Quantifying smoking exposure, genomic correlates, and related risk of treatment failure in p16+ squamous cell carcinoma of the oropharynx

OBJECTIVES: HPV‐associated (p16+) squamous cell carcinoma of the oropharynx (OPSCC) has improved survival as compared to HPV‐negative, smoking‐associated disease. Intermediate outcomes have been noted in patients with p16+ tumors and smoking exposure. However, the extent of smoking exposure required for outcomes to decrease has not been delineated due to low failure rates and poor availability of quantitative tobacco smoke exposure data. Our primary objective is to characterize the dose‐dependent relationship between recurrence‐free survival (RFS) and tobacco smoke exposure in p16+ OPSCC and secondarily correlate tobacco smoke exposure with genomic alterations. METHODS: Single institution chart review was performed of patients diagnosed with p16+ OPSCC from 2003 to 2015. Patients were excluded if staging, treatment details, recurrence status, or smoking exposure in pack‐years were not available. Two hundred and forty‐four patients were included. RESULTS: Patients with 25 pack‐years or greater smoking history exhibited a dose‐dependent decrease in RFS compared to never smokers. This was robust to multivariate analysis for including staging and demographic factors. Forty‐three patients with available targeted tumor sequencing data were identified. A strong trend was observed for increased C to A transversion mutations above 25 pack‐years, which are known to be associated with exposure to tobacco smoke. Similarly, the proportion of COSMIC Signature 4 mutations were also found to be more common in patients with more than 25 pack‐years of smoking exposure. CONCLUSION: Evidence‐based smoking exposure thresholds are needed to define inclusion criteria for trials of de‐escalation therapy for p16+ OPSCC. Patients with smoking exposure greater than 20 pack‐years have increased risk of recurrence and a distinct pattern of genomic alterations. Further studies are needed to delineate the potential consequences of mild smoking exposure. Smoking‐related mutational signatures may hold potential for biomarker development in p16+ OPSCC. LEVEL OF EVIDENCE: 2B