Human papillomavirus in oropharyngeal cancer in Canada: analysis of 5 comprehensive cancer centres using multiple imputation

Steven Habbous, Karen P. Chu, Harold Lau, Melissa Schorr, Mathieos Belayneh, Michael N. Ha, Scott Murray, Brian O’Sullivan, Shao Hui Huang, Stephanie Snow, Matthew Parliament, Desiree Hao, Winson Y. Cheung, Wei Xu, Geoffrey Liu

The incidence of oropharyngeal cancer has risen over the past 2 decades. This rise has been attributed to human papillomavirus (HPV), but information on temporal trends in incidence of HPV-associated cancers across Canada is limited. We collected social, clinical and demographic characteristics and p16 protein status (p16-positive or p16-negative, using this immunohistochemistry variable as a surrogate marker of HPV status) for 3643 patients with oropharyngeal cancer diagnosed between 2000 and 2012 at comprehensive cancer centres in British Columbia (6 centres), Edmonton, Calgary, Toronto and Halifax. We used receiver operating characteristic curves and multiple imputation to estimate the p16 status for missing values. We chose a best-imputation probability cut point on the basis of accuracy in samples with known p16 status and through an independent relation between p16 status and overall survival. We used logistic and Cox proportional hazard regression. We found no temporal changes in p16-positive status initially, but there was significant selection bias, with p16 testing significantly more likely to be performed in males, lifetime never-smokers, patients with tonsillar or base-of-tongue tumours and those with nodal involvement (p < 0.05 for each variable). We used the following variables associated with p16-positive status for multiple imputation: male sex, tonsillar or base-of-tongue tumours, smaller tumours, nodal involvement, less smoking and lower alcohol consumption (p < 0.05 for each variable). Using sensitivity analyses, we showed that different imputation probability cut points for p16-positive status each identified a rise from 2000 to 2012, with the best-probability cut point identifying an increase from 47.3% in 2000 to 73.7% in 2012 (p < 0.001). Across multiple centres in Canada, there was a steady rise in the proportion of oropharyngeal cancers attributable to HPV from 2000 to 2012.