Oral cancer is the sixth leading cancer worldwide, and the mortality for this disease has not significantly changed in decades. It accounts for more deaths than cervical cancer, testicular cancer, kidney cancer, liver cancer, melanoma, and Hodgkin’s disease. The cost of care for oral cancer is twice that of most other malignancies, with more than $3 billion in annual expenditure in the United States alone. Most patients with oral cancer do not return to the workforce, adding additional financial burdens beyond the human burdens and the costs of medical care. Two thirds of oral cancers are detected at stages III and IV, and this contributes to the morbidity, mortality, and cost of treatment. Patients identified with oral squamous cell carcinoma in early stages have a substantially improved prognosis and reduced costs of care compared with those with regional or distant spread. Nonetheless, most patients do not receive a thorough oral cancer examination, despite the recommendations of the ADA, AGD, and the American Cancer Society.
DOCTORS ARE NOT ALWAYS COMFORTABLE
Most practicing dentists see patients with oral cancer very infrequently and therefore may not feel comfortable with screening for this deadly disease. In addition, it is often difficult to determine the likelihood of cancer based on the physical exam alone. More than 95% of oral biopsies are negative, and the US Preventative Task Force cites concern for excessive negative oral biopsies as a potential downside of more oral cancer screening exams. This can create further uneasiness on the part of many primary providers when confronted with the decision for referral for consideration of biopsy when suspicious oral lesions are identified.
PATIENTS FEARFUL OF BIOPSIES
It should be noted, in gathering feedback from attendees in various continuing education (CE) and lecture settings, that a number of doctors have expressed that their screening protocol consists of simply referring all patients out for biopsies when suspicious oral lesions are found that cannot be positively identified. This reduces the screening protocol simply down to a find-and-refer-for-biopsy process. Sounds easy enough, right? However, is this the best course of patient management in all cases? Is this truly a patient-centered decision, or is it done as a simple way to pass on the responsibility for care on the part of the general dentist? Patients with oral lesions are also understandably fearful of a recommendation for a surgical consultation for a potential biopsy. Should it be a surprise then, based upon oral surgery office records, that many patients do not comply with recommendations/referrals made for a biopsy? The discussions between the primary caregivers and patients regarding these sensitive issues could be facilitated by the availability of additional informative and objective quantitative data with salivary biomarker testing.
BRIEF UPDATE ON SALIVARY DIAGNOSTICS AND NEW TEST
Salivary diagnostics has been studied for more than a decade and has been a priority of the National Institutes of Health and the National Institute of Dental and Craniofacial Research. The salivary biomarker alphabet has been well characterized and includes RNA, DNA, proteins, metabolites, and microbes. Animal models of lung cancer and melanoma indicate the presence of disease-specific alterations in salivary proteins and messenger RNAs. Ongoing investigations have elucidated some of the mechanisms by which saliva acts as a mirror of the body and reflects disease at remote sites. Multiple clinical trials have identified disease-specific salivary biomarker footprints for a number of malignancies and other systemic diseases. These are in various stages of clinical development. In these clinical trials, informative multimarker models have been demonstrated to provide better discriminatory power than relying on single biomarkers.
Salivary biomarkers for the identification of oral cancer are the most advanced of the salivary biomarkers under development for a number of clinical applications. After their discovery by Dr. David Wong at the University of California, Los Angeles (UCLA), these biomarkers were demonstrated to be more informative than blood markers. The biomarkers were then independently validated by the National Cancer Institute–Early Detection Research Network (NCI–EDRN). The newest scientifically proven salivary biomarker test (SaliMark OSCC [PeriRx]) is based on these studies as well as a prospective blinded clinical trial that was recommended by the NCI–EDRN to further validate their findings. The test is based on a model that combines 3 cancer-associated messenger RNAs and 2 internal housekeeping genes into a single composite score.
This test is designed to quantify the hazard in at-risk patients identified on oral screening evaluations. It can be applied to patients identified to be at-risk during conventional examination as well as those identified with the use of adjunctive visual aids. Low-risk scores have a very high negative predictive value. In the prospective trial, the negative predictive value was more than 98% in a relatively high-risk population. The negative predictive value would be higher in patient groups with a lower incidence of disease. These low-risk scores identify patients who can be followed to assure stability of chronic lesions or resolution of new lesions before the consideration of a biopsy. This can help to mitigate the fears of many patients while also helping to identify those patients who would most benefit from a surgical referral and additional evaluation.
