Microbiome, Immune-system and Tumor Interaction in Colorectal Cancer

Overview

Colorectal cancers represent the second leading cause of cancer-related death in the United States Western world. In Italy they represent the second most frequent neoplasm (49,000 cases in 2019). Despite the advancement of surgical techniques and medical therapy programs systemic, it is estimated that approximately 40-50% of colorectal cancers recur after being treated for a limited loco-regional disease. Patients who develop metastases throughout their history clinic have a 5-year overall survival of just over 10%. Adjuvant systemic chemotherapy can reduce the risk of disease recurrence in patients with colorectal adenocarcinomas, however, the standard drugs used to date for this use (fluoropyrimidines and oxaliplatin) have not undergone substantial changes in the last 20 years or so. A crucial point is the need to have more precise information regarding risk factors above all biomolecular to base therapeutic choices. It has now become urgent to overcome the T-tumor N-node M- metastasis (TNM) staging, to have more modern knowledge on the factors capable of impacting significantly on the prognosis, influence the real risk of disease recurrence, Identify new prognostic categories and subcategories, therefore being able to predict the clinical benefit of treatments that can be more targeted, personalized and effective. In this panorama it has developed in recent years an ever-growing literature also regarding the role of bacterial flora intestinal (microbiota) in patients with colorectal cancer. In particular, recent discoveries have highlighted the immunoregulatory role of the microbiota in the anti-tumor response. This study aims of evaluating how the molecular characteristics of the tumor, of the infiltrating immune system cells and of the associated intestinal microbiota correlate with the development of colorectal cancer, its progression and response to treatments.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality. Despite the improvement of surgical techniques, \~30-50% of patients with locoregional CRC who undergo potentially curative surgery ultimately relapse and die of metastatic disease. On the other hand, it is also well established that adjuvant systemic chemotherapy can decrease the risk of death in these patients. Currently, the standard treatment of locoregional CRC is based on curative surgery alone or followed by adjuvant systemic chemotherapy based on risk factors. In this regard, international guidelines recommend chemotherapy for stage III and stage II colon cancer with high risk prognostic characteristics, including T4 lesions, poorly differentiated tumors, lymphovascular or perineural invasion, tumour presentation with obstruction or tumour perforation, positive margins, and inadequate (\<12) number of lymph nodes analyzed after surgery. In patients treated with surgery and adjuvant systemic chemotherapy the 3-year disease-free survival (3y DFS) is 72% in stage III patients and 87% in stage II patients.The risk factors known to date do not always correctly predict the prognosis in these patients. For example, tumors of the same stage can largely differ in both prognosis, which can lead to wrong treatment decisions. This means that our knowledge about factors influencing the chance of recurrence and the prediction of benefit from systemic treatment is limited. Identification of these factors along with better treatment strategies may help in reducing the recurrence rate and raising the life expectancy of CRC patients. In this regard, the role of commensal microbiota in CRC development and response to treatments is emerging as a critical factor. The term microbiome "refers to the microorganisms involved but also encompasses their theatre of activity". In a mutually beneficial and dynamic equilibrium, bacteria coexist on our body stimulating the basal production of tissue repair factors while immune system surveils on pathogens outgrowth. The gut microbiota has been consistently shown to play a role in the development of CRC, The present project will establish the foundation of methods for early detection of the microbiome-immune-induced mutator phenotypes involved in the relapse. Results from this study will pave the way for future interventions to constrain the mutation rates of tumor. Through this prospective observational Microbiome Immune-system Tumor Interaction in Colorectal Oncology (MITICO) project a new platform will be established integrating patient's clinical and lifestyle information with genomic data from both, CRC and the commensal microbiota, along with profiling of local and systemic immune responses.