Meningiomas are common central nervous system tumors. Although slow growing, at times, they continue to be a major cause of morbidity and mortality. Persistent risk of recurrence of these tumors is a compelling reason to seek adjuvant therapies to decrease the rates of relapse. Recent publications report an intense search for new molecular markers that may serve as potential therapeutic targets [21–28]. EGFR has emerged as one of the novel receptors expressed on the surface of a variety of cancers such as colorectal, head and neck, and lung malignancies. While its activation stimulates tumor proliferation, overexpression of EGFR in various epithelial tumors is associated with a poor patient prognosis. The notion of its function prompted development of inhibitors of EGFR which have been approved for clinical use [21–28]. Our motivation for this analysis was the fact that, to date, there is no effective pharmacologic therapy for meningioma. This study was designed to determine whether meningiomas express EGFR, and if so, to establish a correlation between the histopathologic grade of these tumors and the degree of EGFR expression.
To our knowledge, this analysis represents the largest series of meningiomas evaluated for EGFR expression in the literature to date. We demonstrated that meningiomas express EGFR and found that there was a significant association between the intensity of EGFR staining and tumor grade. While the majority of samples had a moderate level of staining intensity, the malignant tumor grade exhibited the lowest scores. Our data demonstrate significantly greater degree of EGFR expression in benign and atypical meningiomas as compared to the malignant meningiomas. With respect to percentage of immunorectivity, the malignant grade of meningioma revealed lower scores in contrast with the benign and atypical samples. Further, malignant tumors exhibited the lowest immunohistochemical scores and were different from the scores of the benign and the atypical specimens in a statistically significant fashion. Therefore, we conclude that EGFR expression is inversely correlated with tumor grade in meningiomas.
Some investigators, utilizing ligand-binding techniques, demonstrated a broad range of EGFR expression in meningiomas, varying from approximately 30% to 100% [29–32]. The discrepancies in the literature regarding the expression levels of EGFR in meningiomas may be accounted for by the different techniques used in each of these studies. In our study, we determined the expression of EGFR in meningiomas by immunohistochemical analysis of archival tissue, and EGFR expression was detected in 86% of all meningiomas tested. While the majority of studies previously reported a specific EGFR immunoreactivity in the vascular endothelial cells of meningiomas [33–36], there were others that demonstrated no such correlation [37–40]. We presented our data with respect to the percent of immunoreactivity (SP) in our meningioma samples and found a significant association between percentage of immunoreactive cells staining for EGFR and histopathologic subtype.
What does overexpression of EGFR in tumors indicate? Carroll et al provide an explanation by examining EGFR expression in human meningiomas by Western blot and immunohistochemical analyses . The authors speculate that activation of EGFR is not a result of any mutations of the EGFR, but it is secondary to autocrine/paracrine stimulation by their endogenous ligands, EGF and TGF alpha, which are also expressed in meningiomas and may contribute to meningothelial cell proliferation . Kong et al also supports that EGFR receptors are regulated by autocrine mechanism . An alternative theory is that the benign histologic subtypes have a more efficient autocrine/paracrine stimulation, which makes them significantly different from all other types not only in their behavior but also in their expression of EGFR . Lusis et al in a report evaluating the expression of EGFR in 41 meningiomas identified a relatively higher incidence of EGFR expression among incidental asymptomatic meningiomas discovered at autopsy compared with those removed during surgical treatment . This finding is consistent with the EGFR pathway of meningioma growth stimulation resulting in a relatively less aggressive tumor . Smith et al reported that absence of EGFR expression correlates with poor prognosis in patients with meningioma . Although it may be expected that increased expression of EGFR would provide a growth advantage and thus correlate with a worse prognosis, the opposite was true in his series. This finding does not necessarily cast doubt on the theory that EGFR is involved in the development of meningiomas, as considerable evidence implicates this receptor in tumor development. Instead, these data suggest that in tumors lacking EGFR expression, other even more potent growth-stimulatory mechanisms may exist .
EGFR activation increases resistance to apoptosis, promotes angiogenesis, and impairs immune surveillance; hence, intervention with an EGFR inhibitor may decrease tumorigenic progression in patients with this disease. While radiation therapy plays an important role in the management of meningioma, an association between high EGFR expression and clinical radioresistance has been reported in patients with cancer. Correlation between EGFR overexpression and response to radiotherapy has been well described in human head and neck cancers . Furthermore, overexpression of EGFR may act as an independent prognostic factor for relapse and recurrence of disease. Ang et al reported on patients with squamous cell carcinomas of the head and neck (SCCHN) as part of the correlative biomarker study, where the overall survival (OS) and disease-free survival (DFS) rates of patients with high EGFR-expressing SCCHN were highly significantly lower and the local recurrence (LR) relapse rate was significantly higher compared with those of patients with low EGFR-expressing SCCHN . Multivariate analysis showed that EGFR expression was an independent determinant of OS and a robust independent predictor of LR relapse. The data suggest that EGFR immunohistochemistry should be considered for selecting patients for more aggressive combined therapies or enrollment into trials targeting EGFR signaling pathways . A phase III randomized clinical trial evaluated the addition of cetuximab (Erbitux TM) to high dose radiation in patients with locoregionally advanced SCCHN and demonstrated a statistically significant prolongation of OS in the combined modality arm versus radiation alone [45, 46]. EGFR overexpression was also found to be a significant and independent prognostic indicator for OS after radiation therapy in patients with astrocytic gliomas . The addition of EGFR inhibitors to patients receiving radiation therapy has not been found to significantly increase the toxicity of treatment [32, 45, 46]. Most toxicities associated with cetuximab in the treatment of head and neck cancers are low grade and cutaneous. The rationale for combination of inhibitors of EGFR with ionizing radiation is, therefore, a potentially attractive combination for recurrent or benign meningioma.
There are now several EGFR inhibitors- Herceptin (Trastuzumab), Erbitux (IMC-C225, cetuximab), Tarceva (OSI-774, erlotinib), Iressa (ZD 1839), Maztuzumab (EMD 72000) - which exhibit anti-cancer activity and are being used in clinical practice for the tumors of breast, colon, head and neck, lung, and others. Although the precise mechanism by which EGFR inhibitors exert their anti-cancer effect remains unknown, compelling evidence exists to further explore whether inhibitors of EGFR will be of clinical benefit to patients with benign/low-grade or recurrent meningioma, which represent the vast majority of patients. The association of EGFR and meningioma grade is a potential new avenue for therapeutic intervention with selective EGFR inhibitors, either as an adjuvant treatment or in combination with radiation therapy. Additional clinical studies will be needed before inhibitors of EGFR can be incorporated into clinical practice.