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

Francois Ghiringhelli 1, 2, 3, * Corentin Richard 4, 3 Sandy Chevrier 3 Frédérique Végran 1, 3 Romain Boidot 1, 3
* Auteur correspondant
1 LNC - Lipides - Nutrition - Cancer (U866)
2 Département d'oncologie médicale [Centre Georges-François Leclerc]
3 Plateforme de transfert en biologie cancérologique [Dijon]
CEP - Centre d'épidémiologie des populations, CRLCC - CGFL - Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc
4 LCE - Laboratoire Chrono-environnement - UFC (UMR 6249)
Abstract : 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.
Keywords : Colorectal cancer Exome analysis Genetic aberrations Homologous repair deficiency Precision medicine
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01452654
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : jeudi 2 février 2017 - 10:08:13
Dernière modification le : mercredi 5 septembre 2018 - 17:04:01

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UNIV-BOURGOGNE | CGFL | FNCLCC | LNC-UMR866 | CHRONO-ENVIRONNEMENT | CNRS | UNIV-FCOMTE | ENSBANA | AGROSUP-DIJON

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Francois Ghiringhelli, Corentin Richard, Sandy Chevrier, Frédérique Végran, Romain Boidot. Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein.. World Journal of Gastroenterology, Baishideng Publishing Group Co. Limited, 2016, 22 (48), pp.10680-10686. ⟨10.3748/wjg.v22.i48.10680⟩. ⟨hal-01452654⟩

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