Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

Abstract

Epithelioid sarcoma is a rare, malignant, soft tissue neoplasm that can be classified into proximal, distal and fibroma-like subtypes. Regardless of subtype, epithelioid sarcoma often shows morphologic and immunophenotypic evidence of epithelial differentiation. Current therapeutic strategies include surgical resection, amputation, radiation or chemotherapy, although the overall prognosis remains poor. The epidermal growth factor receptor (EGFR) is a novel therapeutic target in carcinomas. In some carcinomas, EGFR kinase domain mutations or gene amplification may correlate with response to specific inhibitors. EGFR expression has been reported in some sarcoma types, but expression, amplification and mutations have not been studied in epithelioid sarcoma. We evaluated 15 cases of epithelioid sarcoma from 14 patients for EGFR expression using immunohistochemistry, EGFR copy number aberration using fluorescence in situ hybridization and screened for mutations in the tyrosine kinase domain of the EGFR gene using direct sequencing. In all, 14 of the 15 epithelioid sarcomas (93%) showed expression of EGFR by immunohistochemistry. A majority of the cases (n ¼ 11, 73%) showed strong (2 þ to 3 þ ) and homogeneous (475% of cells) membrane staining. No amplification or polysomy of the EGFR gene or mutations of the tyrosine kinase domain of EGFR (exons 18-21) were detected. These results imply that although EGFR is expressed in most epithelioid sarcomas regardless of subtype, gene amplification and activating mutations in the tyrosine kinase domain appear to be rare or absent. Thus, the benefit of targeted therapy against EGFR in patients with epithelioid sarcoma remains to be determined.

Significance of Phosphorylated Epidermal Growth Factor Receptor and Its Signal Transducers in Human Soft Tissue Sarcoma

“…We have previously reported that in a cohort of 46 consecutive STS patients, 78% demonstrated positive expression of total EGFR [4]. This finding is consistent with other series in STS with a mean of 68% (range 60–77%) [5,6,7,8,9]. In a large Japanese study, total EGFR expression was significantly associated with histologic grade, but was not an independent prognostic factor of survival [5].…”

“…Those who respond may have prolonged benefit but treatments typically do not result in a cure. In STS, we and others have provided evidence that the EGFR pathway may be a potential therapeutic target [3,4,5,6,7,8,9,10]. However, there have been very few, if any, informative clinical trials or objective radiologic responses to EGFR inhibition [16].…”

Combining EGFR and mTOR Blockade for the Treatment of Epithelioid Sarcoma

“…Prior to evaluating the potential utility of EGFR as an ES therapeutic target we sought to expand previous observations of enhanced EGFR expression in this STS histological subtype (13). A pre-constructed TMA containing human ES specimens retrieved from 27 patients was used for immunohistochemical analysis (Fig 1A and Table S2).…”

“…First, a recent observation (13) identifying EGFR over-expression as commonly occurring in ES was validated, and was further expanded to demonstrate receptor activation in human ES samples. Moreover, a role for EGFR activation in supporting the malignant phenotype of ES was demonstrated.…”

“…While not yet extensively investigated in the context of ES, a recent report has identified enhanced EGFR expression in a cohort of human ES tumor samples (13). This initial finding has provided the impetus for the studies presented here, seeking to ascertain EGFR and activated EGFR (pEGFR) expression levels in an independent subset of human ES specimens.…”