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Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein

Precision medicine is defined by the administration of drugs based on the tumor’s particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC...

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Autores principales: Ghiringhelli, Francois, Richard, Corentin, Chevrier, Sandy, Végran, Frédérique, Boidot, Romain
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Baishideng Publishing Group Inc 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192280/
https://www.ncbi.nlm.nih.gov/pubmed/28082821
http://dx.doi.org/10.3748/wjg.v22.i48.10680
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author Ghiringhelli, Francois
Richard, Corentin
Chevrier, Sandy
Végran, Frédérique
Boidot, Romain
author_facet Ghiringhelli, Francois
Richard, Corentin
Chevrier, Sandy
Végran, Frédérique
Boidot, Romain
author_sort Ghiringhelli, Francois
collection PubMed
description Precision medicine is defined by the administration of drugs based on the tumor’s particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.
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spelling pubmed-51922802017-01-12 Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein Ghiringhelli, Francois Richard, Corentin Chevrier, Sandy Végran, Frédérique Boidot, Romain World J Gastroenterol Case Report Precision medicine is defined by the administration of drugs based on the tumor’s particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency. Baishideng Publishing Group Inc 2016-12-28 2016-12-28 /pmc/articles/PMC5192280/ /pubmed/28082821 http://dx.doi.org/10.3748/wjg.v22.i48.10680 Text en ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved. http://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
spellingShingle Case Report
Ghiringhelli, Francois
Richard, Corentin
Chevrier, Sandy
Végran, Frédérique
Boidot, Romain
Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein
title Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein
title_full Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein
title_fullStr Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein
title_full_unstemmed Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein
title_short Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein
title_sort efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192280/
https://www.ncbi.nlm.nih.gov/pubmed/28082821
http://dx.doi.org/10.3748/wjg.v22.i48.10680
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