Personalizing Colorectal Cancer Medicine (ImmuCol2)

Overview

Colorectal cancers are the leading cancers for both sexes combined. They represent 15-20% of all cancers. This cancer has a severe prognosis, the survival rate at 5 years is around 55% and in France it is estimated, all colorectal cancers are responsible for an annual mortality of 15,000 patients. The prognosis of colon cancer knows no significant improvement. The treatment of colon cancer is surgical. It is intended for removal of colonic segment bearing the tumor with margins of healthy colon. The therapeutic attitude following the surgery is essentially driven by histopathology of the tumor. Adjuvant chemotherapy for all patients with localized stage II provides no benefit because the effectiveness of chemotherapy is limited and vulnerable to systemic toxicity. However, nearly 30% of patients with stage II disease will have a recurrence / metastasis. These patients could benefit from adjuvant chemotherapy. Intense research efforts have been made to identify markers predictive of relapse. Over thirty biological markers (eg. Mutations, deletions, chromosomal instability, ...) were highlighted. None of them has so far sufficient prognostic value (independent of TNM) to justify routine application in clinical practice in order to adapt the treatment of patients. The identification of new prognostic markers is a major issue for colorectal cancer. We showed that the intratumoral density memory T lymphocytes (CD45RO) and cytotoxic (CD8) strongly influenced the clinical outcome of patients. We have developed and validated a "immunoscore" technique intratumoral immune quantification and creates a platform to facilitate the clinical immuno transfer. We are currently conducting a large international retrospective study (22 centers,\> 9000 patients) with promotion of cancer immunotherapy Company (SITC) to validate the method "immunoscore." At the same time, we are conducting a prospective multicenter study "ImmuCol" (National PHRC) to validate the prognostic value of "immunoscore" in colorectal cancer stage I-IV. The goal of inclusion has been achieved, as 420 patients were included for 18 months. Clinical follow-up will be 3 years after surgery. The program ImmuCol2 research takes advantage of the ImmuCol study to extend the investigation beyond the immunoscore to define the combination of interest, prognostic and theranostic parameters at diagnosis and during the clinical course patients with an objective of personalized medicine.

The project aims: (i) to combine at time of diagnosis the immunoscore with parameters related to the patient, its tumor and the associated microenvironment (ii) to detect events occurring during the follow up period that could modify the initial prognosis and lead to a repositioning of the patient, to move towards a dynamic personalized medicine. (iii) to explore the Theranostic aspect of the parameters monitored at the time of diagnosis for patients with colonic cancers treated with adjuvant chemotherapy. To this end we will investigate: * Tumor's features: \- We will determine the microsatellite instability status and search for mutations of 46 genes (ABL1, AKT1, ALK, APC, ATM, BRAF, CCDH1, CDKN2A, CSF1R, CTNNB, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, NOTCH1, NPM1, NRAS, PDGFRA, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, STK11, TP53, VHL) by next generation sequencing (NGS). * Tumor immune microenvironment features: \- 24 immune related genes, 24 miRNA and co-inihibitory molecules (PD1, PD1-L, LAG-3, TIM3, CTLA-4) will be explored on tumor samples. * Systemic disorders: * Autoimmunity, allergy or inflammatory diseases will be sought with a dedicated questionnaire filled out by the patient and a serum examination for the screening of immune disorders at the time of diagnosis and during the survey. * The nutritional status (% of weight loss) and the deficiencies in vitamins, folic acid, trace elements and thyroid hormones that synergise with immune cells will be determined at the time of diagnosis. * Psychological status: \- The impact of the psychological profile of the patient will be investigated with a dedicated questionnaire, given at the time of diagnosis and every six months. * Data mining to achieve a dynamic personalized medicine: The integration and statistical analysis of heterogeneous data types (clinical and different experimental data) will be performed using with tranSMART, an open source platform and with bioinformatic tools (TMEdb, ClueGO, CluePedia, Genesis) developed by participant teams.