The Challenge of Early Oral Cancer Detection and the Promise of Salivary Diagnostics
Early identification may save lives, reduce cost of care
It has been a vision of the National Institutes of Health for more than a decade to use saliva to detect and monitor systemic diseases.1,2 The salivary biomarker profile has been well characterized. Animal models have demonstrated that there is a disease-specific change in the salivary protein and mRNA footprint in response to the growth of systemic malignancy.3 Discriminatory salivary biomarker panels have been identified for a number of cancers and other systemic diseases.4-7
Messenger RNA (mRNA) and protein salivary biomarkers have been identified for oral squamous cell cancer. These discriminatory markers have also been confirmed in several ethnic groups and in a large case-control study by the National Cancer Institute–Early Detection Research Network (NCI– EDRN).2,8,9 Case-control studies can be limited by control patient selection bias, and the NCI recommends final validation in prospective studies of patients who represent the intended population for clinical application.
This is referred to as PRoBE (prospective-specimen-collection, retrospective-blinded-evaluation) design and represents the highest level of biomarker validation.10 Recently, PeriRx successfully completed a validation of the mRNA markers in such a trial at the University of Michigan, Michigan State University, and the St. Johns Providence Health System in Detroit.
Salivary specimens were collected in patients with suspicious oral lesions before clinically driven biopsy, and the biomarkers were evaluated in a central laboratory blinded to the final diagnosis. The detailed report of this validation study is currently undergoing peer review.
Oral squamous cell cancer is the sixth leading cancer worldwide, and the mortality from this disease has not significantly decreased in many decades.11-13 It is well known that the mortality of this disease is substantially improved with early detection, but the overall 5-year survival is only approximately 60% due to frequent late diagnosis.12,13
Although a recent report calls into question the value for oral cancer screening, this report does not apply to screening by oral healthcare professionals. It also does not apply to high-risk populations where screening has been demonstrated to improve early detection and to reduce mortality.14,15 In an effort to enhance early detection, routine oral cancer screening exams are recommended by the Academy of General Dentistry, the American Dental Association, and the American Cancer Society.14,16
The limitations of oral screening examinations for the identification of oral squamous cell cancer are well documented and highlight the need for objective and quantitative risk stratification tools.17 The initial intended use of oral cancer salivary markers is to aid primary care providers in the identification of patients in need of oral lesion biopsy.
As with other multi-marker panels known as multivariate index assays, which are used for risk stratification of other diseases, the scores can be divided into low, moderate, and high risk.18,19 A low-risk score identifies a group where biopsy can be deferred and reserved for lesions that do not resolve. High-risk scores identify patients who should be referred to a cancer specialist for consideration of biopsy. Intermediate scores would identify a group requiring early follow-up and referral for consideration of biopsy based on clinical features.
While single markers have been tested for oral cancer detection, multiple-marker models can enhance discriminatory performance.2,20 To make such tests cost effective, high throughput multiplex analysis platforms are necessary to facilitate high-volume laboratory testing.
This methodology was applied in the recent prospective validation trial. The use of these discriminatory markers with these efficient laboratory methods has the potential to save costs in part due to the reduction of unnecessary biopsies. In addition, the cost of oral cancer treatment is substantially reduced when the disease is detected early.21-23 Further studies are required to fully assess these potential economic and clinical benefits.
Salivary diagnostics can be easily incorporated into routine care in primary care dental and medical offices. Saliva is painlessly collected at the point of care without the need for special techniques or training. Stabilization reagents are available to maintain biomarker integrity while shipping the samples to a central laboratory for analysis.24 Recent studies have identified reagents with a long shelf life that can stabilize both mRNAs and proteins, making for an ideal solution for testing informative biomarkers for multiple clinical applications.25
Advanced salivary molecular diagnostics holds great promise to provide an objective and quantifiable tool to aid primary caregivers in the early identification of patients with oral squamous cell cancer. The early identification of these patients has the potential to save lives as well as to reduce the cost of care of this deadly disease, which has gone largely unchecked in large part due to late diagnosis.
Once incorporated into routine practice, the use of salivary markers has the potential to impact the detection and surveillance of additional diseases commonly treated in dental practices.
About the Authors
Jack Martin, MD, is the chief medical officer of PeriRx LLC and is in private practice in Bryn Mawr, Pennsylvania. Neil Gottehrer, DDS, is the chief dental officer of PeriRx LLC and is in private practice in Havertown, Pennsylvania.
