Creating a new oral tradition

NEW YORK—Patients with oral cancer may have more targeted,personalized treatment options available to them if a new clinical studysuccessfully identifies genomic markers in tumors that predict if an oralcancer is likely to metastasize to the neck.

The study, the work of the NYU College of Dentistry and theHelen Diller Family Comprehensive Cancer Center at the University ofCalifornia-San Francisco (UCSF), was recently awarded a two-year grant from theNational Cancer Institute (NCI), part of the National Institutes of Health(NIH). More funding is needed to advance the trial, but the study's leaders areconfident that they will be able to harness the power of genomics to yieldgroundbreaking results for oral cancer patients, for whom current treatmentoptions are limited.

Oral cancer, a subtype of head and neck cancer, is anycancerous tissue growth located in the oral cavity. Oral cancers may originatein any of the tissues of the mouth, and most commonly involve the tongue—butthe disease may also occur on the floor of the mouth, cheek lining, gums, lipsor palate.

"People don't realize that oral cancer is an incrediblydifficult-to-treat cancer," says Dr. Brian L. Schmidt, professor of oral andmaxillofacial surgery at the NYU College of Dentistry, former faculty member atUCSF and a leader of the study. "Head and neck and oral cancers have a lot ofDNA mutations, so it is a very tricky cancer when you compare it to othercancers. People don't realize they can die from this, but in fact, survival isvery poor, with about half of patients surviving only five years afterdiagnosis. One of the things that drew me to treating patients with oral andhead and neck cancer is that they often have a low quality of life. They canhave a lot of pain or disfigurement, so this is a group that needs a lot ofattention."

Oral cancer is often fatal if it spreads to the neck andremains untreated. Nearly all cancers within the oral cavity must be surgicallyremoved in a neck dissection, which may also be performed to remove lymph nodesif there is any clinical or radiographic evidence of neck metastasis. Currentclinical and radiographic examination provides limited information fordiagnosis of early neck metastasis of oral cancer.

"We currently have no reliable methods of detecting whethera patient already has metastasized disease. The instruments we have cannotdetect small metastasis," says Schmidt. "When I finished my fellowship in 2002[in head and neckcancer at Legacy Emanuel Hospital and Health Center in Portland, Ore.],the Human Genome Project was just being completed. I realized there was the potentialthat this could be used to somehow predict which patients might developmetastasis."

Enter his colleague, Dr. Donna G. Albertson, a professor atthe UCSF Helen Diller Family Comprehensive Cancer Center. Albertson, one of thepioneers in the development of fluorescent in-situhybridization (FISH) and its applications in single-copy gene mapping in thehuman, is working to develop microarray technology for measurement of DNA copynumber alterations, and applications of this technology in medical genetics andstudies of genomic alterations in cancer.

"We had a project to see if we could find genomic copynumber alterations that were biomarkers for metastasis of oral cancer,"Albertson says. "If you can use a brush or swab to take a sample of cells fromthe cancer, you can isolate DNA from that material and carry out the assay forthe biomarker. Such a test could be performed during routine office visitsprior to surgery, and one could have the answer back quickly—in time to plansurgical treatment. Use of the swab or brush looks very promising."

Grant funding has been used to develop that assay, but thereis more work to be done and other problems to solve—and thus, more funding toobtain. Patients who present with no evidence of metastasis in the neck oftenundergo a preemptive neck surgery, because untreated occult metastasis reduceslife expectancy by half.

"Right now, we just throw everything we can at the patient,assuming the patient is going to have the worst possible outcome," saysSchmidt. "Many people are receiving neck dissections to remove the lymph nodes,but they are not necessarily benefitting from it. These are significantsurgeries. There is morbidity associated with it, including a high rate ofstroke compared to other surgeries. In addition, patients have a long recoverytime and have to spend extra time in the hospital and delay going back to work,so there are significant downsides to performing neck dissections when it comesto patient productivity and healthcare time and costs."

In a larger confirmation study, Schmidt and Albertson willwork to validate genomic markers that will ultimately be used to rule out neckdissection in oral cancer patients with no clinical evidence of neck metastasisand who have tumors containing specific genomic profiles.

Schmidt will conduct the clinical portion of the studythrough the NYU Bluestone Center for Clinical Research, which he directs,recruiting subjects, enrolling patients and collecting specimens. The sampleswill then be sent to Albertson's laboratory at UCSF, where her team willprocess and analyze the samples.

Ultimately, Schmidt and Albertson foresee improved care fororal cancer patients once their newly identified genomic marker is validated.

"It has taken us eight years of research to converge on agenomic marker that could be used to tailor treatment for oral cancerpatients," says Schmidt. "We look forward to testing this marker in a clinicalstudy, and this funding will help up us to develop the appropriate laboratorytest for such a trial."