KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma

OBJECTIVES: There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreat...

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Autores principales: Bournet, Barbara, Muscari, Fabrice, Buscail, Camille, Assenat, Eric, Barthet, Marc, Hammel, Pascal, Selves, Janick, Guimbaud, Rosine, Cordelier, Pierre, Buscail, Louis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822095/
https://www.ncbi.nlm.nih.gov/pubmed/27010960
http://dx.doi.org/10.1038/ctg.2016.18
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author Bournet, Barbara
Muscari, Fabrice
Buscail, Camille
Assenat, Eric
Barthet, Marc
Hammel, Pascal
Selves, Janick
Guimbaud, Rosine
Cordelier, Pierre
Buscail, Louis
author_facet Bournet, Barbara
Muscari, Fabrice
Buscail, Camille
Assenat, Eric
Barthet, Marc
Hammel, Pascal
Selves, Janick
Guimbaud, Rosine
Cordelier, Pierre
Buscail, Louis
author_sort Bournet, Barbara
collection PubMed
description OBJECTIVES: There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer. METHODS: The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan–Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment. RESULTS: A total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7–12.3) and the wild-type (9 months; 95% CI: 8.7–12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4–9.7) compared with the other patients (OS: 9 months; 95% CI: 10–13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02). CONCLUSIONS: The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.
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spelling pubmed-48220952016-04-14 KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma Bournet, Barbara Muscari, Fabrice Buscail, Camille Assenat, Eric Barthet, Marc Hammel, Pascal Selves, Janick Guimbaud, Rosine Cordelier, Pierre Buscail, Louis Clin Transl Gastroenterol Original Contributions OBJECTIVES: There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer. METHODS: The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan–Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment. RESULTS: A total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7–12.3) and the wild-type (9 months; 95% CI: 8.7–12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4–9.7) compared with the other patients (OS: 9 months; 95% CI: 10–13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02). CONCLUSIONS: The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways. Nature Publishing Group 2016-03 2016-03-24 /pmc/articles/PMC4822095/ /pubmed/27010960 http://dx.doi.org/10.1038/ctg.2016.18 Text en Copyright © 2016 American College of Gastroenterology http://creativecommons.org/licenses/by-nc-sa/4.0/ Clinical and Translational Gastroenterology is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Original Contributions
Bournet, Barbara
Muscari, Fabrice
Buscail, Camille
Assenat, Eric
Barthet, Marc
Hammel, Pascal
Selves, Janick
Guimbaud, Rosine
Cordelier, Pierre
Buscail, Louis
KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma
title KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma
title_full KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma
title_fullStr KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma
title_full_unstemmed KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma
title_short KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma
title_sort kras g12d mutation subtype is a prognostic factor for advanced pancreatic adenocarcinoma
topic Original Contributions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822095/
https://www.ncbi.nlm.nih.gov/pubmed/27010960
http://dx.doi.org/10.1038/ctg.2016.18
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