Expression and prognostic significance of directed therapy targets and mutational analysis of the EGFR pathway in malignant salivary gland tumors.

Abstract

5554 Background: Malignant salivary gland tumors are rare and pleomorphic entities (24 sub types, WHO 2005). Curative treatment relies on surgery sometimes completed by radiotherapy. Management of non-surgical, locally advanced or metastatic tumors is difficult as conventional chemotherapies are ineffective. Directed therapies may provide important benefits for these patients. The aim of this work was to assess the expression and prognostic value of directed therapy targets on salivary gland tumors and search for mutations within the key players of the EGFR pathway. Methods: Immunochemistry on formalin fixed paraffin embedded (FFPE) samples from 124 patients for c-KIT, EGFR, c-ERBB2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was performed and related to progression free interval and survival. DNA was extracted from FFPE samples and conditional for treatment mutations of EGFR/KRAS/BRAF were assessed. An additional high throughput screening for mutations of key oncogenic genes was performed. Results: EGFR was the most expressed marker, found across almost all histotypes. Expression of the other markers was heterogeneous but some potential therapy leads were suggested by high levels of C-ERBB2 and androgen receptors in salivary duct carcinomas or C-KIT over expression in myoepithetial carcinomas. Tumor grade and a high proliferation index (Ki67>20%) were associated with progression free interval and survival. None of the other marker was. No mutation was found in EGFR/KRAS/BRAF. 7% (7/104) of the tumors harbored a mutation at the codon 61 of HRAS. In epithelial and epithelial-myoépithélial carcinoma, the mutation rate reached 33%. Mutations of PI3K and p53 were the most frequently found in the broader screen. Conclusions: Several tumor subtypes expressed frequently some targets of directed therapies suggesting potential therapy leads. The EGFR/MAPK pathway seems intact suggesting a low efficacy of small kinase inhibitors such as erlotinib or gefitinib. The mutation of H-RAS, known to be important but not sufficient to trigger urothelial carcinoma, could be a key oncogenic event in tumors with a myoepithelial component.