Abstract
3565 Background: Angiogenesis involves endothelial cell (EC) sprouting, proliferation, and differentiation and recruitment of mural cells to stabilize new vessels. The proteins Epidermal Growth Factor Domain-Like 7 (EGFL-7) and Activin Receptor-like Kinase 1 (ALK1) play critical roles. EC-secreted EGFL7 antagonizes Notch to promote EC proliferation, sprouting, and motility. EGFL7 also regulates mural cell recruitment and extracellular matrix deposition. ALK1 is an EC-restricted TGF-β Type 1 receptor with downstream repression of Vascular Endothelial Growth Factor (VEGF) signaling. ALK1 also promotes pericyte-EC adhesion. EGFL7 or ALK1 inhibition enhances antitumor efficacy when combined with BV in murine models. Both are overexpressed in many cancers and may be critical for efficacy of anti-VEGF therapy. We tested whether EGFL7 (rs1051851, rs2297538) and ALK1 polymorphisms (rs2293094, rs11169953, rs706819) will predict efficacy of BV-based therapy in mCRC pts. Methods: Genomic DNA was extracted from peripheral whole blood samples from 455 mCRC pts treated with first-line BV and FOLFIRI. SNPs were analyzed by PCR-based direct DNA sequencing and evaluated for association with tumor response rate (RR), overall survival (OS), and progression free survival (PFS). Results: Male/female: 272/183; median age: 62 (range: 25-81); median PFS and median OS: 10.9 (95%CI: 10.1-11.6) and 29.9 (95%CI: 25.9-34.6) months, respectively; response to therapy: 59% (215 pts); median follow-up:23.6 (range: 1.8-60.4) months. Pts carrying the EGFL7 rs1051851 G/G alleles had a 62% RR versus 56% in pts with A/G and 29% in patients with A/A (p=0.0130, Cochran-Armitage trend test). The result remained significant after adjustment for baseline pt characteristics (p=0.026, Multivariable logistic regression test). There was no statistically significant association between tested polymorphisms and OS or PFS. Conclusions: The EGFL7 SNP rs1051851 may predict tumor response in mCRC pts treated with FOLFIRI and BV. To our knowledge, this is the first study demonstrating predictive significance of genetic variations in EGFL7. Prospective validation of this study is warranted.
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