Hypoxia, Angiogenic Markers, and Response to Neoadjuvant Radiotherapy in Soft-Tissue Sarcomas

10567 Background: Hypoxia is common in soft-tissue sarcomas (STS) and may correlate with radiotherapy (RT) resistance and worse outcomes. We aimed to quantify intratumoral hypoxia with 18-fluoroazamycin arabinoside (FAZA)-PET in resectable STS and correlate this to 18-fluorodeoxyglucose (FDG)-PET, tumour response, angiogenesis biomarkers and patient (pt) outcomes. Methods: This phase II prospective study enrolled pts with resectable STS prior to neoadjuvant RT. Pts underwent FDG-PET and FAZA-PET prior to RT. Circulating and immunohistochemical (IHC) markers of hypoxia and vessel architecture were measured weekly. Response to RT was measured by surgically resected pathologic necrosis (PN), radiological response and relapse-free survival. Results: 23 pts were recruited. 47% (8/17) demonstrated hypoxia on FAZA-PET with a possible association between hypoxia and enhanced metabolic activity on FDG-PET (FDG SUVmax=15.33 with hypoxia; SUVmax=5.86 without hypoxia p=.08). FDG-PET response to RT correlated with PN (good/equivocal FDG-PET response: 59% PN; poor FDG-PET response: 19%PN p=.008). All relapses were distant (n=10) at average follow up of 5 years. Relapse was associated with higher FAZA-PET SUV (1.94 vs 1.28 p=0.02), FDG-PET SUVmax (14.4 vs 6.2 p=0.05), and poorer response to RT (PN 36% vs 66%, p=0.04). Baseline VEGF-C (531±82pg/ml, mean±SEM) were higher than VEGF-A (35±8pg/ml) and VEGF-D (131±17pg/ml), and correlated with protein expression on IHC staining. Hypoxia on FAZA-PET correlated with lower baseline VEGF-A/C (VEGF-C: (292pg/ml vs 688pg/ml p=0.16) and VEGF–A (14pg/ml vs 46pg/ml p=0.13). Low VEGF-C correlated with resistance to RT assessed by FDG-PET. In hypoxic tumors after 1 week of RT, VEGF-A and C levels were significantly increased (VEGF-A 80pg/ml vs 14pg/ml; VEGF-C 541ng/ml vs 292ng/ml). Response to RT correlated with less induction of VEGF-A/C. Relapse was associated with lower baseline VEGF and higher IHC levels of other hypoxic markers (GLUT-1, CA 9). Conclusions: In STS, hypoxia is common, measurable, predicts poorer response to RT and is associated with adverse outcomes. Circulating levels of VEGF-C, the dominant isoform, inversely correlated with hypoxia and is induced by RT.