T32: Human papilloma virus association with survival of head and neck cancer patients

Abstract

The most important development in head and neck oncology of the past decade is the demonstration that patients with human papillomavirus (HPV)-mediated oropharyngeal cancers have significantly improved outcomes, compared to HPV-negative counterpart patients. We examined racial disparities among 102 oropharyngeal carcinoma (OPC) patients (30 African Americans, 72 Whites) comparing the present of HPV16/18 E6 and E7 oncoproteins, and p16Ink4A overexpression, with times to disease progression (DP) and disease specific survival (DSS). Expression of HPV16/18 transcripts was assessed by reverse transcription and polymerase chain reaction using type-specific E6/E7 primers; p16Ink4A was evaluated by immunohistochemistry. African Americans were significantly more likely to present with high T stage disease and receive nonsurgical treatment. HPV16/18 was present in 63% of patients; no racial differences were observed. Silenced p16Ink4A in OPC was significantly more common in African Americans (15/24) than Whites (20/69) ( p = 0.004), and HPV16 + African Americans (6/24) than HPV + Whites (2/42) ( p = 0.023). Kaplan Meier analysis for DSS revealed a protective effect for p16Ink4A overexpression ( p = 0.0028), HPV16+ ( p = 0.036), and Whites ( p = 0.0039). Shorter DSS was associated with primary definitive chemoradiation ( p = 0.019) and T3/T4 disease ( p = 0.0001). A protective effect with respect to disease progression was observed for HPV16+ ( p = 0.007), Whites ( p = 0.0006) and p16Ink4A overexpression ( p = 0.0001). African Americans with OPC experience poorer outcomes likely due to p16Ink4A silencing, higher T stage, and nonsurgical treatment, but not lower rates of transcriptionally active HPV16/18. We studied patients with oral cavity squamous cell carcinoma for HPV16 and HPV18, local immune response, p16 expression and outcome. Overexpression of p16INK4a was uncommon in oral cavity squamous cell carcinoma (17/112 or 15.2%). HPV16 and HPV18 were detected in 22.6% and 11% patients respectively. We demonstrated that the presence of transcriptionally active HPV16 in oral cavity squamous cell carcinomas does not correlate with p16INK4a overexpression, enhanced local tumor immunity, or improved outcome. To investigate the possible mechanism of protective effect of HPV and p16INK4a, we have developed primary cancer cell lines from resections with known patterns of invasion. Given that cell lines derived from HPV-mediated oropharyngeal squamous cell carcinomas are less invasive than their HPV-negative counterparts, we tested the hypothesis that viral oncoproteins E6, E7, and p16INK4a can affect tumor invasion. We demonstrated that p16INK4a overexpression in two cancer cell lines (UAB-3 and UAB-4), derived from oral cavity squamous cell carcinomas with the most aggressive invasive phenotype, dramatically decrease tumor invasiveness by altering expression of extracellular matrix remodeling genes. Pathway analysis integrating changes in RNA expression and kinase activities reveals different potential p16INK4a-sensitive pathways. In summary, we presented clinical data from a large cohort of head and neck squamous cell carcinoma patients with respect to transcriptionally active HPV16, p16INK4a overexpression, local adaptive tumor immunity, and outcome. Observed differences in clinical outcomes could be perhaps due to differential immune responses and gene activation profile. The detection of a HPV-positivity in HNSCC has important clinical implications as independent prognostic factor for treatment deintensification and improved survival of HPV-mediated oropharyngeal cancers. In our knowledge the further studies are needed to dissect the HPV-positive HNSCC in more detail to find the effective prognostic markers as well as molecular targets to affect tumor behavior.