Erika Cecchin1, Elena De Mattia2, Eva Dreussi2, Marcella Montico3, Elisa Palazzari4, Federico Navarria4, Francesca Bergamo5, Claudio Belluco6, Luca Quartuccio7, Salvatore De Vita7, Vincenzo Canzonieri8, Sara Gagno2, Chiara Zanusso2, Angela Buonadonna9, Salvatore Pucciarelli10, Antonino De Paoli4, Giuseppe Toffoli2. 1. Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy. Electronic address: ececchin@cro.it. 2. Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy. 3. Scientific Direction, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy. 4. Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy. 5. Medical Oncology 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy. 6. Surgical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy. 7. Department of Medical Area (DAME), Rheumatology Clinic, Santa Maria della Misericordia University Hospital, Udine (UD), Italy. 8. Pathology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, Italy. 9. Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy. 10. Clinica Chirurgica II, Padova University, Padova, Italy.
Abstract
BACKGROUND AND PURPOSE: The role of the immune system in tumor response to chemo-radiotherapy (CRT) is an emerging issue. This work aimed at identifying predictive and prognostic immunogenetic variants in LARC patients after preoperative (po)-CRT and surgery. MATERIALS AND METHODS: A set of 192 polymorphisms in 34 candidate genes involved in the regulation of the immune response signalling network, was selected and analyzed in 370 LARC patients treated with po-CRT and surgery, split into a Test Set (n = 233) and a Validation Set (n = 137). Immunogenetic markers were selected based on a concordant significant effect on 2-year relapse-free survival (2-yrRFS) (bootstrapped P < 0.05) in both patients Sets. The effect of the selected immunogenetic variants on 5-year metastases-free (5yrMFS), 5-year disease-free (5yrDFS), and 10-year overall (10yrOS) survival was tested in the entire Set of 370 patients. RESULTS: Two immunogenetic IL17F (IL17F-rs641701 and IL17F-rs9463772) markers predictive of 2yrRFS, 5yrDFS, 5yrMFS, and 10yrOS were identified. The combination of tumor regression grade (TRG) and patients genotype for IL17F-rs641701 and IL17F-rs9463772 allowed the identification of subgroups of patients with differential prognosis in term of both 5yrDFS (HR 11.29, P-value <0.001, and HR 5.86, P-value = 0.001, respectively) and 10yrOS (HR 7.07, P-value = 0.005, and HR 6.05, P-value = 0.002, respectively). CONCLUSION: IL17F-rs641701 and IL17F-rs9463772 were highlighted as promising immunogenetic markers significantly associated with the prognosis of LARC patients. After a prospective validation of the herein reported findings, the combination of TRG and patients genotype should be considered to provide additional stratification criteria for the selection of a personalized multimodality treatment.
BACKGROUND AND PURPOSE: The role of the immune system in tumor response to chemo-radiotherapy (CRT) is an emerging issue. This work aimed at identifying predictive and prognostic immunogenetic variants in LARCpatients after preoperative (po)-CRT and surgery. MATERIALS AND METHODS: A set of 192 polymorphisms in 34 candidate genes involved in the regulation of the immune response signalling network, was selected and analyzed in 370 LARCpatients treated with po-CRT and surgery, split into a Test Set (n = 233) and a Validation Set (n = 137). Immunogenetic markers were selected based on a concordant significant effect on 2-year relapse-free survival (2-yrRFS) (bootstrapped P < 0.05) in both patients Sets. The effect of the selected immunogenetic variants on 5-year metastases-free (5yrMFS), 5-year disease-free (5yrDFS), and 10-year overall (10yrOS) survival was tested in the entire Set of 370 patients. RESULTS: Two immunogenetic IL17F (IL17F-rs641701 and IL17F-rs9463772) markers predictive of 2yrRFS, 5yrDFS, 5yrMFS, and 10yrOS were identified. The combination of tumor regression grade (TRG) and patients genotype for IL17F-rs641701 and IL17F-rs9463772 allowed the identification of subgroups of patients with differential prognosis in term of both 5yrDFS (HR 11.29, P-value <0.001, and HR 5.86, P-value = 0.001, respectively) and 10yrOS (HR 7.07, P-value = 0.005, and HR 6.05, P-value = 0.002, respectively). CONCLUSION:IL17F-rs641701 and IL17F-rs9463772 were highlighted as promising immunogenetic markers significantly associated with the prognosis of LARCpatients. After a prospective validation of the herein reported findings, the combination of TRG and patients genotype should be considered to provide additional stratification criteria for the selection of a personalized multimodality treatment.