Nuclear Factor-κB–Related Serum Factors as Longitudinal Biomarkers of Response and Survival in Advanced Oropharyngeal Carcinoma

Abstract

Purpose: Cytokines and growth factors modulated by transcription factor nuclear factor-nB and secreted by tumor and stromal cells are detectable in serum of patients with advanced cancers, including head and neck squamous cell carcinomas (SCC). Longitudinal changes in these serum factors could be early biomarkers of treatment response and survival. Experimental Design: Interleukin (IL)-6, IL-8, growth-related oncogene-1 (GRO-1), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) concentrations were determined by Luminex multiplex assay using serum obtained at baseline and every 3 months in a prospective study of 30 patients with locally advanced (stage III/IV) oropharyngeal SCC receiving chemoradiation therapy. The relationship between baseline and direction of change in individual and multiple cytokines with cause-specific and disease-free survival was determined by Cox proportional hazards models and Kaplan-Meier survival analysis. Statistical analyses included adjustment for smoking status and response to chemoradiation. Results: Three-year cause-specific and disease-free survival was 74.4% and 68.9 %. Nonsmoking history (P = 0.05) and higher baseline VEGF (P = 0.003) correlated with increased survival. Longitudinal increases in levels of individual factors predicted decreased cause-specific survival when adjusted for smoking history [IL-6: relative risk (RR), 3.8; 95% confidence interval (95% CI), 2.0-7.4; P = 0.004; IL-8: RR, 1.6; 95% CI, 1.2-2.2; P = 0.05; VEGF: RR, 3.0; 95% CI, 1.6-5.6; P = 0.01; HGF: RR, 2.9; 95% CI, 1.9-4.4; P = 0.02; and GRO-1: RR, 1.2; 95% CI, 1.1-1.3; P = 0.02]. For a given individual, large increases in the upper quartile for any three or more factors predicted poorer cause-specific survival compared with patients with two or fewer large increases in factor levels (P = 0.004). Conclusions: Pretreatment VEGF levels and longitudinal change in IL-6, IL-8, VEGF, HGF, and GRO-1 may be useful as biomarkers for response and survival in patients with locally advanced oropharyngeal and head and neck SCC treated with chemoradiation.

Expression of growth-regulated oncogene-1, hepatocyte growth factor, platelet-derived growth factor-AA and soluble E-selectin and their association with high-risk human papillomavirus infection in squamous cell carcinoma of the uterine cervix

“…It is highly expressed in numerous types of carcinomas, including oropharyngeal cancer (19), colorectal cancer (13) and gastric cancer (14). Ogata et al (13) demonstrated that the expression of GRO-1 is associated with tumor size, staging, lymph node metastasis and invasion depth in colorectal cancer using immunohistochemistry.…”

Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer

“…For example, low baseline plasma intercellular adhesion molecule-1 predicted a greater PFS benefit from the addition of bevacizumab to carboplatin-paclitaxel compared with carboplatin-paclitaxel alone in the randomized phase III Eastern Cooperative Oncology Group 4599 trial (35). In squamous cell carcinoma of the head and neck treated with chemoradiation, baseline levels and coordinate changes in multiple cytokines, including VEGF, were associated with poor outcomes (36). This suggests that VEGF may be one of several circulating factors that alone, or in combination with other cytokines or angiogenic factors, may be prognostic or predictive of clinical benefit following treatment with vandetanib or other VEGFR signaling inhibitors.…”

The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications

“…HNSCC microenvironment is characterized by a deranged cytokine profile, promoting the secretion of immunosuppressive over stimulating cytokines. VEGF, an inflammatory cytokine released from tumor cells, inhibits DC function; it has been found in high concentrations in patients with HNSCC and has been correlated with relapse (46,47). Upregulation of IL-6 activates the STAT3 pathway, which subsequently inhibits DC maturation and NK, T and macrophage activation.…”