A validated prognostic genetic profile independent of smoking in HPV-positive oropharynx cancer
Jacob Lilja-Fischer,
Denmark
MO-0383
Abstract
A validated prognostic genetic profile independent of smoking in HPV-positive oropharynx cancer
Authors: Jacob Lilja-Fischer1,2, Magnus Stougaard3, Morten Horsholt Kristensen1, Torben Steiniche4, Jesper Grau Eriksen1, Jens Overgaard1
1Aarhus University Hospital, Department of Experimental Clinical Oncology, Aarhus, Denmark; 2Aarhus University Hospital, Otolaryngology - Head & Neck Surgery, Aarhus, Denmark; 3Aarhus University, Institute of Pathology, Aarhus, Denmark; 4Aarhus University Hospital, Institute of Pathology, Aarhus, Denmark
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Purpose or Objective
Prognosis after primary radiotherapy of oropharyngeal squamous cell carcinoma (OPSCC) is significantly better in patients with HPV+ disease, but previous smoking is associated with a worse prognosis. The reason is unknown, but in a previous study using patient-derived xenografts, we found differing radiosensitivity even in HPV+ OPSCC, pointing to a radiobiological cause.
The aim of this study was to explore and validate tumor genetic differences in patients with HPV+ OPSCC with differing tobacco exposure, and test in an independent cohort whether these genetic differences hold prognostic information.
Material and Methods
In the exploratory phase of the study, we analyzed tissue samples from 54 patients. Forty patients had HPV+ disease, and 20 of those had a history of significant tobacco smoking (>10 pack-years).
Molecular analyses included targeted DNA-sequencing of more than 400 cancer-related genes in the exploratory phase. Patients were divided in to three groups according to HPV- and smoking status (HPV-positive non-smokers, HPV-positive smokers and HPV-negative). A genetic profile was developed according to differences between these groups.
In the validation phase, we utilized a custom-made panel including 59 genes, and included 77 patients. Thirty-nine had HPV+ disease, 18 of these had a significant smoking history. Patients were assigned in to three groups according to their HPV-status and genetic profile (HPV+ high-risk, HPV+ low-risk, HPV-neg).
All patients were contemporary patients with OPSCC identified in the DAHANCA database, and treated with curatively intended primary (chemo-)radiotherapy according to national guidelines.
We compared event-free survival (EFS) and loco-regional failure (LRF) between groups.
Results
In the test-cohort we found that in patients with HPV+ disease, a history of tobacco smoking was associated with mutations in ATR, MET, RB1 and PIK3CA genes.
In the validation-cohort, we were able to re-establish a distinct group of patients with HPV+ OPSCC who were characterized by one or more of these alterations (“HPV+ high-risk”). These patients had a worse prognosis in terms of LRF and EFS, than patients with HPV+ OPSCC without these changes (Figure). There was no difference in tobacco pack-years between HPV+ high-risk and HPV+ low-risk groups in the validation phase.
Conclusion
We were able to establish a group of patients with HPV+ OPSCC who are characterized by distinct genetic alterations. This profile was reproduced in an independent validation cohort, and was shown to confer a worse prognosis, approaching that of patients with HPV-negative disease, independent of smoking history.
