Speaker Abstracts
Use of biomarkers in human papillomavirus Is human-papillomavirus infection Therapeutic human papillomavirus vaccines Prevalence, natural history, and transmission
screening programmes prognostic, predictive, or both? of oral human papillomavirus in relation to
Cornelia Trimble oropharyngeal cancer
Nicolas Wentzensen Lisa Licitra Center for Cervical Disease, Johns Hopkins, Baltimore, USA
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto nazionale Human-papillomavirus (HPV) associated intraepithelial neoplasias are Gypsyamber D’Souza
Bethesda, MD , USA dei Tumori, Via Venezian 1, Milano, Italy lesions that should be susceptible to an HPV-specific T-cell immune response. Johns Hopkins Bloomberg School of Public Health, USA
Randomised trials have shown that human papillomavirus (HPV) DNA HPV positivity is recognised to be a biomarker for oropharyngeal cancer. Indeed, a substantial percentage of cervical intraepithelial neoplasias (CIN)
Oral human papillomavirus (HPV) infection is recognised as an important
testing can be efficiently used in primary cervical cancer screening. Several Biomarkers can be broadly classified as prognostic (associated with disease grade 2 or 3 regress, and findings from clinical trials testing therapeutic
cause of head and neck cancer, primarily oropharyngeal cancers. While
challenges need to be addressed when restructuring current cytology- outcome) or predictive (associated with tumour response). A prognostic vaccination and also topical imiquimod for vulvar intraepithelial neoplasia
the overall incidence of head and neck cancers has declined in the past
based screening programmes: first, although HPV DNA testing has very marker is able to separate a certain population according to the outcome (VIN) show that a subset of VIN can also regress. However, immune responses
few decades, the incidence rates for oropharyngeal cancers has increased,
good sensitivity for detection of cancers and cancer precursors, and its high of interest in the absence of treatment or despite standard non-targeted to HPV antigens required for disease initiation and persistence, measured in
especially in men under the age of 60 years. Despite this risk, oral HPV
negative predictive value allow extended screening intervals, it cannot treatment. A predictive marker, on the contrary, separates a population the blood, do not reliably predict regression of intraepithelial lesions, either
infection has not been well studied, and risk factors for infection and the
discriminate between an innocuous transient infection and a prevalent high- according to outcome in response to a targeted treatment. Survival of patients in unvaccinated or vaccinated cohorts. Memory T cells preferentially circulate
natural history of these infections are not well understood.
grade lesion. A good triage strategy needs to be developed to decide which with HPV-associated head and neck tumours has been analysed in a meta- in the tissue in which they encountered their cognate antigen. Tissue-
women with HPV need to undergo further assessment. Second, up to 50% of analysis, which showed a low risk of dying (hazard ratio 0·85) and a low risk resident T cells are antigen-experienced, are predominantly effector memory Initial studies suggest oral HPV prevalence in the general population is low
prevalent precancers might be missed using conventional colposcopy-biopsy of recurrence (0·62) in patients with HPV-positive tumours. Different reasons cells, and have a partially activated phenotype. Immediate challenges for (4·5%), with oral HPV type 16, responsible for 95% of HPV-associated head
procedures. New clinical algorithms and biomarker discovery and validation of favourable survival outcome have been postulated, which include intact development of therapeutic HPV vaccines include eliciting HPV-specific and neck cancers, prevalent in 1·3% of adults. Oral HPV infection is detected
studies need to address these limitations of disease ascertainment. Third, apoptotic machinery in response to radiation and possibly chemotherapy, effector cell responses that are capable of trafficking to and accessing the in 1–2% of children, supporting some non-sexual transmission. Prevalence
vaccination against HPV type 16 and 18 greatly reduces the number of cancer absence of field-related secondary cancer, immune-system activation by target tissues; questions that remain to be answered include how T cells increases with age and is higher in women with genital HPV infection and
precursors, whereas low grade abnormalities, frequently caused by other viral specific tumour-associated antigens, and effects of radiotherapy or home to the genital tract and head and neck mucosae, how they are retained, individuals infected with HIV than in the general population. The natural
types, are less affected. As the signal-to-noise ratio is reduced, identification chemotherapy. In patients with HPV-positive tumours, those able to mount a how they are functionally polarised at the initial antigenic exposure, the history of oral HPV infection is unknown, and whether the well established
of new biomarkers with strong discriminatory values is important. Currently, serological immune response against viral E6 or E7 have improved outcomes. degree of elasticity of polarisation of tissue T cells, and how lesion-mediated natural history of cervical HPV is similar for HPV in the oral cavity, which has a
several biomarker candidates are being investigated in clinical trials. The most Improved outcome has been reported for patients undergoing primary surgery mechanisms of immune evasion can be identified and circumvented. Clinical distinct immunological environment, is unclear.
widely studied markers are HPV mRNA and p16. Recently, several promising for oropharyngeal cancer. Moreover, improved outcome has been reported trials testing immune therapies for HPV disease should incorporate the study Evidence strongly supports the sexual transmission of HPV to the oral region;
host gene-methylation markers have been proposed. Biomarker validation for most measures of outcome, including overall survival, progression-free of tissue measures of immunological parameters, and systemic measures of however, because sexual behaviours are colinear (related), establishing which
studies need to focus on the effect of biomarkers on risk stratification in the survival, local-regional control, and second primary tumours—except for immune response. behaviours are involved in transmission and the level of risk each might pose
study population early on during the assessment process. distant metastases for more than 400 patients with oropharyngeal cancer is difficult. Initial studies suggest that oral HPV can be sexually transmitted
undergoing primary concomitant chemoradiation in a randomised phase 3 between couples and that spouses of cervical cancer patients have increased
study, which showed that treatment intensification might be useless, especially rates of oropharyngeal cancer.
in HPV-positive oropharyngeal tumours. Despite improved outcome, studies
reported a trend towards advanced N-stage HPV-positive tumours. This finding
confirmed, together with advanced T-stage HPV-positive tumours, possible
effects on the risk of distant metastases. HPV-positive tumours showed a
statistical improvement of response rates with chemotherapy and organ
preservation data, disease-free survival, and improved survival. One study
pointed out that response rate to induction chemotherapy is associated with
HPV16 gene copies quantified in the single tumour. The same observation
was made in p16 tumour staining, which is now recognised as an effective
and reliable marker of HPV positivity in head and neck cancer. Indeed, p16
immunohistochemical expression has been strongly correlated with in-situ
hybridisation and HPV-gene expression through PCR analysis.
Smoking status—categorised as never smoked, past smoker, current smoker,
or by packs smoked per year—has been associated with the outcome of
patients with HPV-positive oropharyngeal cancer. An inverse correlation
between epidermal growth factor receptor (EGFR) expression and smoking
exists, suggesting a role of the EGFR pathway in determining prognosis.
Association between HPV positivity and tumour response to EGFR inhibitors
has not been reported.
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