Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
Pain is the initial symptom reported by nearly 75% of individuals diagnosed with head and neck squamous cell carcinoma (HNSCC). Despite the substantial burden of pain associated with HNSCC, effective management remains elusive, leading to increased reliance on opioid prescriptions. Yet, even with opioid prescriptions, 80% of HNSCC patients will report inadequate pain management. Current pain management in HNSCC is unsustainable and fails to consider other factors that can influence pain. Adequate pain management is essential to quality of life (QoL) and there is a need to understand the drivers of pain to be able to provide patient-centered and equitable pain management to all HNSCC patients. Pretreatment pain is an independent predictor of survival in newly diagnosed HNSCC and is associated with recurrence within the first year. Unfortunately, very little is known about the molecular pathophysiology of pain development in HNSCC. The purpose of this study was to explore the relationship between patient perceived pain severity and blood-based gene expression profile in individuals with newly diagnosed with HNSCC of the oral cavity (OCSCC; n=7) or the oropharynx (OPSCC; n=6) prior to definitive treatment. Perceived worst pain score was measured using the Brief Pain Inventory-Worst Pain (BPI-WP) item. Peripheral whole blood RNA-Seq was performed using TruSeq Total RNA Library Prep kits (Illumina), and differential gene expression (DEG) and pathway analysis were carried out using our R Bioconductor pipeline. The R Bioconductor package DESeq2 was used to test differential expression based on a model using the negative binomial distribution. Biological pathways were defined by the MSigDB Hallmark pathway database. Pain phenotype and blood collection occurred on the same day, after diagnosis but prior to definitive treatment. In this cohort, 100% of OCSCC patients and 33% of OPSCC patients report pretreatment pain. Patients with OCSCC presented at a higher tumor stage (p=0.047) and have higher BPI-WP scores than those with OPSCC (7.0 ± 3.2 vs. 1.3 ± 2.2, p=0.004). Perineural invasion (PNI) was limited to the OCSCC cohort (n=5, 71.4%). PNI+ patients had a lower BPI-WP score than PNI- (6.4±3.6 vs. 8.5±2.1, p=n.s.). Differential gene expression analysis of whole blood from participants revealed broad alterations revealed significant enrichment of genes related to immune activation (chemokines and cytokines) in patients with greater pain. For example, the chemokine Interleukin 8 (p<0.001, Log2FC=2.3) was more highly expressed in OCSCC patients with higher pain scores. Pathway enrichment analysis demonstrated pathway enrichment for adrenoceptor activity (p=0.02, Log2FC=0.726) in patients with OCSCC, although no specific adrenergic receptor genes were significantly enriched for pain. The β2-adrenoceptor (ADRB2) trended toward increased expression in participants reporting more intense pain (p=0.08, Log2FC=0.47). Individuals diagnosed with OCSCC present at a higher tumor stage and report more intense pain prior to definitive treatment than those diagnosed with OPSCC. Enrichment of the IL8 gene and adrenoceptor pathway suggests greater interaction between the nervous system and cancer in those reporting more severe pain. Understanding the molecular pathophysiology of pain in each cancer subtype can help develop interventions to prevent or reduce the severity of pain in HNSCC.