4047 Background: The prognosis of resectable PDAC reflects a complex interaction between genotype, growth factor levels, and tumor microenvironment. We performed genetic, plasma, and tissue-based biomarker analysis for a phase I/II study of neoadjuvant short course proton-based chemoradiation. Methods: Patients with radiographically resectable PDAC were treated on an IRB approved, phase I/II trial of neoadjuvant short course-proton-based chemoradiation. Genotyping included KRAS, BRAF, NRAS, TP53, and PIK3CA. Tissue-based IHC on resection specimens included DPC4, CXCR4, CXCR7, and SDF1a in the central and peripheral regions of PDAC. The trial was amended to evaluate plasma biomarkers, drawn before and after chemoradiation, including HGF, VEGF, sVEGFR2, SDF1α, bFGF, PlGF, TNF-α, CAIX, sFLT1, IL-6, IL-8, and IL-1β. Correlation with OS was evaluated by the Wald test in a univariable Cox regression using log-transformed covariates. Results: Surgical specimens from all 38 patients who underwent resection and serial plasma samples from the last 12 patients enrolled were analyzed. Disease-specific results were previously reported (ASCO 2012, abs 4021). DPC4 intact (37% of evaluated patients) was associated with oligometastatic disease (p<0.05) but not OS. KRAS mutation 31/38 patients (82%), did not affect OS (HR=1.57, p=0.88) , but the specific KRAS G12D mutation (14/38, 37%) had a worse OS (HR=2.44, p<0.05). SDF1α and CXCR7 expression was higher and CXCR4 expression was lower in the tumor center versus periphery. Higher CXCR7 expression in the periphery was associated with poor OS (HR=2.29, p<0.05). High baseline plasma HGF was associated with a worse OS (HR=6.60, p<0.05), with a trend for association between high post-treatment plasma HGF and poor OS (HR=9.28, p=0.08). No other biomarker evaluated was significantly associated with OS. Conclusions: In this exploratory analysis, KRAS G12D status, CXCR7 expression, and plasma HGF level were associated with worse OS. DPC4 status correlated with oligometastatic disease. Additional IHC evaluations, including c-MET expression, are ongoing and will be reported. Clinical trial information: NCT00438256.