Serum Signature of Hypoxia-Regulated Factors Is Associated with Progression after Induction Therapy in Head and Neck Squamous Cell Cancer

Abstract

Tumor hypoxia regulates many cytokines and angiogenic factors (CAF) and is associated with worse prognosis in head and neck squamous cell cancer (HNSCC). Serum CAF profiling may provide information regarding the biology of the host and tumor, prognosis, and response to therapy. We investigated 38 CAFs in HNSCC patients receiving induction therapy on a phase II trial of carboplatin, paclitaxel, and cetuximab. CAFs were measured by multiplex bead assay and enzyme-linked immunosorbent assay in 32 patients. Baseline and postinduction CAF levels were correlated with disease progression (PD) and human papilloma virus (HPV) status by Wilcoxon rank sum test. Baseline levels of eight hypoxia-regulated CAFs (the "high-risk signature" including vascular endothelial growth factor, interleukins 4 and 8, osteopontin, growth-related oncogene-alpha, eotaxin, granulocyte-colony stimulating factor, and stromal cell-derived factor-1alpha) were associated with subsequent PD. Elevation in >or=6 of 8 factors was strongly associated with shorter time to progression (P = 0.001) and was 73% specific and 100% sensitive for PD. Increasing growth-related oncogene-alpha from baseline to week 6 was also associated with PD. Progression-free and overall survival were shorter in patients with HPV-negative tumors (P = 0.012 and 0.046, respectively), but no individual CAF was associated with HPV status. However, among 14 HPV-negative patients, the high-risk CAF signature was seen in all 6 patients with PD, but only 2 of 14 without PD. In conclusion, serum CAF profiling, particularly in HPV-negative patients, may be useful for identifying those at highest risk for recurrence.