Head and neck squamous cell carcinoma (HNSCC) is the most common malignant neoplasm arising in the upper aerodigestive tract, accounting for approximately 40,000 new cases each year in the United States. Despite increasing awareness of the importance of early cancer detection, the majority of patients continue to present with advanced-stage (stage III/IV) disease. Standard therapy has included surgical resection followed by externalbeam radiation or chemotherapy in conjunction with radiotherapy (chemoradiation). Although no prospective clinical trials have compared surgical with nonsurgical therapies, only 50% of patients are cured of their primary tumors. Even with successful eradication of the primary tumor, second primary tumors can be expected to occur at the rate of 4% to 5% per year and are often fatal. Given the extreme morbidity and mortality of HNSCC, new and innovative treatments based on the biologic alterations that characterize these tumors are required.
EGFR Inhibitors
The epidermal growth factor receptor (EGFR) is overexpressed in the majority of HNSCC tumors for which increased expression levels have been shown to correlate with decreased survival. Targeting EGFR using a variety of strategies including monoclonal antibodies, tyrosine kinase- specific inhibitors (TKIs), ligand-linked toxins, or antisense approaches inhibits the growth of HNSCC cell lines in vitro and xenograft tumors. A number of these modalities to target EGFR have been extensively studied in clinical trials, and the first EGFR TKI (gefitinib, ZD1839 [Iressa]) and monoclonal antibody (cetuximab, C225 [Erbitux]) are now approved by the US Food and Drug Administration.
Preclinical studies suggested that inhibitors of EGFR appear to work additively or synergistically with standard cytotoxic agents and radiotherapy. The paper by Drs. Song and Raben is focused on providing insights into the emerging role of EGFR inhibitors as a complement to radiation therapy in the management of HNSCC. These authors nicely review the biology of EGFR signaling in HNSCC and provide the rationale for using EGFR-targeting agents in the treatment of this malignancy.
Further justification for the combined use of EGFR blockade and radiation is demonstrated by the association between EGFR overexpression and radioresistance in HNSCC. While the results of early phase clinical trials combining EGFR inhibition with radiation have been encouraging, the results of phase III trials to firmly establish the therapeutic benefit of adding an EGFR-blocking agent to radiotherapy are still pending.
Unresolved Issues
Several issues must still be addressed to firmly establish the role of EGFR inhibitors in the prevention and/or treatment of HNSCC. First, why has such limited antitumor efficacy been observed when these agents are administered as monotherapy in contrast to the augmented effects when combined with chemotherapy or radiation? This finding is in contrast to the results in non-small-cell lung cancer (NSCLC) patients, for whom the addition of standard cytotoxic therapies did not improve survival.
Despite the same cellular phenotype (squamous cell carcinoma), HNSCC lesions are genetically heterogeneous. Recent data from NSCLC patients treated with gefitinib(Drug information on gefitinib) demonstrated that therapeutic response was correlated with activating mutations of EGFR in the primary tumor.[1,2] These exciting results emphasize the need to characterize HNSCC tumors with respect to the role of EGFR signaling in the proliferation and survival of these lesions. Such an approach would be expected to optimize therapy by selecting patients for treatment with EGFR inhibitors based on the EGFR-signaling profile in the cancer.
As Drs. Song and Raben note, it is essential that the administration of EGFR inhibitors to HNSCC patients should always be accompanied by correlative biomarker studies to determine the mechanisms of response and resistance. Although the use of surrogate tissue such as skin has demonstrated inhibition of EGFR phosphorylation in cancer patients treated with an EGFR TKI and EGFR antibodies, it is clear that the results that are critical to designing improved therapeutic strategies can only be found in the tumor tissue. HNSCC is a unique tumor model in that such tissue is generally accessible for biopsy and analysis with minimal morbidity.
Optimizing EGFR-Inhibitor Therapy
The authors discuss potential strategies to optimize EGFR targeting including the use of broad inhibitors of the erbB family, such as CI-1033 (an irreversible pan-erbB TKI), or ZD6474, a small-molecule inhibitor that displays dual action against EGFR and the vascular endothelial growth factor receptor (VEGFR).
In addition, they note that activation of downstream signaling pathways may account for the relative lack of response to upstream EGFR inhibition. Such pathways include signal transducers and activators of transcription 3 (STAT3) and phosphoinositide-3- kinase (PI3K), which can potentially be blocked by inhibiting mTOR. In addition, recent studies have demonstrated that EGFR can also be activated by G-protein-coupled receptors (GPCRs) in HNSCC including thrombin, bradykinin, and gastrinreleasing peptide receptor (GRPR).[3] Such "transactivation" of EGFR by GPCRs has been shown to involve both intracellular and extracellular pathways, which may escape the inhibition of EGFR using monoclonal antibodies or TKI.
A continued emphasis on delivering EGFR inhibitors in the context of mechanistic biomarker studies is needed. Such information will enhance our understanding of the biology of EGFR in HNSCC and contribute to optimizing the design of treatment regimens that combine EGFR-targeting agents with standard therapies, including radiation and chemotherapy.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
