A model using concomitant markers for predicting outcome in human papillomavirus positive oropharyngeal cancer
Introduction
Human papillomavirus (HPV) was in 2007 accepted as a risk factor for oropharyngeal squamous cell carcinoma (OSCC), dominated by the tonsillar (TSCC) and base of tongue (BOTSCC) cancer subtypes [1]. Lately, the incidences of HPV-positive (HPV+) TSCC and BOTSCC have increased [2], [3], [4], [5], [6], [7], [8]. Notably, HPV+ TSCC and BOTSCC have better prognosis than corresponding HPV-negative tumors, with 80% vs. 40% disease-specific survival [9], [10], [11], [12], [13], [14].
Therapy for head and neck cancer has, due to poor outcome (similar to HPV− TSCC and BOTSCC), become more intensified, with radiotherapy, induction/concomitant chemoradiotherapy, targeted therapy and surgery. Many HPV+ TSSC and BOTSCC patients may not need intensified therapy and may benefit from less therapy, maintaining survival and reducing treatment-related morbidity, and therefore it is important to identify these patients [13]. Age, stage, smoking, absent/low HLA class I expression, CD44, LMP10 expression, high LRIG1 expression, absence of HLA-A∗02, high CD8+ tumor infiltrating lymphocyte (TIL) counts and CD98 have been proposed as prognostic markers in HPV+ TSCC and BOTSCC [14], [15], [16], [17], [18], [19], [20].
Previously, in a regression model using several markers to predict risk of death/relapse in patients with HPV+ TSCC and BOTSCC, low age, low clinical stage and high CD8+ TIL counts were found to be strong prognostic markers, followed to a lesser extent by low/absent HLA class I expression [21]. Recently, patients with HPV16 DNA, E7 mRNA-positive TSCC and BOTSCC expressing HPV16 E2 mRNA were identified to have better clinical outcome than those with tumors lacking HPV16 E2 mRNA expression [22]. Here, we have extended upon the model above by including data on HPV16 E2 mRNA expression in combination with already existing clinical and molecular data to improve patient stratification by building a model that could reliably predict good survival for a large fraction of patients.
Section snippets
Patients and tumor characteristics
Patients diagnosed with TSCC (ICD-10 code C09.0-9) or BOTSCC (ICD-10 code C01.9) between 2000 and 2011 and treated with curative intent at Karolinska University Hospital, having an HPV16 E7 mRNA positive tumor, with data on p16, HLA class I expression and CD8+ TILs were included in this study. Data on CD8+ TIL counts and HLA class I expression were available for 315 HPV DNA positive/p16 overexpressing tumors from a previous report [21]. Of these 315 tumors, 116 had previously been tested for
HPV16 mRNA analysis and total number of patients included in the analysis
From 148 available HPV16 DNA positive TSCC/BOTSCC samples, 141 had extractable mRNA and were HPV16 E7 mRNA positive and included with the other 117 HPV16 E7 mRNA positive cases in the continued analysis. Thus 258 patients with HPV16 E7 mRNA positive tumors (where 257 also overexpressed p16), were divided (65/35) in a training set of 168 patients and a validation set of 90 patients. Patients, tumor characteristics and treatments are summarized in Table 1.
Data distribution
For an overview of data distribution,
Discussion
This study presents a model, where clinical outcome for patients with HPV16 DNA/E7 mRNA positive TSCC and BOTSCC is predicted based on four factors: age and CD8+ TILs above median, T-stage <3 and HPV16 E2 mRNA expression. When at least three of these factors are present, >50% of patients who do not relapse can be identified with >97% PPV. The selected numerical model, comprising six variables, had an area under curve (AUC) of 76% both in the training and validation set, showing that it was not
Conflict of interest
The authors disclose no potential conflicts of interest.
Acknowledgements
This research was supported by the Swedish Cancer Foundation, the Stockholm Cancer Society, the Swedish Cancer and Allergy Foundation, Henning and Ida Persson’s Research Foundation, the Stockholm City Council and Karolinska Institutet, Sweden.
References (32)
- et al.
Oral and oropharyngeal cancer in The Netherlands between 1989 and 2006: increasing incidence, but not in young adults
Oral Oncol
(2009) - et al.
CD8+ and CD4+ tumour infiltrating lymphocytes in relation to human papillomavirus status and clinical outcome in tonsillar and base of tongue squamous cell carcinoma
Eur J Cancer
(2013) - et al.
