Use of intratumoral mRNA expression of genes involved in angiogenesis and HIF1 pathway to predict outcome to VEGFR tyrosine kinase inhibitor (TKI) in patients enrolled in CONFIRM1 and CONFIRM2

Abstract

4002 Background: Recent clinical trials (CONFIRM 1 and CONFIRM2) have shown that pts with mCRC with high serum LDH benefited from PTK787/ZK 222584 (PTK/ZK), a VEGFR TKI. We tested the hypothesis that pts with high intratumoral mRNA levels of genes involved with hypoxia (hypoxia inducible factor (HIF 1a) and lactate dehydrogenase A (LDHA) and glycolysis (glucose transporter 1 (Glut-1) and genes involved in angiogenesis such as vascular endothelial growth factor A (VEGF) and its receptors (VEGFR1 and VEGF2) will predict outcome in pts enrolled in CONFIRM1 and CONFIRM2. Methods: 191 formalin fixed paraffin embedded (FFPE) tumor samples from pts enrolled in CONFIRM 1 and CONFIRM2 were analyzed. 85 patients from CONFIRM1 (42 pts treated with FOLFOX, 43 pts with FOLFOX/PTK) and 106 from CONFIRM2 (54 pts treated with FOLFOX, 52 with FOLFOX/PTK). FFPE tissues were dissected using laser-captured microdissection and analyzed for gene expression using a quantitative real-time RT-PCR method. Relative mRNA levels are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: LDHA (p=0.024), Glut1 (p=0.045) and VEGFR1 (p=0.012) mRNA levels predicted response in pts treated with FOLFOX/PTK/ZK in CONFIRM1 but not in pts treated with FOLFOX. There was a significant interaction for VEGFR1 and Glut1 to predict PTK activity (p=0.031 and p=0.036). HIF1a gene expression predicted response in pts treated with FOLFOX/PTK in CONFIRM2 (p=0.049). HIF1a mRNA levels were significantly associated with PFS in CONFIRM1 and 2. There was significant interaction for VEGFR2 showing benefit for patients treated with PTK in CONFIRM1 (p=0.001). VEGFR2 was significantly associated with OS in CONFIRM1 with VEGF mRNA levels showing significant interaction for pts receiving PTK in CONFIRM1. LDHA and Glut1 were significantly associated with OS in pts treated in CONFIRM 2 when receiving PTK. Conclusions: These results suggest that mRNA levels of genes involved in angiogenesis and in the HIF pathway may predict outcome to VEGFR TKI. These are the first data suggesting genes associated with specific PTK effect. Further studies are warranted to validate these exploratory findings. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Schering Pharma AG, Novartis, Response Genetics Bristol-Myers Squibb, Genentech, ImClone, Merck, Pfizer, Response Genetics,Inc Novartis, Response Genectics,Inc Genentech, Merck, Pfizer, Roche, sanofi-aventis Dhont Family Foundation, NCI, NIH, Novartis