IMMUNOlogical Microenvironment in REctal Adenocarcinoma Treatment.

Background The current management on rectal cancer based on TNM staging has some limitations. 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. 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 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 project aim is to identify, among locally advanced rectal cancer, those with sustained complete response to neoadjuvant chemo/radiotherapy. The study is articulated in two steps. 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.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. locally advanced (cT3-4 and/or N+, TNM stage II-III) low and medium rectal cancer (\<11 cm) or low rectum adenocarcinoma cT≤2, at risk for abdominoperineal amputation, undergoing neoadjuvant therapy will be included in the study group.
2. Only neoadjuvant therapy protocols including long course radiotherapy (45 Gy) and fluoropyrimidine-based regimens will be included while short radiation therapy of radiation therapy or chemotherapy alone will be excluded
3. at least 6 weeks after the end of the neoadjuvant therapy will be included
4. Full availability of clinical records at least 1 year of follow up

• DERIVEDBecherucci G, Ruffolo C, Scarpa M, Scognamiglio F, Stepanyan A, Maretto I, Kotsafti A, De Simoni O, Pilati P, Franzato B, Scapinello A, Bergamo F, Massani M, Stecca T, Pozza A, Cataldo I, Brignola S, Pellegrini V, Fassan M, Guzzardo V, Dal Santo L, Salmaso R, Carlotta C, Dei Tos AP, Angriman I, Spolverato G, Chiminazzo V, Negro S, Vignotto C, Marchegiani F, Facci L, Rivella G, Bao QR, Baldo A, Pucciarelli S, Zizzo M, Businello G, Salmaso B, Parini D, Pirozzolo G, Recordare A, Tagliente G, Bordignon G, Merenda R, Licia L, Pozza G, Godina M, Mondi I, Verdi D, Da Lio C, Guerriero S, Piccioli A, Portale G, Zuin M, Cipollari C, Noaro G, Cola R, Candioli S, Gavagna L, Ricagna F, Ortenzi M, Guerrieri M, Tomassi M, Tedeschi U, Marinelli L, Barbareschi M, Bertalot G, Brolese A, Ceccarini L, Antoniutti M, Porzionato A, Agostini M, Cavallin F, Tussardi G, Di Camillo B, Bardini R, Castagliuolo I, Scarpa M. IMMUNOREACT 8: Immune markers of local tumor spread in patients undergoing transanal excision for clinically N0 rectal cancer. Surgery. 2025 Feb;178:108902. doi: 10.1016/j.surg.2024.09.043. Epub 2024 Nov 20. PMID 39572264
• DERIVEDSpolverato G, Fassan M, Scarpa M, Stepanyan A, De Simoni O, Scognamiglio F, Chiminazzo V, De Nardi C, Tamponi G, Negro S, Angriman I, Kotsafti A, Ruffolo C, Vignotto C, Zizzo M, Marchegiani F, Facci L, Bergamo F, Brignola S, Businello G, Guzzardo V, Dal Santo L, Salmaso R, Ceccon C, Massani M, Pozza A, Cataldo I, Stecca T, Dei Tos AP, Zagonel V, Pilati P, Franzato B, Scapinello A, Pirozzolo G, Recordare A, Merenda R, Bordignon G, Laurino L, Guerriero S, Romiti C, Portale G, Cipollari C, Candioli S, Gavagna L, Pozza G, Godina M, Mondi I, Noaro G, Ortenzi M, Guerrieri M, Tagliente G, Tomassi M, Tedeschi U, Porzionato A, Agostini M, Maretto I, Bao QR, Cavallin F, Di Camillo B, Bardini R, Castagliuolo I, Pucciarelli S, Scarpa M; IMMUNOREACT Study Group. IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer. Br J Surg. 2023 Oct 10;110(11):1490-1501. doi: 10.1093/bjs/znad219. PMID 37478362