Association of Aurora kinase A and epidermal growth factor receptor (EGFR) gene copy number with overall survival in KRAS wild-type patients with metastatic colorectal cancer.

Abstract

e14056 Background: Aurora kinase A (AURKA) regulates cell cycle progression and is under investigation as a therapeutic target. Increased AURKA gene copy number (AURKA-CN) is common in metastatic colorectal cancer (mCRC) but its relationship with the RAS pathway and clinical outcome is unknown. Increased EGFR gene copy number (EGFR-CN) in mCRC is independent of KRAS mutation status with unknown correlation with AURKA. We evaluated the frequency of high AURKA-CN in mCRC patients and correlated this finding with KRAS mutation status, EGFR-CN, and clinical outcome. Methods: We analyzed tumor DNA samples from 61 mCRC patients for KRAS mutation status and AURKA-CN, and 45 samples for EGFR-CN. Treatment information was available for 53 patients. AURKA-CN and EGFR-CN were determined by quantitative genomic PCR (“high” > 4.0 copies/cell; normal < 4.0 copies/cell). KRAS mutations were identified by direct sequencing of codons 12 and 13 of the gene. Kaplan-Meier Curve and log-rank statistics were used to estimate and compare the median survival between the groups. Hazard ratios were estimated from Cox proportional hazard method. Results: High AURKA-CN and KRAS mutation were found in 48% and 30% of samples respectively without any correlation between the two (p = 0.381). High EGFR-CN was found in 38% of samples and correlated with high AURKA-CN (p = 0.02). No significant difference in overall survival (OS) was seen between high and normal AURKA-CN (HR = 0.53, p = 0.14), yet among KRAS wild type patients high AURKA-CN was associated with improved OS (HR = 0.26, p = 0.04). Improved OS was also seen among patients with high EGFR-CN compared to normal EGFR-CN (HR-0.14, p = 0.02). Among patients receiving first or second-line chemotherapy, no difference in progression-free survival was noted between high and normal AURKA-CN patients. Conclusions: Our data demonstrate a high frequency of increased AURKA-CN which correlates with increased EGFR-CN. High AURKA-CN is associated with improved survival in KRAS wild type tumors. Further study of AURKA-CN in larger groups of homogenously treated patients with mCRC is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, AstraZeneca, Genentech, Genomic Health, Helsinn Group, Saladax, sanofi-aventis Saladax Amgen