Test scores identifying and quantifying increased risk can be an effective tool to assist with patient communication when recommending a referral to a surgical specialist. This objective and quantitative test can help the primary provider on the front line to make these referrals with more confidence and potentially increase patient compliance. When communicating with the patient, it is important to note that, like other effective tests that have been successfully incorporated into cancer screening protocols such as mammograms and PAP (Papanicolaou) smears, the SaliMark OSCC test can produce an “abnormal” result without cancer being present. Based on the incidence of oral and other cancers in the general population, one should not expect the majority of patients with abnormal test results to have cancer. Although all valuable screening tests for cancer have false positives, these tests are extremely useful in identifying those patients who have an increased chance of cancer and would most benefit from further evaluation. It is also important to note that the majority of patients with dysplasia in the SaliMark OSCC prospective blinded trial had abnormal tests, and this is an important group to place on increased surveillance due to the propensity for conversion to cancer at a later date. For these reasons, it is recommended that patients with abnormal SaliMark OSCC test results be told that they need further evaluation, but not that cancer is as yet diagnosed. This is comparable to the patient approach made by the physician after an abnormal mammogram or PAP smear.
Salivary Diagnostics Offer Valuable Information
The oral surgeon’s decision to biopsy or not can sometimes be clearly based on the clinical features alone. The value of salivary diagnostics in this situation is to aid in getting the most at-risk patients to the surgeon earlier. Often the decision for biopsy is not as clear to the surgeon. In this setting, the quantitative SaliMark OSCC test score is a valuable adjunctive tool for the surgical specialist’s decision-making process.
The primary responders in the battle against oral cancer are hygienists, dentists, oral surgeons, and otolaryngologists. Prior studies have documented that primary care physicians generally have limited knowledge related to oral cancer and need to adopt a more active role in screening for this disease. With growing interest in the oral systemic connection, better collaboration between dental and medical healthcare providers has been advocated for many years but is not fully realized. Salivary diagnostics has the potential to improve these communications by providing informative biomarkers that make the referrals more standardized. In addition to SaliMark OSCC, there are informative salivary biomarkers in development for other systemic diseases—including lung cancer and diabetes—that will soon be available for clinical applications. Given the incidence of smoking and diabetes in general dental practices, these and other tests in the pipeline will position dental practitioners to take an expanded role in the healthcare team and enhance multidisciplinary collaboration.
CLOSING COMMENTS
The scientific merit of screening your patients using SaliMark OSCC has been well documented in multiple publications. In the authors’ opinion, the next challenge is to apply this advanced technology in appropriate clinical settings in which additional informative testing can aid in critical decisions that can have a major impact on patient outcomes. This requires a team approach, and the primary caregivers are positioned to be the key players in this effective team. These providers on the front lines must be comfortable with their roles, and salivary diagnostics has the potential to aid in this process and to improve collaboration with other healthcare professionals.
Dr. Martin graduated from the Columbia University School of Medicine (1975), and his postgraduate training included resident in surgery, New York University Medical Center; intern in medicine and resident in medicine, Mary Imogene Bassett Hospital (Cooperstown, NY); and a Fellow in cardiology at the Hospital of the University of Pennsylvania (Philadelphia). He is board-certified by the American Board of Cardiovascular Diseases and American Board of Internal Medicine, with subspecialties in cardiovascular diseases and interventional cardiology. He is an associate professor of clinical medicine at Thomas Jefferson University (Philadelphia). He has been on the faculty at both University of Pennsylvania School of Medicine and Temple University School of Medicine. Previously, he served as chief of interventional cardiology for Main Line Health, chief of the division of cardiovascular diseases at Bryn Mawr Hospital, and president of the medical staff at the Northeast Methodist Hospital (San Antonio, Tex). For many years, he has served as president and an officer of the Sharpe-Strumia Research Foundation as well as an investigator at the Lankenau Institute for Medical Research. He can be reached via email at martinj@mlhs.org.
Disclosure: Dr. Martin has equity in PeriRx, LLC, the manufacturers of SaliMark OSCC.
Dr. Wolanin graduated from Villanova University, earned his DDS from Temple University Kornberg School of Dentistry, and did a residency at Temple University Hospital. He is a Diplomate of the American Board of Oral and Maxillofacial Surgery, the National Dental Board of Anesthesiology, and the American Academy of Pain Management as well as a Fellow of the American College of Oral and Maxillofacial Surgeons. He has been in private practice for 30-plus years in Havertown, Pa, and he is the chief of oral surgery and dentistry of the Main Line Health System and an oral surgery consultant for the Philadelphia 76ers NBA team. A retired captain of the Dental Corps, United States Navy Reserve, he was recalled to active duty and deployed to Saudi Arabia, Gulf War (Desert Storm) in 1991. He can be reached via email at sos@suburbanoralsurgery.com.
Disclosure: Dr. Wolanin reports no disclsoures.
Dr. Lerner earned his DDS from Emory University School of Dentistry (1982). He maintains private practices in both Brooklyn Heights and Oceanside, NY, and was an attending dentist at Methodist Hospital (2000 to 2005). He is a member of the New York State Dental Society; a member, past president, and a former board of trustees member of the Second District Dental Society; a member and former chairman of Council on Dental Benefit Programs; and a member and current advisory chairman of the Greater New York Dental Meeting. He can be reached at imldds@aol.com.
Disclosure: Dr. Lerner reports no disclosures.
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