Cargando…

A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes

BACKGROUND: It is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other...

Descripción completa

Detalles Bibliográficos
Autores principales: Tomkiewicz, Céline, Hans, Stéphane, Mucchielli, Marie Hélène, Agier, Nicolas, Delacroix, Hervé, Marisa, Laetitia, Brasnu, Daniel, Aggerbeck, Lawrence P., Badoual, Cécile, Barouki, Robert, Aggerbeck, Martine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467249/
https://www.ncbi.nlm.nih.gov/pubmed/23056603
http://dx.doi.org/10.1371/journal.pone.0047170
_version_ 1782245772612337664
author Tomkiewicz, Céline
Hans, Stéphane
Mucchielli, Marie Hélène
Agier, Nicolas
Delacroix, Hervé
Marisa, Laetitia
Brasnu, Daniel
Aggerbeck, Lawrence P.
Badoual, Cécile
Barouki, Robert
Aggerbeck, Martine
author_facet Tomkiewicz, Céline
Hans, Stéphane
Mucchielli, Marie Hélène
Agier, Nicolas
Delacroix, Hervé
Marisa, Laetitia
Brasnu, Daniel
Aggerbeck, Lawrence P.
Badoual, Cécile
Barouki, Robert
Aggerbeck, Martine
author_sort Tomkiewicz, Céline
collection PubMed
description BACKGROUND: It is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other therapeutic options. Further, it is of interest to know to what extent a gene signature, which identifies patients with tumors that will not respond to a particular induction chemotherapy, is applicable when additional chemotherapeutic agents are added to the regimen. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes that predict tumor resistance to induction with cisplatin/5-fluorouracil (PF) or PF and a taxane, we analyzed patient tumor biopsies with whole genome microarrays and quantitative reverse transcriptase-PCR (TLDA) cards. A leave one out cross-validation procedure allowed evaluation of the prediction tool. A ten-gene microarray signature correctly classified 12/13 responders and 7/10 non-responders to PF (92% specificity, 82.6% accuracy). TLDA analysis (using the same classifier) of the patients correctly classified 12/12 responders and 8/10 non-responders (100% specificity, 90.9% accuracy). Further, TLDA analysis correctly predicted the response of 5 new patients and, overall, 12/12 responders and 13/15 non-responders (100% specificity, 92.6% accuracy). The protein products of the genes constituting the signature physically associate with 27 other proteins, involved in regulating gene expression, constituting an interaction network. In contrast, TLDA-based prediction (with the same gene signature) of responses to induction with PF and either of two taxanes was poor (0% specificity, 25% accuracy and 33.3% specificity, 25% accuracy). CONCLUSIONS/SIGNIFICANCE: Successful transfer of the microarray-based gene signature to an independent, PCR-based technology suggests that TLDA-based signatures could be a useful hospital-based technology for determining therapeutic options. Although highly specific for tumor responses to PF induction, the gene signature is unsuccessful when taxanes are added. The results illustrate the subtlety in developing “personalized medicine”.
format Online
Article
Text
id pubmed-3467249
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-34672492012-10-10 A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes Tomkiewicz, Céline Hans, Stéphane Mucchielli, Marie Hélène Agier, Nicolas Delacroix, Hervé Marisa, Laetitia Brasnu, Daniel Aggerbeck, Lawrence P. Badoual, Cécile Barouki, Robert Aggerbeck, Martine PLoS One Research Article BACKGROUND: It is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other therapeutic options. Further, it is of interest to know to what extent a gene signature, which identifies patients with tumors that will not respond to a particular induction chemotherapy, is applicable when additional chemotherapeutic agents are added to the regimen. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes that predict tumor resistance to induction with cisplatin/5-fluorouracil (PF) or PF and a taxane, we analyzed patient tumor biopsies with whole genome microarrays and quantitative reverse transcriptase-PCR (TLDA) cards. A leave one out cross-validation procedure allowed evaluation of the prediction tool. A ten-gene microarray signature correctly classified 12/13 responders and 7/10 non-responders to PF (92% specificity, 82.6% accuracy). TLDA analysis (using the same classifier) of the patients correctly classified 12/12 responders and 8/10 non-responders (100% specificity, 90.9% accuracy). Further, TLDA analysis correctly predicted the response of 5 new patients and, overall, 12/12 responders and 13/15 non-responders (100% specificity, 92.6% accuracy). The protein products of the genes constituting the signature physically associate with 27 other proteins, involved in regulating gene expression, constituting an interaction network. In contrast, TLDA-based prediction (with the same gene signature) of responses to induction with PF and either of two taxanes was poor (0% specificity, 25% accuracy and 33.3% specificity, 25% accuracy). CONCLUSIONS/SIGNIFICANCE: Successful transfer of the microarray-based gene signature to an independent, PCR-based technology suggests that TLDA-based signatures could be a useful hospital-based technology for determining therapeutic options. Although highly specific for tumor responses to PF induction, the gene signature is unsuccessful when taxanes are added. The results illustrate the subtlety in developing “personalized medicine”. Public Library of Science 2012-10-09 /pmc/articles/PMC3467249/ /pubmed/23056603 http://dx.doi.org/10.1371/journal.pone.0047170 Text en © 2012 Tomkiewicz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tomkiewicz, Céline
Hans, Stéphane
Mucchielli, Marie Hélène
Agier, Nicolas
Delacroix, Hervé
Marisa, Laetitia
Brasnu, Daniel
Aggerbeck, Lawrence P.
Badoual, Cécile
Barouki, Robert
Aggerbeck, Martine
A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes
title A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes
title_full A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes
title_fullStr A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes
title_full_unstemmed A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes
title_short A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes
title_sort head and neck cancer tumor response-specific gene signature for cisplatin, 5-fluorouracil induction chemotherapy fails with added taxanes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467249/
https://www.ncbi.nlm.nih.gov/pubmed/23056603
http://dx.doi.org/10.1371/journal.pone.0047170
work_keys_str_mv AT tomkiewiczceline aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT hansstephane aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT mucchiellimariehelene aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT agiernicolas aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT delacroixherve aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT marisalaetitia aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT brasnudaniel aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT aggerbecklawrencep aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT badoualcecile aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT baroukirobert aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT aggerbeckmartine aheadandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT tomkiewiczceline headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT hansstephane headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT mucchiellimariehelene headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT agiernicolas headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT delacroixherve headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT marisalaetitia headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT brasnudaniel headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT aggerbecklawrencep headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT badoualcecile headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT baroukirobert headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes
AT aggerbeckmartine headandneckcancertumorresponsespecificgenesignatureforcisplatin5fluorouracilinductionchemotherapyfailswithaddedtaxanes