IMMUNOlogical Microenvironment in REctal Adenocarcinoma Treatment

ABSTRACT Background The current management on rectal cancer based on TNM staging has some limitations. In early rectal cancer T stage can be not sufficient to predict the nodal status and, in locally advanced rectal cancer after neoadjuvant therapy the persistence of a complete response to therapy cannot be accurately predicted by the simple tumor regression grade. For both cases the current guidelines recommend the complete rectal resection with a total mesorectal excision. The implications for patients' quality of life are evident even in case of sphincter sparing surgery. Moreover, in both cases the cancer sample available for the analysis can be small or inexistent. Hypothesis The main hypothesis underlying our research is that the aggressiveness of rectal cancer is determined by the complex interactions between the malignant cells and their immune microenvironment. The second hypothesis is that relevant trace of this cross talk between tumor cells and immune microenvironment can be detected in the normal mucosa surrounding the cancer according to the concept of field cancerization. Aims The aim of this project is to analyze the healthy rectal mucosa surrounding the cancer to identify traces of immunosurveillance mechanisms and of field cancerization and to use them to obtain a composite prognostic test to predict nodal metastasis in early rectal cancer and recurrence after complete response at neoadjuvant therapy in case of locally advanced rectal cancer. Experimental Design This prognostic test will be constructed on the combinatory analysis of the transcriptome, immune and epithelial cells cross-talk, immune checkpoints and miRNA expression in normal rectal mucosa surrounding cancer. The aim is to predict the presence of nodal metastasis in patients with early rectal cancer. In step A, we will retrospectively analyze archival tissue samples in order to identify the most performing biomarkers; in step B, we will validate the prognostic performance of the markers identified in phase I through a prospective analysis of rectal mucosa specimen. Expected Results The anticipated outcome of this project is to generate one or different combination of markers to optimize rectal management and to predict rectal cancer patients outcome more accurately than traditional TNM staging or tumore regression grade. We expect to obtain a prognostic test from normal tissue that accurately predicts rectal cancer behavior even in case when the tumor samples are scarce (early rectal cancer) or absent (complete response to therapy) to avoid unnecessary total rectal excision. Impact On Cancer An immunoscore specific for rectal cancer may predict tumor progression and clinical outcome more accurately and may contribute to better design a personalized therapeutic algorithm. Moreover, nowadays patients with early rectal cancer without nodal involvement and patients with potential complete response to neoadjuvant therapy still undergo total rectal excision which is a risky procedure that impairs quality of life. The use of this new prognostic test may make possible to adopt a minimally invasive approach or even simple observation if nodal involvement or residual disease are reasonably excluded.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1\. T1 and T2 rectal carcinoma operated on will be included in the study group. 2. A minimal number of 10 retrieved lymph nodes will be required for the inclusion in case of anterior resection or Miles abdominal perineal resection 3. Full availability of clinical records and at least 1 year of follow up

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