title: Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein.
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,NRASandBRAFgenetic 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 theTP53BP1gene 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.
authors.affiliation: Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Ghiringhelli
authors.affiliation: Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.
authors.forename: Corentin
authors.initials: C
authors.lastname: Richard
authors.affiliation: Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Chevrier
authors.affiliation: Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.affiliation: Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Boidot
mesh_terms: D015746:Abdominal Pain / Q000209:etiology; D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001706:Biopsy; D002272:Carcinoembryonic Antigen / Q000097:blood; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000209:etiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D056687:Off-Label Use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D010793:Phthalazines / Q000009:adverse effects / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D057285:Precision Medicine / Q000379:methods*; D012007:Rectum / Q000473:pathology; D016896:Treatment Outcome; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics*
chemical_list: D002272:Carcinoembryonic Antigen; D004268:DNA-Binding Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C448305:RAD51C protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C531550:olaparib
keywords: Colorectal cancer; Exome analysis; Genetic aberrations; Homologous repair deficiency; Precision medicine