The use of genetic markers in the clinical care of patients with head and neck cancer.

During the past few years, there has been an explosion in the number of articles investigating genetic markers and head and neck cancer. This is interesting for the scientist but confusing for the clinician. It is difficult to decipher the utility of the “alphabet soup” of molecular markers found in the literature. The genes described are unfamiliar to most otolaryngologists treating patients with head and neck cancer, and the articles are confounded by conflicting data. The investigation of molecular markers of head and neck cancers is certainly intellectually challenging. The real question for the clinician is, Will these data translate into improvements in locoregional control and survival? The present article will investigate the current clinical utility of molecular markers and comment on the hypothesis that these markers are not currently useful in the treatment of patients with head and neck cancer. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with a yearly incidence of 500000. Despite aggressive treatment, there has been no improvement in 5-year survival over the past 20 years. This reflects continued problems with local, regional, and distant recurrence. Historically, treatment strategies have relied on the clinical staging of disease as well as the performance status of the patient. Traditional staging methods consist of physical examination, radiographic examination, and serologic testing. Despite advances in imaging (computed tomography, magnetic resonance imaging, and positron-emission tomography), current staging systems are limited in their ability to predict locoregional control and survival for head and neck cancer. Contributing factors include an underlying heterogeneity in the tumors. Investigators currently are working to identify DNA, RNA, or proteins (biomarkers) that may better characterize head and neck cancers. A great deal of research is being done at the nuclear level. Cellular growth is directed by the genome of the cell. Specific types of genes have been identified that are important in carcinogenesis. Proto-oncogenes are a family of genes that encode for proteins that promote cellular growth. In the normal cell, these genes are well regulated, resulting in a stable population. Mutations in these proto-oncogenes may result in the formation of oncogenes and uncontrolled cell cycling. Cyclin D1 is a well known proto-oncogene that is overexpressed in up to 59% of patients with HNSCC. Tumor suppressor genes are another family of genes that are important in carcinogenesis. In the normal host, they inhibit cellular proliferation. The p53 gene is the most well-known tumor suppressor gene. The p53 protein is important in apoptosis (programmed cell death) and p53 abnormalities are found in approximately 50% of HNSCCs. Mutations in proto-oncogenes and tumor suppressor genes may result in the formation of oncogenes and uncontrolled cycling leading to tumor formation. Another class of biomarkers is the proteins and growth factors that help mediate the environment surrounding the neoplastic cells. Angiogenesis and basement membrane invasion are important for tumor growth and metastasis. Vascular endothelial growth factor is a protein that is important for neovascularization. Basement membrane loss of collagen VII and cell surface loss of the anchoring protein E-cadherin are being used to predict the invasive and metastatic potential of tumors. Transforming growth factor and epidermal growth factor (EGFR) also play a role. A summary of these markers and their mechanisms of action is provided in the Table. A great deal of research is aimed at identifying and testing these biomarkers. Identification of these biomarkers may allow for improved detection, treatment, and prevention of head and neck cancers. The ultimate question for the clinician and the patient is, Will this information improve the treatment of head and neck cancer? The hypothesis that Paul L. Friedlander, MD