Prognostic biomarkers in phase II trial of cetuximab-containing induction and chemoradiation in resectable HNSCC: Eastern cooperative oncology group E2303.
OBJECTIVE
We sought to evaluate the correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in the E2303 trial.


METHODS
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, β-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-κB, 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.
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Amanda
A
Psyrri
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Ju-Whei
JW
Lee
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Eirini
E
Pectasides
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Maria
M
Vassilakopoulou
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Efstratios K
EK
Kosmidis
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Barbara A
BA
Burtness
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
David L
DL
Rimm
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Harold J
HJ
Wanebo
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Arlene A
AA
Forastiere
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000032:analysis*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000628:therapy*; D000068818:Cetuximab; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000401:mortality / Q000628:therapy*; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000077195:Squamous Cell Carcinoma of Head and Neck; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D016190:Carboplatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; D017239:Paclitaxel; D000068818:Cetuximab