Abstract Pain is one of the worst symptoms experienced by patients with oral squamous cell carcinoma (OSCC), which impairs patients' function and quality of life. Yet its clinical and molecular determinants remain poorly defined. The objective of this study was to investigate how pain, quality of life (QoL), and tumor biology intersect to improve prognostication and patient-centered care. This prospective multi-institutional study enrolled 196 OSCC patients from Loma Linda University (LLU) and the University of Alabama at Birmingham (UAB). Pain was assessed using the UCSF Oral Cancer Pain Questionnaire and, Brief Pain Inventory (BPI). Functional and symptom disturbance (QoL) were characterized using EORTC QLQ-C30/H0.05), entirely independent of their cancer stage at diagnosis. Additionally, morphine milligram equivalents (MME/day) were strongly correlated with pain severity and worse QoL metrics (p0.05). Kaplan-Meier analysis showed that high pain (UCSF and BPI), higher symptom score, and higher H0.05). After adjustment for confounders (age, sex, race, pathologic stage, PNI, LVI, smoking status), Cox hazard regression analysis revealed functional score (HR = 0.5, CI 95% 0.287-0.873), symptom score (HR = 2.144, CI 95% 1.169-3.934), HN35 scores (HR = 2.192, CI 95% 1.195-4.023) and opioid use (HR = 2.665, CI 95% 1.510-4.706) as independent predictors of survival. RNAseq analysis of 128 patients comparing high- and low-pain tumors identified significant enrichment in GO pathways related to axonogenesis, neuron to neuron synapse, and in KEGG involved pathways of neurodegeneration-multiple disease, Alzheimer’s, and Huntington’s disease pathways. In addition, the top dysregulated GO pathways in patients with low function (low functional score) were cytoplasmic translation, ribosome biogenesis, and regulator of signal transduction by p53 class mediator. In conclusion, these findings demonstrated that pain severity, opioid requirement, and diminished quality of life are tightly linked to aggressive tumor features and poorer survival in OSCC. Molecular analyses highlight the potential of neural-associated dysregulation in OSCC pain. Citation Format: Minh Phuong Dong, Gary Yu, Michele Arambula, Bac An Luong, Paul Walker, Traeden Wilson, Khanh Nguyen, Carissa M. Thomas, Yi Ye, Bradley Aouizerat, Chi Viet. Pain severity is related to molecular pathways underlying aggressive disease and poor survival in OSCC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1240.
Dong et al. (Fri,) studied this question.