Background

Oral cancer is a global health burden with 377,713 cases worldwide, with the highest number of cases (248,360 cases) recorded in Asia. Nearly two-thirds of these cases are reported in the developing countries. The number of new cases of oral cancer is on the rise due to tobacco smoking and alcohol consumption. Despite significant advancements in management, the survival rate of oral cancer has not changed significantly over the past 30 years. Epidemiological studies report a shift in the incidence rate of oral cancer among women and younger patients.

Current limitations to early diagnosis of oral cancer.  

Squamous cell carcinoma (SCC) is the most predominant histological type of oral malignancy and is mostly preceded by oral potentially malignant disorders (OPMDs, a precancerous stage). OPMD is a term that includes a range of conditions that predispose to oral cancer development. A key condition of OPMD includes histopathologically diagnosed epithelial dysplasia. Research indicates a 12.1% annual malignant transformation rate for oral epithelial dysplasia. In both OPMDs and oral cancers, the clinical risk assessment and examination for diagnostic and therapeutic decisions are largely based on histopathological grading of oral epithelial dysplasia, often followed by definitive treatment ranging from surveillance (for low-grade lesions) to wide surgical excision (for high-grade lesions). However, histopathological assessment alone does not provide an accurate assessment of the complete nature of an OPMD lesion, because the incisional biopsy only represents the area that was biopsied. An early invasive cancer within an area of field change can hence be missed leading to inadequate management. Additionally, as an invasive procedure, biopsies pose risks, including pain, bleeding, bruising, and potential infections. Also, biopsy requires trained surgical personnel, and the expertise of anatomical pathologists to ensure the most accurate diagnosis. Hence, there is an unmet clinical need to develop non-invasive adjunct tests, in addition to histopathology analysis. This will enable accurate profiling of the lesion leading to early targeted treatment. Unfortunately, the absence of precise and sensitive molecular biomarkers for accurate diagnosis and prediction of malignant transformation in OPMD patients is one of the reasons for high morbidity and mortality associated with this disease.

The Power of Early Detection

Several studies highlighted that when OC is detected at an early stage (Stage I or II), the overall five-year survival rate exceeds 80%, whereas late-stage diagnosis (Stage III or IV) results in a survival rate of only 20%. Hence, in a patient with an OPMD lesion, accurately characterizing the nature of the lesion provides an opportunity to intervene at an earlier stage, identifying those that have early evidence of invasive cancer, or appropriately managing those likely to transform imminently. Early detection facilitates timely treatment and reduces the need for aggressive interventions. This may reduce the chance of loco-regional/distant metastasis and related complications, ultimately improving survival rates. 

The use of miRNAs present in easily accessible collection methods is a game-changer.

Our recent study investigated the diagnostic and predictive potential of a novel eight miRNAs sampled using saliva. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are released from cancer cells into body fluids through various mechanisms. Research shows that miRNAs can either promote or inhibit cancer growth in various types, including oral cancer. We identified and validated miR-7-5p, miR-10b-5p, miR-182-5p, miR-215-5p, miR-431-5p, miR-486-3p, miR-3614-5p and miR-4707-3p as potential diagnostic and predictive biomarkers. We created a new and reliable saliva test using this panel of miRNAs. This test was able to detect oral cancer early with an accuracy of 86% sensitivity and 90% specificity (Area Under Curve: 0.954). Most importantly, we have developed a cancer risk probability score to predict the risk or presence of OC in high-risk OPMD patients. For instance, two patients initially diagnosed with high-grade dysplasia (OPMD) when biopsied were found to have superficially invasive squamous cell carcinoma (SCC) on complete excision within 6 weeks of initial biopsy. Our risk probability score successfully predicted the presence of OC using the 6-week saliva sample (treatment naïve). It is important note that the management would have been different had the initial biopsy not underestimated the extent of the disease. 

Impact

Early diagnosis of oral cancer in patients with OPMD lesions can significantly impact management and potentially impact overall survival. Even small delays in diagnosis of an OC may lead to progression to more advanced stage of the disease and poor locoregional outcomes, resulting in more advanced treatment requirements and high healthcare costs.  The salivary miRNA panel aims to stratify the risk of developing oral cancer in OPMD patients, sparing the need for repeated invasive biopsies, when biopsy is not required, while providing a window of opportunity to intervene early. Surgical management of early oral cancers is often less morbid to patients and more effective. This approach of using miRNAs will provide new evidence for clinicians to exercise better-informed clinical decision-making to comprehensively capture OPMD and OC dynamics in real-time. Given the ease of use of the salivary miRNA test, there is a great potential to enhance the role of dental and medical practitioners, irrespective of living in urban or rural communities, in the early diagnosis of malignant changes in OPMD patients particularly when it is combined with adjunctive molecular testing. Accurate profiling of oral cancer-specific miRNAs in a field-setting or remote setting will now be possible because of the use of a non-invasive sampling matrix as saliva.  This miRNA test is a game changer and will challenge the status quo of current clinical practice.