The NIH roadmap identifies the development of evidence-based, individualized medicine to improve survival rates and quality of life as important goals for the next decade. Oral and oropharyngeal cancer together are the 6th most common cancer worldwide. Most patients have advanced (stage III &IV) disease at the time of diagnosis and dismal 5 year survival rates that range from 0-40% depending on tumor site and stage. These survival rates are poorer than those for lymphoma, breast cancer and malignant melanoma. Conventional treatments based on radical surgery and radiation are associated with profound functional morbidity affecting communication, taste, smell, swallowing, cosmesis, sense of self, and overall quality of life. Combined chemotherapy and radiation are very effective in some patients but not others. Current data suggest that surgical treatment produces better outcome for oral cancer and worse for oropharynx, whereas many oropharynx patients have an excellent response chemotherapy and radiation whereas many with oral cavity do poorly with this treatment. In both sites, treatment failures and excess morbidity from an ineffective treatment approach indicate that it is necessary to identify and understand the molecular basis for treatment response and assign patients individually to maximize treatment effectiveness to improve survival and quality of life. The objective of this proposal is to identify biomarkers of oral and oropharyngeal cancers that predict outcome and identify the most appropriate treatment strategy. To accomplish this we will use pre- and post-treatment specimens from completed and on-going clinical trials for oral and oropharyngeal cancers and a panel of biomarkers that have already shown predictive value in oropharynx cancers treated by chemotherapy and radiation. Specifically, we will assess protein expression in tissue microarrays as well as genetic status of a panel of biomarkers. Tissue microarrays of surgical specimens from patients enrolled in surgery and radiation protocols or in organ sparing trials for which both pretreatment biopsies and surgical salvage specimens are available will be used. DNA and RNA will also be harvested from these tissues. Biomarkers will include: High risk human papilloma virus type and copy number, p53 status and expression, BCLXL expression, the epidermal growth factor receptor (EGFR), and p16. All have predictive value for response to therapy and survival in oropharynx cancers treated by induction chemotherapy and concurrent chemoradiation. We postulate that these and some additional markers to be developed can differentiate those oral cavity tumors that will respond to organ sparing and those that won't. Similarly, these markers can identify oropharynx tumors that require alternative therapy. We will use in vitro systems to analyze the functional role of biomarkers in resistance and model targeted therapy that may be effective in new clinical trials.
Oral and oropharyngeal cancers affect more than 500,000 people worldwide and the incidence is increasing, particularly in younger individuals and non-smokers. Most cancers at these sites are already at an advanced stage when discovered and survival is poor. Radical surgery combined with radiation to remove the tumors leaves the patient with visible and functional deficits. Organ sparing therapies have been developed based on chemotherapy and radiation but some patients fail to respond and then cannot be cured with surgery. The development of tumor biomarkers that identify those tumors best suited to organ sparing therapy and those best suited to surgery based on tumor biology should increase both survival and the quality of life of the patient. A panel of biomarkers that predict outcome has been identified and these will now be applied to oral cavity and oropharynx cancers to distinguish those most likely to respond to different therapies. The results of this investigation will lead to new treatment strategies that are individualized for each patient.
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