Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer

Abstract

Purpose: Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients. Experimental Design: Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays. Results: EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014). Conclusions: EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials. (Clin Cancer Res 2009;15(23):7389-97) Standard treatment of locally advanced cervical cancer has changed from radiotherapy alone to concurrent platinum-based chemoradiation. Despite this change, the 5-year survival in patients with locally advanced cervical cancer is still ∼52% (1). Currently, there are no (biological) markers available that accurately predict response to (chemo)radiation.Epidermal growth factor receptor (EGFR) is involved in the ErbB signaling pathway, which is often dysregulated in cancer. Autophosphorylation of EGFR to phosphorylated EGFR (pEGFR) leads to activation of two downstream pathways: the Ras/Raf/ mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK pathway and the phosphatidylinositol 3-kinase/ AKT pathway. PTEN (phosphatase and tensin homologue deleted on

Epithelial–mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy

“…Moreover, CC patients with increased EGFR expression exhibit lower PFS and OS 21. Our study was consistent with these findings as assessed independently by multivariate analysis.…”

“…EGFR overexpression has been associated with worse prognosis in locally advanced and metastatic CC patients 21. Moreover, CC patients with increased EGFR expression exhibit lower PFS and OS 21.…”

“…Negative controls consisted of the same cervical tissue samples not exposed to the primary antibody. Samples were considered positive when staining was at least twice as high on a scale of 1–4 +  and if at least 10% or more of the tumor cells were stained relative to healthy tissue or the negative control 21.…”

“…Noordhuis and collaborators demonstrated that increased epidermal growth factor receptor (EGFR) in women with locally advanced tumors treated with CRT was negatively associated with progression‐free survival (PFS). Moreover, altered EGFR immunoreactivity, including the phosphorylated fraction, was useful in predicting the response to treatment independently of tumor stage and histological pattern 21.…”

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

“…Positive staining of PTEN was defined as the presence of 410% cytoplasmic immunostaining. 20 Cyclin D1 and hormone receptor expression was considered positive when 410% tumor cells had moderate to strong nuclear expression. MSH2, MSH6 and MLH1 expression was scored as either negative (ie, total absence of detectable nuclear staining of tumor cells) or positive.…”