Oropharyngeal squamous cell carcinoma (OPSCC) is an increasingly prevalent cancer type in
Scotland, with an annual incidence rate of 23.4 per 100,000 of population in 2017
compared to 17.3 per 100,000 in 1993 [1]. This is due in part to an increased frequency
of human papillomavirus (HPV) -related disease, which accounts for >70% of cases of
OPSCC, and to continuing high rates of smoking. The current standard of care in OPSCC
rests on clinical assessment and cross-sectional imaging followed by biopsy with
histopathological diagnosis via immunohistochemistry (IHC) and PCR testing of the tumour
for HPV. Follow-up is by chemo-radiotherapy (CRT) in most cases, with interval imaging to
gauge post-treatment response to therapy and salvage surgery as required [2]. HPV+ve
OPSCC has a generally good prognosis after treatment with CRT (3-year survival 82%),
whilst HPV-ve OPSCC has a much poorer prognosis (3-year survival 57%)[3]. Surgical access
to post-treatment OPSCC for biopsy can be difficult and even with recent advances in
functional imaging there are still significant numbers of patients, at first presentation
and at relapse, with indeterminate results [4]. The poor prognosis of HPV-ve disease and
the major differences in prognosis and management between HPV+ve and -ve disease
underline the importance of accurate identification of HPV status in patients with OPSCC
and emphasise the need for more reliable markers of residual or recurrent disease.
The analysis of circulating tumour-derived DNA (ctDNA) from patient blood - "liquid
biopsy" - represents a minimally invasive approach to cancer diagnosis and management,
with the potential to transform clinical care through identification in blood ctDNA of
actionable tumour-derived mutations, detection of minimal residual disease and early
detection of disease recurrence [5]. There has been significant interest in developing
liquid biopsy approaches in HPV+ve OPSCC, with several studies including our own
indicating that real-time monitoring of HPV levels in plasma cell-free DNA (cfDNA) can
accurately determine HPV status, indicate completeness of response to treatment and
provide evidence of tumour recurrence earlier than routine surveillance and before
symptomatic presentation [6-8] (Thomson et al 2020, MedRxiv). In HPV-ve OPSCC, a
particular problem in Scotland due to high rates of smoking, no such blood-based markers
are available. As well as the opportunities to validate and translate HPV cfDNA as a
biomarker for remission and relapse in HPV+ve OPSCC, there is therefore a need to develop
new diagnostic assays to assist clinical decision-making steps in the management of
HPV-ve disease.
The investigators aim to carry out liquid biopsy studies that will improve diagnostic
accuracy and clinical management of Scottish OPSCC patients. In HPV+ve OPSCC, The
investigators will expand our existing cohort and prospectively evaluate the clinical
utility of cfDNA HPV analysis as a biomarker for routine care. In HPV-ve patients, The
investigators will study the development and evolution of HPV-ve disease through combined
genomic analyses of tumour DNA and circulating cfDNA, with the aim of identifying
blood-based biomarkers and new targets for personalised therapy in this poor prognosis
form of OPSCC. Understanding the molecular events surrounding OPSCC development and
responsiveness to treatment, and identifying biomarkers for blood-based disease
monitoring stand to have a significant impact on patient survival and quality of life of
Scottish patients with OPSCC. The work proposed here - built upon a strong foundation of
pilot data and collaboration between academia and the NHS - will directly assist clinical
care and treatment efficacy for OPSCC patients in Scotland.