Jessica Arden, MD, PhD
Radiation and Cancer Biology
Purpose/Objective(s): Tissue microarrays are useful in defining molecular pathways driving HNSCC and identifying potential therapeutic targets. However, standard methods for quantification immunhistochemical (IHC) protein expression have limitations, including the inherent bias of scoring by visual inspection. Therefore, we performed automated assessment of IHC biomarker expression of CD44, c-MET, MTOR, EGFR, and GLUT1 in tissue samples from HNSCC patients treated with chemoradiation and correlated automated biomarker expression levels with clinical outcomes.
Materials/Methods: A tissue microarray consisting of 109 Stage II-IV HNSCC patients treated with definitive chemoradiation underwent IHC staining. IHC protein expression was quantified in an automated manner using digitally scanned images processed with Definiens Tissue Studio software to generate a histologic score (range 0-300), a combined parameter that corresponds to the percent positivity and intensity of expression within areas of tumor. Biomarker scores were stratified by high and low expression using cut points determined with ROC analysis. Effects of biomarker and p16 status on locoregional failure (LRF), disease-free survival (DFS), and overall survival (OS) were analyzed using Kaplan Meier and Cox proportional hazard modeling for uni- and multivariate analyses (UVA, MVA), respectively.
Results: UVA examining p16 status and biomarker scores with clinical outcomes are shown in table 1. On MVA, p16 remained independently associated with improved OS (HR 0.32, 95% CI 0.13-0.77) and high CD44 and EGFR with inferior OS (HRs 2.7, 95% CI 1.2-5.8; 2.3, 95% CI 1.1-4.6), while c-MET and GLUT1 were not independently associated with OS.
Conclusion: This study demonstrates that high expression of CD44 and EGFR predict for worse OS on UVA and MVA, while high expression of c-MET and GLUT1 were associated with worse OS on UVA only. Similar patterns were seen with respect to LRR and DFS. Use of an automated system to quantify IHC expression provides unbiassed confirmation showing high CD44, c-MET and EGFR expression correlate with decreased OS, providing further evidence that therapies targeting these pathways may be necessary to improve outcomes in the treatment of select subsets of HNSCC patients.
|Table 1: UVA, hazard ratios for elevated biomarker scores (95% CI), (* = statistically significant)|
|p16 +||0.19* (0.08-0.45)||0.22* (0.13-0.38)||0.19* (0.10-0.36)|
|CD44||4.0*(2.0-8.1)||3.0* (1.7-5.0)||3.0* (1.7-5.3)|
|c-MET||2.8* (1.3-5.6)||1.8* (1.1-3.0)||2.2* (1.3-3.7)|
|MTOR||1.5 (0.7-3.2)||1.6 (0.9-2.8)||1.6 (0.9-2.9)|
|EGFR||2.1 (0.9-4.6)||2.0* (1.2-3.6)||2.2* (1.2-4.0)|
|GLUT1||2.2 (0.8-5.8)||2.5* (1.2-5.0)||2.5* (1.2-5.3)|
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