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EBioMedicine. 2017 Nov;25:50-57. doi: 10.1016/j.ebiom.2017.10.015. Epub 2017 Oct 16.

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.

Author information

1
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA. Electronic address: huifeng.niu@takeda.com.
2
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
3
Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
4
Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
5
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Sarah Cannon Research Institute at HealthONE, Denver, CO, USA.
7
Centre Oscar Lambret, Lille, France.
8
Department of Gynecologic Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
9
Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA.
10
UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
12
Gynecologic Oncology Program, Dana-Farber Cancer Institute, Boston, MA, USA.
13
Department of Oncology and Chemotherapy, L. Rydygiera District Hospital, Torun, Poland.

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.

KEYWORDS:

Alisertib; Aurora A kinase inhibitor; Correlative analysis; Predictive biomarker; Prognosis; SNP

PMID:
29122619
PMCID:
PMC5704062
DOI:
10.1016/j.ebiom.2017.10.015
[Indexed for MEDLINE]
Free PMC Article

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