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SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy

Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to invest...

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Autores principales: De Mattia, Elena, Canzonieri, Vincenzo, Polesel, Jerry, Mezzalira, Silvia, Dalle Fratte, Chiara, Dreussi, Eva, Roncato, Rossana, Bignucolo, Alessia, Innocente, Roberto, Belluco, Claudio, Pucciarelli, Salvatore, De Paoli, Antonino, Palazzari, Elisa, Toffoli, Giuseppe, Cecchin, Erika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740633/
https://www.ncbi.nlm.nih.gov/pubmed/35002714
http://dx.doi.org/10.3389/fphar.2021.778781
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author De Mattia, Elena
Canzonieri, Vincenzo
Polesel, Jerry
Mezzalira, Silvia
Dalle Fratte, Chiara
Dreussi, Eva
Roncato, Rossana
Bignucolo, Alessia
Innocente, Roberto
Belluco, Claudio
Pucciarelli, Salvatore
De Paoli, Antonino
Palazzari, Elisa
Toffoli, Giuseppe
Cecchin, Erika
author_facet De Mattia, Elena
Canzonieri, Vincenzo
Polesel, Jerry
Mezzalira, Silvia
Dalle Fratte, Chiara
Dreussi, Eva
Roncato, Rossana
Bignucolo, Alessia
Innocente, Roberto
Belluco, Claudio
Pucciarelli, Salvatore
De Paoli, Antonino
Palazzari, Elisa
Toffoli, Giuseppe
Cecchin, Erika
author_sort De Mattia, Elena
collection PubMed
description Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group (n = 378), a set of SMAD3 polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity >55% (OR:10.36, p = 0.0004), or moderate/high intensity (OR:5.20, p = 0.0038), or an H-score≥1 (OR:9.84, p = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48, p = 0.0093), a longer OS (HR:0.65, p = 0.0307), and a trend for longer PFS (HR:0.75, p = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45, p = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens.
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spelling pubmed-87406332022-01-08 SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy De Mattia, Elena Canzonieri, Vincenzo Polesel, Jerry Mezzalira, Silvia Dalle Fratte, Chiara Dreussi, Eva Roncato, Rossana Bignucolo, Alessia Innocente, Roberto Belluco, Claudio Pucciarelli, Salvatore De Paoli, Antonino Palazzari, Elisa Toffoli, Giuseppe Cecchin, Erika Front Pharmacol Pharmacology Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group (n = 378), a set of SMAD3 polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity >55% (OR:10.36, p = 0.0004), or moderate/high intensity (OR:5.20, p = 0.0038), or an H-score≥1 (OR:9.84, p = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48, p = 0.0093), a longer OS (HR:0.65, p = 0.0307), and a trend for longer PFS (HR:0.75, p = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45, p = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens. Frontiers Media S.A. 2021-12-24 /pmc/articles/PMC8740633/ /pubmed/35002714 http://dx.doi.org/10.3389/fphar.2021.778781 Text en Copyright © 2021 De Mattia, Canzonieri, Polesel, Mezzalira, Dalle Fratte, Dreussi, Roncato, Bignucolo, Innocente, Belluco, Pucciarelli, De Paoli, Palazzari, Toffoli and Cecchin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
De Mattia, Elena
Canzonieri, Vincenzo
Polesel, Jerry
Mezzalira, Silvia
Dalle Fratte, Chiara
Dreussi, Eva
Roncato, Rossana
Bignucolo, Alessia
Innocente, Roberto
Belluco, Claudio
Pucciarelli, Salvatore
De Paoli, Antonino
Palazzari, Elisa
Toffoli, Giuseppe
Cecchin, Erika
SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy
title SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy
title_full SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy
title_fullStr SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy
title_full_unstemmed SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy
title_short SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy
title_sort smad3 host and tumor profiling to identify locally advanced rectal cancer patients at high risk of poor response to neoadjuvant chemoradiotherapy
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740633/
https://www.ncbi.nlm.nih.gov/pubmed/35002714
http://dx.doi.org/10.3389/fphar.2021.778781
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