Genetic Variants Modulating Response to Celecoxib Chemoprevention in Oral Leukoplakia: Correlation with Histopathological Grading in Pakistani Patients

Background: The risk of developing oral squamous cell carcinoma varies for oral leukoplakia, a common premalignant lesion. Cyclooxygenase-2 (COX-2) inhibitors, like celecoxib, have demonstrated promise in chemoprevention; however, inter-individual variability in treatment response is still a significant obstacle. Celecoxib sensitivity may be impacted by genetic variations in drug metabolism and inflammation-related pathways. Objective: The purpose of this study was to evaluate associations with lesion grading and examine the relationship between specific genetic variants and the clinical and histopathological response to celecoxib chemoprevention in patients with oral leukoplakia from Pakistan. Methods: Celecoxib was administered to a group of Pakistani patients with oral leukoplakia for a predetermined amount of time. Biopsies taken before and after treatment were analyzed for histopathological grading, and standardized criteria were used to measure clinical regression. Candidate variants in COX-2 and associated pathways (such as prostaglandin synthesis and xenobiotic metabolism) were genotyped. Using the proper statistical models, relationships between genotypes, histopathological response, and clinical outcomes were examined. Results: Distinct genetic variants demonstrated significant associations with response to celecoxib. Patients carrying specific alleles exhibited greater histopathological regression and down-grading of dysplasia compared to non-carriers. Conversely, certain polymorphisms were linked with limited or no improvement, highlighting genetic heterogeneity in treatment outcomes. The correlation between genotype and histological grading provided mechanistic insights into celecoxib’s chemo preventive efficacy. Conclusion: This study identifies genetic variants that modulate the response to celecoxib chemoprevention in oral leukoplakia among Pakistani patients. Incorporating genetic profiling may enable personalized chemo preventive strategies, improving risk stratification and treatment outcomes in premalignant oral lesions. Larger studies are warranted to validate these findings and guide precision medicine approaches in oral cancer prevention