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The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab

BACKGROUND: The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection...

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Autores principales: Demurtas, Laura, Puzzoni, Marco, Giampieri, Riccardo, Ziranu, Pina, Pusceddu, Valeria, Mandolesi, Alessandra, Cremolini, Chiara, Masi, Gianluca, Gelsomino, Fabio, Antoniotti, Carlotta, Loretelli, Cristian, Meriggi, Fausto, Zaniboni, Alberto, Falcone, Alfredo, Cascinu, Stefano, Scartozzi, Mario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537494/
https://www.ncbi.nlm.nih.gov/pubmed/28632725
http://dx.doi.org/10.1038/bjc.2017.178
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author Demurtas, Laura
Puzzoni, Marco
Giampieri, Riccardo
Ziranu, Pina
Pusceddu, Valeria
Mandolesi, Alessandra
Cremolini, Chiara
Masi, Gianluca
Gelsomino, Fabio
Antoniotti, Carlotta
Loretelli, Cristian
Meriggi, Fausto
Zaniboni, Alberto
Falcone, Alfredo
Cascinu, Stefano
Scartozzi, Mario
author_facet Demurtas, Laura
Puzzoni, Marco
Giampieri, Riccardo
Ziranu, Pina
Pusceddu, Valeria
Mandolesi, Alessandra
Cremolini, Chiara
Masi, Gianluca
Gelsomino, Fabio
Antoniotti, Carlotta
Loretelli, Cristian
Meriggi, Fausto
Zaniboni, Alberto
Falcone, Alfredo
Cascinu, Stefano
Scartozzi, Mario
author_sort Demurtas, Laura
collection PubMed
description BACKGROUND: The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting. METHODS: We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months. RESULTS: Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001). CONCLUSIONS: In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies.
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spelling pubmed-55374942018-07-25 The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab Demurtas, Laura Puzzoni, Marco Giampieri, Riccardo Ziranu, Pina Pusceddu, Valeria Mandolesi, Alessandra Cremolini, Chiara Masi, Gianluca Gelsomino, Fabio Antoniotti, Carlotta Loretelli, Cristian Meriggi, Fausto Zaniboni, Alberto Falcone, Alfredo Cascinu, Stefano Scartozzi, Mario Br J Cancer Clinical Study BACKGROUND: The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting. METHODS: We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months. RESULTS: Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001). CONCLUSIONS: In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies. Nature Publishing Group 2017-07-25 2017-06-20 /pmc/articles/PMC5537494/ /pubmed/28632725 http://dx.doi.org/10.1038/bjc.2017.178 Text en Copyright © 2017 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Clinical Study
Demurtas, Laura
Puzzoni, Marco
Giampieri, Riccardo
Ziranu, Pina
Pusceddu, Valeria
Mandolesi, Alessandra
Cremolini, Chiara
Masi, Gianluca
Gelsomino, Fabio
Antoniotti, Carlotta
Loretelli, Cristian
Meriggi, Fausto
Zaniboni, Alberto
Falcone, Alfredo
Cascinu, Stefano
Scartozzi, Mario
The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab
title The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab
title_full The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab
title_fullStr The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab
title_full_unstemmed The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab
title_short The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab
title_sort role of primary tumour sidedness, egfr gene copy number and egfr promoter methylation in ras/braf wild-type colorectal cancer patients receiving irinotecan/cetuximab
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537494/
https://www.ncbi.nlm.nih.gov/pubmed/28632725
http://dx.doi.org/10.1038/bjc.2017.178
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