1. Wong DT. Salivary diagnostics: Amazing as it might seem, doctors can detect and monitor diseases using molecules found in a sample of spit. Am Sci. 2008;96(1):37-43.
2. Elashoff D, Zhou H, Reiss J, et al. Prevalidation of salivary biomarkers for oral cancer detection. Cancer Epidemiol Biomarkers Prev. 2012;21(4)664-672.
3. Gao K, Zhou H, Zhang L, et al. Systemic disease-induced salivary biomarker profiles in mouse models of melanoma and non-small cell lung cancer. PLoS One. 2009;4(6):e5875. doi: 10.1371/journal.pone.0005875.
4. Zhang L, Xiao H, Zhou H, et al. Development of transcriptomic biomarker signature in human saliva to detect lung cancer. Cell Mol Life Sci. 2012;69(19):3341-3350.
5. Zhang L, Farrell JJ, Zhou H, et al. Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer. Gastroenterology. 2010;138(3)949–957.
6. Hu S, Wang J, Meijer J, et al. Salivary proteomic and genomic biomarkers for primary Sjögren’s syndrome. Arthritis and Rheum. 2007;56(11)3588–3600.
7. Hu S, Gao K, Pollard R, et al. Preclinical validation of salivary biomarkers for primary Sjögren’s syndrome. Arthritis Care Res (Hoboken). 2010;62(11):1633–1638.
8. Li Y, St John MA, Zhou X, et al. Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res. 2004;10(24):8442-8450.
9. Brinkmann O, Kastratovic DA, Dimitrijevic MV, et al. Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population. Oral Oncol. 2011;47(1)51–55.
10. Pepe MS, Feng Z, Janes H, et al. Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design. J Natl Cancer Inst. 2008;100(20)1432–1438.
11. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Onco. 2009;45(4-5)309–316.
12. American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society; 2011.
13. National Cancer Institute. SEER Stat Fact Sheets: Oral Cavity and Pharynx Cancer. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov. Accessed December 5, 2014.
14. Moyer VA; U.S. Preventive Services Task Forces. Screening for oral cancer: U.S. Preventive Services Task Force - recommendation statement. Ann Intern Med. 2014;160(1):55-60.
15. Sankaranarayanan R, Ramadas K, Thara S, et al. Long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in Kerala, India. Oral Oncol. 2013;49 (4)314–321.
16. Rethman MP, Carpenter W, Cohen EE, et al. Evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas. Tex Dent J. 2012;129:509-520.
17. Epstein JB, Güneri P, Boyacioglu H , Abt E . The limitations of the clinical oral examination in detecting dysplastic oral lesions and oral squamous cell carcinoma. J Am Dent Assoc. 2012;143(12):1332-1342.
18. Zhang Z. An in vitro diagnostic multivariate index assay (ivdmia) for ovarian cancer: harvesting the power of multiple biomarkers. Rev Obstet Gynecol. 2012;5(1):35-41.
19. Bristow E, Smith A, Zhang Z, et al. Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay gynecologic oncology. 2013;128(2)252-259.
20. Nagler R, Bahar G, Shpitzer T, Feinmesser R. Concomitant analysis of salivary tumor markers—a new diagnostic tool for oral cancer. Clin Cancer Res. 2006;12(13):3979-3984.
21. Lang K, Menzin J, Craig CE, et al. The economic cost of squamous cell cancer of the head and neck—findings from linked SEER-Medicare data. Arch Otolaryngol Head Neck Surg. 2004;130(11):1269-1275.
22. Kim K, Amonkar MM, Högberg D, Kasteng F. Economic burden of resected squamous cell carcinoma of the head and neck in an incident cohort of patients in the UK. Head Neck Oncol. 2011;3:47.
23. National Cancer Institute. Cancer Prevalence and Cost of Care. National Cancer Institute Website. http://costprojections.cancer.gov. Accessed December 5, 2014.
24. Jiang J, Park NJ, Hu S, Wong DT. A universal pre-analytic solution for concurrent stabilization of salivary proteins, RNA and DNA at ambient temperature. Arch Oral Biol. 2009; 54(3):268-273.
25. Cussenot O, Sighar K, Mohammed M, et al. Detection of specific chromosomal aberrations in urine using BCA-1 (oligo-CGH-array) enhances diagnostic sensitivity and predicts the aggressiveness of non-muscle-invasive bladder transitional cell carcinoma. World J Urol. 2014;32(2):551-557.