Novel blood test to personalise Early Stage Colorectal Cancer treatment

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? 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. 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. Objectives: 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 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 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 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 V. To potentially pool analyses from similar studies occurring globally Methods: This will be a UK-wide, multi-site, prospective, two-arm, parallel group, randomised trial 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. 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.