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Psyrri A , Lee JW , Pectasides E , Vassilakopoulou M , Kosmidis EK , Burtness BA , Rimm DL , Wanebo HJ , Forastiere AA
Prognostic biomarkers in phase II trial of cetuximab-containing induction and chemoradiation in resectable HNSCC: Eastern cooperative oncology group E2303
Clin Cancer Res. 2014 Jun 1;20(11) :3023-32
PMID: 24700741   
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PURPOSE: We sought to evaluate the correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in the E2303 trial. EXPERIMENTAL DESIGN: Sixty-three eligible patients with operable stage III/IV head and neck squamous cell cancer (HNSCC) participated in the Eastern Cooperative Oncology Group (ECOG) 2303 phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel, and carboplatin followed by chemoradiation with the same regimen. A tissue microarray (TMA) was constructed and EGF receptor (EGFR), ERK1/2, Met, Akt, STAT3, beta-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-kappaB, 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 the Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate HRs 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 extracellular signal-regulated kinase (ERK)1/2 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.
Psyrri, Amanda Lee, Ju-Whei Pectasides, Eirini Vassilakopoulou, Maria Kosmidis, Efstratios K Burtness, Barbara A Rimm, David L Wanebo, Harold J Forastiere, Arlene A CA16116/CA/NCI NIH HHS/United States CA21115/CA/NCI NIH HHS/United States CA23318/CA/NCI NIH HHS/United States CA27525/CA/NCI NIH HHS/United States CA66636/CA/NCI NIH HHS/United States U10 CA016116/CA/NCI NIH HHS/United States U10 CA180794/CA/NCI NIH HHS/United States U10 CA180820/CA/NCI NIH HHS/United States U24 CA114737/CA/NCI NIH HHS/United States Clinical Trial, Phase II Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. United States Clin Cancer Res. 2014 Jun 1;20(11):3023-32. doi: 10.1158/1078-0432.CCR-14-0113. Epub 2014 Apr 3.