Purpose
We sought to evaluate correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in E2303 trial.
Experimental Design
Sixty-three eligible patients with operable stage III/IV HNSCC participated in ECOG 2303, phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin followed by chemoradiation with same regimen. A tissue microarray (TMA) was constructed and epidermal growth factor receptor (EGFR), ERK1/2, Met, Akt, STAT3, β-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-kappa b, p53, PI3Kp85, PI3Kp110a, PTEN, NRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each dichotomized biomarker, overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) were estimated by Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and test for significance.
Results
Forty-two of 63 patients with TMA data on at least one biomarker were included in the biomarker analysis. Tumor ERK1/2 levels were significantly associated with PFS (HR (low/high)=3.29, p=0.026) and OS (HR (low/high)=4.34, p=0.008). On multivariable Cox regression analysis, ERK1/2 remained significantly associated with OS (p=0.024) and PFS (p=0.022) after controlling for primary site (oropharynx vs. non-oropharynx) and disease stage (III vs. IV), respectively. Clustering analysis revealed that clusters indicative of activated RAS/MAPK/ERK and/or PI3K/Akt pathways were associated with inferior OS and/or PFS and maintained significance in multivariable analysis.
Conclusions
These results implicate PI3K/Akt and RAS/MAPK/ERK pathways in resistance to cetuximab-containing chemoradiation in HNSCC. Large prospective studies are required to validate these results.