A model for predicting clinical outcome in patients with human papillomavirus-positive tonsillar and base of tongue cancer
Eur J Cancer
(2015) - et al.
Studies on human papillomavirus (HPV) 16 E2, E5 and E7 mRNA in HPV-positive cancer in relation to clinical outcome and immunological parameters
Oral Oncol
(2015) - et al.
Human papillomavirus prevalence is high in oral samples of patients with tonsillar and base of tongue cancer
Oral Oncol
(2014) - WHO. IARC Monographs on the Evaluation of carcinogenic risk to humans. Lyon, France: International Agency for Research...
- et al.
Oropharyngeal cancer incidence and mortality in Scotland: are rates still increasing?
Oral Oncol
(2003) - et al.
Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer
Int J Cancer
(2006) - et al.
Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers?
Cancer
(2007) - et al.
Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?
Int J Cancer
(2009)
The role of human papillomavirus in the increased incidence of base of tongue cancer
Int J Cancer
Human papillomavirus and rising oropharyngeal cancer incidence in the United States
J Clin Oncol
Evidence for a causal association between human papillomavirus and a subset of head and neck cancers
J Natl Cancer Inst
Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival
Int J Cancer
Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients
Int J Cancer
Human papillomavirus and survival in patients with base of tongue cancer
Int J Cancer
Cited by (31)
An analysis of distant metastasis cases from HPV-associated oropharyngeal squamous cell carcinoma
2021, Journal of Cranio-Maxillofacial SurgeryCitation Excerpt :HPV-associated OPSCC are regarded to have completely different tumor biology in contrast to HPV-negative HNSCC. The most important fact for patients about HPV-associated OPSCC is the usually good clinical outcome with high survival rates (Bersani et al., 2017). Thus, deintensification of treatment algorithms for HPV-associated OPSCC is currently under evaluation in clinical trials.
Novel prognostic clinical factors and biomarkers for outcome prediction in head and neck cancer: a systematic review
2019, The Lancet OncologyCitation Excerpt :However, whether this non-invasive surveillance tool can identify local or regional recurrence at a timepoint amenable to surgical salvage remains uncertain.108 Bersani and colleagues109 showed that the excellent prognosis of HPV-positive tumours is further improved when additional favourable features are present. The authors analysed data from 258 patients with oropharyngeal carcinoma, two-thirds of whom were randomly selected to a training cohort and the remaining third for a validation set for the investigation of several prognostic factors.
Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma
2018, Oral OncologyCitation Excerpt :Patients with HNSCC that exhibit high infiltration of CD8 T cells also demonstrate a significantly better outcome [5,7–16]. In HNSCC human papillomavirus (HPV) infection is associated with better prognosis, which appears in part to be due to enhanced immune activation in the TME, and especially enhanced infiltration of CD8 T cells [16–18]. Given the direct relationship between TILs and HNSCC, a direct method to assess an immune response within HNSCC would be desirable [19].
MicroRNA-155, -185 and -193b as biomarkers in human papillomavirus positive and negative tonsillar and base of tongue squamous cell carcinoma
2018, Oral OncologyCitation Excerpt :Before therapy de-escalation, the identification of patients with good prognosis is required [13]. Furthermore, today’s intensified therapy does not improve survival for patients with HPV+ tumours and therefore alternative therapies for patients with predicted poor prognosis, such as immunotherapy or novel targeted therapies, would be relevant options [15]. Others and we have, in these tumour types, identified age, stage, smoking, high CD8+ tumour infiltrating lymphocyte (TIL) counts, absent/low HLA class I expression, CD44, LMP10 expression, high LRIG1 expression, absence of HLA-A∗02, CD98 and presence of HPV16 E2 mRNA expression as potential prognostic markers [14,16–22].
Prognostic impact of leukocyte counts before and during radiotherapy for oropharyngeal cancer
2017, Clinical and Translational Radiation OncologyCitation Excerpt :Five-year survival rates remain less than optimal for patients with localized disease (83%), regional disease (59%), and distant disease (36%) [6], although the discovery of human papillomavirus (HPV) as a causal factor in OPC has led to the identification of subgroups of patients with improved prognosis [7]. Although other biomarkers of survival have been examined, none other than HPV status have affected clinical care or are used routinely [8–14]. Both leukocytosis and neutrophilia at diagnosis and leukopenia during treatment have been previously associated with survival.
- 1
Contributed equally.