International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationEpidermal Growth Factor Receptor Expression As Prognostic Marker in Patients With Anal Carcinoma Treated With Concurrent Chemoradiation Therapy
Introduction
The epidermal growth factor receptor (EGFR, HER1) is one of the best evaluated receptors among the ErbB receptor family, which further includes Erb-B2 (HER2), HER3, and HER4. They consist of an extracellular ligand-binding domain, a transmembrane portion, and an intracellular domain with intrinsic tyrosine kinase activity implicated in a variety of downstream signal transduction cascades. These include the mitogen-activated protein kinase (MAPK), Akt, and c-Jun N-terminal kinases pathways, which are involved in cell proliferation, differentiation, angiogenesis, and regulation of apoptosis. Moreover, EGFR is strongly expressed in many human tumors, particularly in those of squamous cell origin 1, 2.
Overexpression of EGFR has been demonstrated as a negative prognostic factor in most series of conventionally fractionated radiation therapy (RT) without concurrent chemotherapy (3). It was suggested that EGFR is functionally related to accelerated tumor cell repopulation during fractionated RT, thus mediating radiation resistance to standard RT. By contrast, in patients treated with accelerated RT, high EGFR expression was predictive for increased tumor response (4). For concurrent chemoradiation (CRT), the data are discordant: In most studies, EGFR expression was demonstrated as an adverse prognostic factor for clinical outcome for a variety of different tumor entities 5, 6, 7. Other studies, however, identified no different tumor response according to EGFR expression (8) or reported an independent favorable prognostic effect of EGFR expression on disease-free survival (DFS) (9).
In anal cancer, several immunohistochemical studies have been performed, indicating that EGFR is expressed in the majority of cases 10, 11. Moreover, it has been shown that K-ras and EFGR mutations only occur rarely in squamous cell carcinoma of the anal canal, indicating a potential role for EGFR inhibitors. Indeed, several clinical studies have been started incorporating the EGFR inhibitors cetuximab or pamitumumab into the treatment of anal cancer patients. The first single reports on cetuximab or panitumumab monotherapy, cetuximab/irinotecan combination therapy, and cetuximab in combination with 5-fluorouracil (5-FU)/cisplatin-based CRT (phase 1 study, 10 patients) for metastatic or locally advanced anal cancer have been published 12, 13. Currently, the EGFR inhibitors cetuximab and panitumumab, combined with concurrent 5-FU/cisplatin or with 5-FU/mitomycin-based CRT, respectively, are evaluated in several ongoing phase 2 anal cancer trials.
Intriguingly, however, there is a paucity of data on the prognostic impact of EGFR expression in anal cancer patients treated with CRT. To the best of our knowledge, only 1 small study comprising 30 patients with anal cancer treated with concurrent CRT has been published that specifically addressed the prognostic value of EGFR expression on long-term clinical endpoints: As a trend, elevated levels of EGFR expression were associated with improved tumor response (P=.12) and DFS (P=.10) in this series (10). Thus, the objective of the present study was to evaluate the expression of EGFR in pretreatment biopsy specimens in a larger cohort of 103 patients with anal cancer treated homogeneously with concurrent 5-FU and mitomycin C-based CRT, and to correlate its expression with long-term clinical outcome, including local and distant control and rates of cancer-specific survival (CSS) and overall survival (OS).
Section snippets
Patients
A total of 103 patients, homogeneously treated with definitive CRT for anal cancer between April 1989 and March 2011 in the Department of Radiotherapy and Oncology of the University Hospital of Frankfurt/Main, the Department of Radiation Therapy of the University Hospital of Erlangen, and the Hospital Klinikum Offenbach, who had available tumor biopsy tissues and provided informed consent, were included in this study. Eligibility criteria were histologic proof of anal carcinoma (squamous cell
EGFR: immunohistochemistry
The EGFR stained primarily at the tumor cell membrane and was detectable in 100 of 103 patients (97%). In Figure 1, representative examples of intense, intermediate, and weak EGFR immunoreactivity are illustrated. The EGFR staining intensity was absent (=0) in 3%, weak (=1) in 23%, intermediate (=2) in 36%, and intense (=3) in 38% of the patients. As a dichotomous variable, EGFR expression was “absent/weak” (intensity <2) in 27 patients (26%) and “intermediate/intense” (intensity ≥2) in 76
Discussion
In this retrospective analysis of anal cancer in 103 patients treated with standard CRT we found that elevated levels of EGFR expression turned out to be a significant favorable parameter for CSS and, as trend, for local control and DMFS in univariate analysis. This is in line with the only other immunohistochemical analysis that specifically addressed the prognostic impact of EGFR expression in anal cancer patients treated by CRT: Ajani and coworkers (10) also found intense EGFR expression to
Acknowledgment
The authors thank Mrs. Gül Caylar and Mrs. Petra Dinse, Pathology Associates, Frankfurt/Main, for technical assistance.
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Conflict of interest: none.