Abstract LB-323: Subclassification of squamous cell carcinomas of the head and neck based on HER/ErbB and c-MET receptor protein expression and activation profiles

Abstract

Abstract The response rates of HER1 antibody monotherapy (∼13%) are comparable to the added response rates of HER1 antibody therapy when used in combination with chemotherapy (∼16%) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Measures of HER1/ErbB1/EGFR protein levels by immunohistochemistry (IHC) or gene copy number by fluorescent in-situ hybridization (FISH) do not correlate with response, therefore, alternative gene or protein expression signatures are needed to identify patients most likely to respond to HER1 targeted therapies. Previously, quantitative VeraTag proximity immunoassays performed on formalin-fixed, paraffin imbedded SCCHN tumor tissue identified an activated HER1 signature (HER1-HER1 homodimers; HER1pY1173) that was significantly more pronounced in SCCHN compared to other carcinoma of the head and neck. In this study, we analyzed the expression of HER1, 2, 3 and c-MET along with the activation of HER1 and HER3 in 56 SCCHN tumors. Our results identified two distinct protein expression profiles: an activated HER1 profile, and a second profile characterized by the different expression levels of HER2, HER3, phosphorylated HER3, and c-MET relative to activated HER1. Our working hypothesis is that the first profile correlates with sensitivity to HER1 targeted therapies while the second profile correlates with either sensitivity or resistance to HER1 targeted therapies. HER1 protein levels measured by VeraTag assay varied over a ∼20-fold dynamic range, and significantly correlated with HER1 IHC staining and mRNA levels determined by qRT-PCR. HER2 and HER3 protein expression spanned a 15- to 20-fold range, and correlated with mRNA levels. Several of the highest HER1 expressing tumors have increased gene copy number; however, similar high values were measured in tumors without amplification, indicating that additional mechanisms of high HER1 expression exist in SCCHN. Although high HER1 activation measured by HER1-HER1 dimer and HER1pY1173 correlates with HER1 levels (r=∼0.6, p<0.05), and are associated with the highest levels of HER1 expression measured by multiple methods, not all high HER1 expressing tumors displayed highly activated HER1. These observations may explain why total HER1 expression in SCCHN tumors, determined by IHC or FISH, does not correlate with response to targeted therapies. On the other hand, approximately 16% of the SCCHN tumors studied here (9/56) exhibit a highly activated HER1 profile; similar in magnitude to the response rate seen with HER1 targeted antibody therapy. Future studies are designed to further validate the HER1 activation signature as a predictor of response to HER1 targeted therapies and/or the attenuation of response due to HER2, HER3 or c-MET expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-323. doi:10.1158/1538-7445.AM2011-LB-323