Current therapy stratification of head and neck squamous cell carcinomas (HNSCCs)
is based on clinical features. This approach often fails to capture the enormous
biologic heterogeneity of the disease entity. Therefore, biomarkers which would act
as indicators of treatment sensitivity could be extremely helpful in tailoring therapy
on a more individualized basis. Human papillomavirus (HPV) has emerged as a
biomarker in oropharyngeal squamous cell carcinoma (OPSCC). De-escalation of
treatment based on p16 as a surrogate marker for HPV infection is a matter of debate.

The aim of this thesis was to evaluate p16 and xCT, an amino acid transporter
that mediates programmed cell death, as biomarkers in HNSCC. Clinical data of all
patients treated for HNSCC at Turku University Hospital during 2005 – 2015 were
investigated. Expression of p16 and xCT were evaluated using
immunohistochemistry in a population-based tissue microarray. Moreover, patterns
of recurrence were studied using dose distribution analyses of hybrid positron
emission tomography - computed tomography (PET-CT) images from radiotherapy
(RT) treatment planning co-registered with PET-CT/MRI (magnetic resonance
imaging) images obtained at the time of relapse.

HNSCCs were observed to respond heterogeneously to RT, and a small subset
of p16-positive diseases relapsed within the high-risk treatment volume despite the
common view of their high radiosensitivity and better prognosis. Moreover, results
from p16-negative tumours suggested that even meticulous treatment planning with
multimodality imaging may fail to detect all clinically significant disease. In
OPSCC, p16 was an independent prognostic factor when adjusted for age, treatment
modality, T class, nodal positivity, and consumption of alcohol and tobacco. The
expression and prognostic value of xCT varied markedly among different primary
tumour sites. In OPSCC, xCT was a powerful prognostic factor.

The thesis suggests that successful treatment de-escalation of patients with p16-
positive OPSCC likely requires further biomarkers predictive of RT response. Also,
the findings encouraged for further studies on therapeutic targeting of xCT to
overcome radioresistance.