According to the Global cancer observatory database (Globocan) estimates, there are 447,136 new cases of Colo-Rectal Cancer (CRC) in Europe annually. This makes CRC the 2nd most common cancer in Europe, accounting for 13.0% of all cancers in 2012 with an estimate of 214,866 deaths from CRC in Europe (12.2% of the total number of cancer deaths, 2nd most common cause of cancer related deaths). In LIMA, the rectal cancer patient sub-group of CRC will be studied, comprising some 80,000 patients annually, as these patients are treated in neoadjuvant setting. Moreover, ineffective NeoAdjuvant Treatment (NAT) in rectal cancer patients will results in surgery with severe side effect, making stratification of patients according to their Neoadjuvant Chemotherapy (NAT) response a real challenge for this pathology.

Cancer is a very heterogeneous disease characterized by high variability of response to therapy. In general, it is unknown which cancers will respond to a certain therapy and which will not. Overall trend is to come to less invasive and more personalized treatment. Personalized medicine for cancer patients aims to tailor the best treatment options for the individual at diagnosis and during treatment. This requires accurate patient stratification based on molecular profiling of the tumour and its heterogeneity, not only at the first diagnosis but during the whole treatment. Treatment of cancer is associated with significant comorbidity and reduced quality of life, especially when an organ like the rectum, would need to be surgically removed to increase chances of curation of the disease. But also side-effects of treatment are important to consider. In the past decade the use of NAT has emerged as an effective therapeutic approach to reduce tumour volume and aggressiveness prior to surgery, resulting in increased chances at curative resection and saving the organ and to test sensitivity of a tumour to a therapy that will be used in adjuvant setting following surgery. The development of drugs that target tumour driving signal transduction pathways provides a very effective set of new cancer drugs to choose from in the neoadjuvant or adjuvant setting. This is based however on the premise that the tumour driving pathway is accurately defined in the tumour tissue and the appropriate targeted drug is selected. Using these drugs requires a personalized approach with careful matching of patient to drug therapy. In the neoadjuvant setting this poses a challenge, since tumours can be heterogenic with respect to the tumour driving signalling pathways, especially when high grade and larger sized. In such a case, multiple biopsies would need to be taken to enable accurate characterization of the whole tumour. Unfortunately this is often not feasible, while recent insights suggest that resulting inflammation of the tumour microenvironment may contribute to a more aggressive behaviour of the cancer cells. Another challenge in neoadjuvant treatment is early assessment of therapy response, to enable timely switching to another, more effective therapy in case of a non-response. In addition, in the case of use of targeted drugs, emerging resistance can be a problem, which should be detected as soon as possible. Aim of this project is to improve monitoring of patients' response at the diagnosis and during neoadjuvant treatment, to stratify the good and poor responders to Neoadjuvant chemotherapy (NAT), earlier and better than is currently possible.

The recently developed liquid biopsy technology (to obtain and characterize tumour cells and tumour components like Deoxyribonucleic Acid (DNA) or Ribonucleic Acid (RNA) from a simple blood draw), in combination with advanced Magnetic Resonance Imaging techniques (MRI), can tackle the following problems: 1. Assessment of tumour heterogeneity from liquid biopsies. 2. Assessment from advanced MRI feature extraction to indicate poor outcome 3. Faster assessment of therapy response in NAT for rectal cancer; 4. Detection of emerging drug/therapy resistance. This project overall objective is to develop and validate technologies and tools to include liquid biopsies in the clinical workflow, aiming at introducing a more precise and dynamic genetic characterization of tumour at the diagnosis and during treatment phases.