Low risk of second primary malignancies among never smokers with human papillomavirus–associated index oropharyngeal cancers

BACKGROUND: Among patients with index oropharyngeal cancer, second primary malignancies (SPMs) may be less common in cases of human papillomavirus (HPV)-associated tumors than HPV-negative tumors. Further modification of these SPM risks by smoking has not been reported. METHODS: SPM outcomes of 356 patients with incident oropharyngeal cancer were analyzed using Cox proportional hazards and Kaplan-Meier models. SPM risk and SPM-free survival were compared in HPV-seronegative patients, HPV-seropositive never smokers, and HPV-seropositive ever smokers. RESULTS: HPV-seropositive patients had a lower 5-year SPM rate than HPV-seronegative patients (5.6% vs 14.6%; p = .051). Compared to HPV-seronegative patients, HPV-seropositive never smokers had a 73% reduced SPM risk, and HPV-seropositive ever smokers had a 27% reduced SPM risk (trend p = .028). Although HPV-seronegative patients had SPMs in traditional locations, 70% of SPMs among HPV-seropositive patients were outside typical tobacco-related sites. CONCLUSION: HPV serologic status and smoking may stratify patients with index oropharyngeal cancers in terms of risk and location of SPMs.