Investigating prognostic and predictive tissue biomarkers in head and neck squamous cell carcinoma

© 2017 Richard James YoungHead and neck squamous cell carcinoma (HNSCC) comprises a diverse group of cancers that arise from a number of subsites of the upper aerodigestive tract, including the oropharynx, oral cavity, larynx and hypopharynx. These cancers have traditionally been linked to tobacco and alcohol use (Gillison et al 2008; Goon et al 2009) and despite improvements in treatment, the outcome for patients with locally advanced HNSCC remains poor. Current treatments are associated with significant acute and late toxicity which can have a significant long term negative impact on function and quality of life. Current tumor staging methods and biomarkers are limited in their capacity to consistently distinguish groups with different outcomes, and to permit tailoring of therapy based on prognosis and biological features. Furthermore, it is recognised that there are significant clinical differences between the different subsites of head and neck cancer, warranting molecular studies focused on individual sites. Thus, to improve patient outcomes, it is becoming increasing important to identify novel biomarkers of prognosis and response to therapy which will empower clinicians with better patient selection strategies for risk-adapted treatments and emerging molecular therapies. It is now accepted that a significant proportion of oropharyngeal cancers, are caused by infection with human papilloma virus (HPV) (Fakhry et al 2008; Ang et al 2010). HPV positive oropharyngeal cancer is known to differ from HPV negative epidemiologically, clinically and molecularly and most importantly, HPV positive status is associated with a greatly improved prognosis (Fakhry et al 2008; Ang et al 2010). The involvement and importance of HPV in non-oropharyngeal HNSCC sites however remains unclear. Other than HPV, which is often determined diagnostically via p16INK4A immunohistochemical staining (an accepted surrogate biomarker in oropharyngeal cancer), there are no clinically useful prognostic or predictive biomarkers in HNSCC. The identification of relevant biomarkers, which can be easily assayed in a diagnostic setting, utilising readily accessible formalin-fixed, paraffin-embedded (FFPE) tissue blocks, is critical to improving patient outcomes. Such assays include immunohistochemistry (IHC) to look at protein expression and fluorescence in situ hybridisation (FISH) for the study of gene copy number. This thesis comprises five published peer reviewed journal articles containing research investigating the role of HPV/p16INK4A in head and neck cancer; both establishing the role of HPV/p16INK4A in oropharyngeal cancer, as well as work demonstrating that the role of HPV in non-oropharyngeal HNSCC subsites including the oral tongue and larynx is not as clear or important as oropharyngeal cancer. Further, I present work investigating several putative predictive biomarkers and their potential roles in providing clinically useful information for potential patient stratification. All of these studies utilised several large unique HNSCC patient cohorts comprising FFPE tissue blocks and comprehensively annotated clinicopathological and outcome data