| Added by | mollevi |
|---|---|
| Group name | EquipeMY |
| Item Type | Journal Article |
| Title | Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor |
| Creator | Niu et al. |
| Author | Huifeng Niu |
| Author | Hyunjin Shin |
| Author | Feng Gao |
| Author | Jacob Zhang |
| Author | Brittany Bahamon |
| Author | Hadi Danaee |
| Author | Bohuslav Melichar |
| Author | Russell J. Schilder |
| Author | Robert L. Coleman |
| Author | Gerald Falchook |
| Author | Antoine Adenis |
| Author | Kian Behbakht |
| Author | Angela DeMichele |
| Author | Elizabeth Claire Dees |
| Author | Kimberly Perez |
| Author | Ursula Matulonis |
| Author | Piotr Sawrycki |
| Author | Dirk Huebner |
| Author | Jeffrey Ecsedy |
| Abstract | BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted. |
| Publication | EBioMedicine |
| Volume | 25 |
| Pages | 50-57 |
| Date | Nov 2017 |
| Journal Abbr | EBioMedicine |
| Language | eng |
| DOI | 10.1016/j.ebiom.2017.10.015 |
| ISSN | 2352-3964 |
| Library Catalog | PubMed |
| Extra | PMID: 29122619 PMCID: PMC5704062 |
| Tags | Adult, Aged, Alisertib, Alleles, Aurora A kinase inhibitor, Aurora Kinase A, Azepines, Biomarkers, Tumor, clinic, Correlative analysis, Disease-Free Survival, Female, Humans, Male, Middle Aged, Neoplasm Staging, Neoplasms, Paclitaxel, Polymorphism, Single Nucleotide, Predictive biomarker, Prognosis, Protein Kinase Inhibitors, Pyrimidines, SNP, Treatment Outcome |
| Date Added | 2018/11/13 - 17:30:25 |
| Date Modified | 2019/05/21 - 13:27:31 |
Institut de Recherche en Cancérologie de
