1. Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI plus bevacizumab (BV). C. Cremolini 1, F. Loupakis 1,2, D. Yang 2, L. Salvatore 1, W. Zhang 2, T. Wakatsuki 2, M. Schirripa 1, S. Lonardi 3, C. Antoniotti 1, G. Aprile 4, G. Masi 1, F. Graziano 5, A. Ruzzo 6, S. Lucchesi 7, M. Ronzoni 8, M.K.H. Maus 9, G. Bocci 10, G. Tonini 11, A. Falcone 1 and HJ Lenz 2 1.U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; 2. University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; 3. Istituto Oncologico Veneto, IRCCS, Padova, Italy; 4.Azienda Ospedaliero-Universitaria di Udine, Udine, Italy; 5. UOC Oncologia, A. O., Pesaro, Italy; 6. Section of Biochemistry and Molecular Biology, Department of Biomolecular Sciences, University of Urbino, Urbino, Italy; 7. U.O. Oncologia Medica, Ospedale, Pontedera, Italy; 8. Dipartimento di Oncologia, Istituto Scientifico San Raffaele, Milano, Italy; 9. Response Genetics Inc., Los Angeles, CA; 10. Division of Chemotherapy and Pharmacology Department of Internal Medicine, University of Pisa, Pisa, Italy; 11. Università Campus Bio-Medico, Rome, Italy; University of Pisa, Pisa, Italy No predictors of benefit from BV have been so far identified The association of the T/T variant of VEGF rs833061 C/T SNP with worse PFS and OS was retrospectively reported by our group in a cohort of 111 pts treated with first-line FOLFIRI plus BV but not in a historical cohort of pts treated with first-line FOLFIRI Loupakis et al, BMC 2011 A potential prognostic or predictive role of other VEGF, VEGFR1 and 2 and EPAS1 SNPs was suggested by other retrospective series and by the post-hoc analysis of phase III randomized trials as reported below Background Geners numberFindingReference VEGF-Ars699947Predictive Schneider et al. JCO ‘08 VEGF-Ars699946Predictive Lambrechts et al. ESMO ‘11 VEGFR-1rs9582036Predictive Lambrechts et al. ECCO ‘09 VEGFR-1rs7993418Predictive Claes et al. AACR ‘12 VEGFR-2rs11133360Predictive Lambrechts et al. ESMO ‘11 VEGFR-2rs12505758Prognostic Lambrechts et al. ESMO ‘11 VEGFR-2rs2305948Predictive Gerger et al. CCR ‘11 EPAS-1rs4145836Prognostic Lambrechts et al. ESMO ‘11 Based on our retrospective findings, we planned a prospective validation trial in mCRC patients treated with first-line FOLFIRI+BV To detect an HR for PFS of 1.7 for VEGF rs833061 T/T variant compared to C-, with α and β errors of 0.05 and 0.20 respectively, 199 events were required. As secondary endpoint, we planned a confirmatory analysis of the following candidate SNPs. Germ-line DNA was extracted by peripheral blood and candidate SNPs were analyzed by PCR and sequencing No association of VEGF rs833061 C/T variants with PFS was found TT (N= 147) median PFS: 10.2 mos C- (N= 276) median PFS: 10 mos HR: 1.17 (0.91-1.50) Log-rank test p=0.218 At the univariate analysis, no association of other candidate SNPs with PFS was found, except for VEGFR2 12505758 C/T variants CC (N= 11) median PFS: 10.7 mos CT (N= 107) median PFS: 9.5 mos TT (N= 306) median PFS: 10.9 mos Log-rank test p=0.047 Conclusions N=424% Sex M/F252/17259/41 Age (median)62 ECOG PS 0/1/2357/63/484/15/1 Primary site Right/Left/Rectum110/187/12726/44/30 Liver-only disease Yes/No136/28832/68 Number of mts sites 1/>1194/23046/54 MAIN PATIENTS’ CHARACTERISTICS This prospective trial does not confirm the predictive impact of VEGF rs833061 C/T SNP suggested by our retrospective experience. Also previous findings on other candidate SNPs are not confirmed. The prospective validation is an essential step on biomarkers’ way toward clinical practice. Future studies on predictors of benefit from BV should provide a comprehensive overlook on the complexity of tumoral angiogenesis not only from the genetic perspective. chiaracremolini@gmail.com Patients and MethodsResults C- (N= 118) median PFS: 9.5 mos TT (N= 306) median PFS: 10.9 mos HR: 1.40 (1.07-1.84) Log-rank test p=0.015 At the multivariate analysis, including Kohne score, mucinous histology, ECOG PS, LDH levels and primary tumor site as covariates, the association of VEGFR2 12505758 C- variants with shorter PFS was still significant (HR: 1.402 [1.079-1.822], p=0.012).Significance was lost when applying multiple testing correction.