencing technologies, this novel blood test for the first time offers a personalised strategy to select patients for chemotherapy after surgery based on the presence or absence of ctDNA. _x000D_ _x000D_ Aim: To evaluate the clinical and cost-effectiveness of using ctDNA as a strategy to precisely guide the use of chemotherapy for CRC following surgery._x000D_ Objectives:_x000D_ I. To compare whether post-operative ctDNA guided therapy (ctDNA negative patients have de-escalated chemotherapy and ctDNA positive patients receive standard of care chemotherapy) is non-inferior to standard selection for chemotherapy for 3 year disease free survival (DFS) in high-risk stage II or stage III CRC _x000D_ II. To define the proportion of patients with high-risk stage II/stage III CRC who are ctDNA negative and positive post-operatively and the proportion who become ctDNA positive during follow-up; to evaluate escalation of chemotherapy in early (3 month) ctDNA emergence_x000D_ III. To compare rates of side effects, especially neurotoxicity, and Quality of Life (QoL) between those who receive ctDNA guided chemotherapy and those who receive standard of care_x000D_ IV. To describe ctDNA directed chemotherapy associated costs; to evaluate the cost-effectiveness of ctDNA-directed chemotherapy arm compared to the standard of care arm_x000D_ V. To potentially pool analyses from similar studies occurring globally_x000D_ _x000D_ Methods: This will be a UK-wide, multi-site, prospective, two-arm, parallel group, randomised trial_x000D_ _x000D_ Timelines for delivery: This study builds on an NIHR adopted observational longitudinal study of ctDNA post CRC surgery (TRACC), open in 18 UK centres. We have ethical approval to amend TRACC for ctDNA directed treatment (interventional) and recruit 1,620 patients over 4 years. With significant interest from more sites and as international leaders in ctDNA studies, we can immediately initiate this study and complete within schedule, should this application be successful._x000D_ _x000D_ Anticipated impact: Implementation of this novel blood test as standard of care could revolutionise treatment for operable CRC within 8 years. Of the ~13,000 people diagnosed with high risk stage II or III every year, half may be potentially spared unnecessary chemotherapy and related harmful side effects with NHS savings of ~ £16m/year.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS