Elsevier

Gynecologic Oncology

Volume 106, Issue 2, August 2007, Pages 394-399
Gynecologic Oncology

Is EGFR a moving target during radiotherapy of carcinoma of the uterine cervix?

https://doi.org/10.1016/j.ygyno.2007.04.019Get rights and content

Abstract

Background

The epidermal growth factor receptor (EGFR) is frequently overexpressed in uterine cervix carcinoma. The role of the pre-treatment EGFR expression levels and the changes of expression induced by ionizing radiation (IR) have not been conclusively defined.

Patients and methods

The staining intensity (SI) and labeling index (LI) of EGFR were determined in 38 patients by immunohistochemistry (IHC). Biopsies were taken before after 1 week of RT. EGFR expression was correlated with cell cycle, apoptosis and angiogenesis.

Results

Before RT, 87% and after 1 week of RT, 95% of samples were positive for EGFR (p = 0.2). Two patterns were observed, either increasing or decreasing expression after initiating RT. An increase of the EGFR SI was seen in 63% of patients from a mean of 57 SI (SD ± 60) before RT to 142 SI (SD ± 80.8) (p = 0.001) during RT. In 32% of cases, EGFR decreased from 165 SI before (SD ± 83.0) to 75 SI (SD ± 73.0) (p  0.001) during RT. Two of five (5%) patients negative for EGFR before RT remained negative. An increase of the RT-induced EGFR LI was associated with reduced microvessel density (MVD) (p = 0.02). Changes of the EGFR LI did neither correlate with cell cycle arrest nor apoptosis.

Conclusions

EGFR expression changes unpredictably during RT. The implications of changing EGFR during RT remain to defined. Repeated biopsies and EGFR reassessment during RT may help to better define EGFR-targeted treatment.

Introduction

Squamous cell carcinoma of the cervix can be successfully treated with radiotherapy (RT). Tumor control and survival rates improve with concomitant chemotherapy (CHX); however, relapse rates remain as high as up to 30–40% [1], [2]. Therefore novel strategies to further improve treatment results are mandatory. During this decade, a novel generation of molecular-defined chemotherapeutics has been investigated in preclinical studies in combination with ionizing radiation (IR). One of the most promising approaches is the combination of EGFR-targeting drugs with RT. The epidermal growth factor receptor (EGFR) belongs to the type I family of receptor tyrosine kinase and consists of an extracellular receptor domain, a transmembrane region and an intracellular domain with tyrosine kinase function. It is involved in the modulation of growth properties of transformed cells, but also in survival signaling, cell migration, metastasis and angiogenesis. EGFR is commonly expressed in normal cells but overexpressed in tumor cells and has been associated with poor prognosis in carcinoma of the uterine cervix [3], [4], [5]. It is estimated that up to 90% of cervical carcinomas overexpress EGFR [6].

EGFR-signaling mediates radioresistance. IR induces autophosphorylation of EGFR in several EGFR-overexpressing cancer cell lines [7], [8]. Inhibition of EGFR signaling with the EGFR-antibody C225 (cetuximab, Erbitux®, Imclone Systems Inc., and Bristol-Myers Squibb, New York, NY) impairs radioresistance. The tyrosine kinase inhibitor ZD1839 (Gefitinib, Iressa®, Astra Zeneca PLC) sensitizes for treatment with IR in clonogenic assays [9] and in tumor xenograft studies [10], [11] as well. Mechanistically, EGFR inhibitors render tumor cells more susceptible to IR-induced apoptosis [12], inhibited cell repair from both sublethal and potentially lethal radiation damage [13] and causes cell cycle redistribution, leading to an increased proportion of cells in the radiosensitive G2/M phase of the cell cycle [14], [15]. Furthermore, the combination of IR with ZD1839 impairs tumor angiogenesis and mediates accelerated repopulation during fractionated RT in vivo[14], [16].

A phase III randomized trial investigated the combination of RT and the epidermal growth factor receptor (EGFR) antibody C225 in head and neck cancer (HNSCC) patients. Local tumor control and survival rates were improved dramatically with additional antibody treatment [17]. However, the role of EGFR-targeted treatment in combination with RT for uterine cervix carcinoma remains unclear and is currently being investigated by at least two ongoing trials, GOG 9918 and NCT00292955 [18], [19].

An important question is whether the amount of immunohistochemically defined EGFR expression may be a useful indicator for additional pharmacological EGFR inhibition with RT or may predict the response to RT alone. In fact, there is some evidence from retrospective analysis of phase III trials in HNSCC that pre-treatment EGFR expression may predict response to fractionated IR alone [20], [21], [22].

The correlation between pre-treatment EGFR expression status and treatment outcome has not been conclusively investigated for cervical carcinoma. High EGFR expression has been associated with residual or recurrent uterine cervix carcinoma [23]. In contrast to HNSCC, the influence of the quality of fractionated RT in respect of EGFR expression in uterine cervix carcinoma is unknown. High EGFR expression levels have been suggested to be predictive for worse outcome if treatment was prolonged in HNSCC [24], [25]. In the present study, bioptic tumor tissue from a series of Egyptian women who were treated with external beam RT with curative intent without additional chemotherapy were analyzed with respect of EGFR staining before and after 1 week of RT. Changes of EGFR expression by means of immunohistochemistry (IHC) were reassessed after 9 Gy of treatment and changes of EGFR expression were correlated with tumor angiogenesis, changes of the cell cycle, and apoptosis induced during RT.

Section snippets

Study population

Forty, 39 informative, consecutive patients presenting for curative RT over a period of 10 months in 2002 at the National Cancer Institute in Cairo, Egypt, were investigated. After internal institutional ethic committee approval and after providing oral and written consent, indicating the aim of the study, patients who agreed to have tumor tissue investigated by means of a biopsy taken prior to the beginning of external beam radiation therapy and after the first week of radiation therapy. Since

EGFR expression

Thirty-eight biopsy samples were informative for EGFR IHC. We analyzed the EGFR expression before and after 9 Gy RT. Before RT, 33 biopsies (87%) stained positive for EGFR. The expression pattern revealed mainly membrane bound EGFR staining (Fig. 1). The mean intensity of the protein expression was 88 SI (SD ± 85). After 9 Gy of treatment, 36 samples of patients (95%) revealed positive EGFR staining. The mean intensity of the protein expression was 114 SI (SD ± 86). Two patients did not stain for

Discussion

EGFR is a proven target in combination with RT in the treatment of human squamous cell carcinoma of the head and neck. EGFR inhibition with antibody C225 in combination with RT increased tumor control and overall survival when compared with RT alone [17]. Patients with uterine cervical carcinoma are potentially good candidates for combined treatment with EGF receptor inhibitors. Cervical carcinomas overexpress EGFR in up to 90% of cases [27], and prospective clinical trials of EGFR targeting

Conclusions

EGFR expression is altered during fractionated RT in an unpredictable way. In a third of patients, EGFR expression is reduced, potentially resulting in a reduction of the molecular target for EGFR-specific agents. We hypothesize, that time- and RT-dose-dependent EGFR expression could be an important predictive feature and that measurement of the EGFR expression levels with IHC at a single time point might be inadequate for defining the predictive value of EGFR. Additionally, the correlation

Acknowledgment

Supported by the Cancer League of Zurich, Switzerland.

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    1

    Current address: Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA.

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