Update on Oral HPV Service and Related Research K Cuschieri, presented at Shine Meeting 25/09/12.

Transcription

1 Update on Oral HPV Service and Related Research K Cuschieri, presented at Shine Meeting 25/09/12.

2 Non Cervical Cancers with an HPV aetiology 1. Anal 2. Penile 3. Vulval 4. Vaginal 5. Component of head and neck squamous cancers, particularly oropharyngeal squamous cell cancers (OSCC) HPV testing no clear role for the management of 1-4, currently Incidence of OSCC has increased over last 20 years Scottish data show rate of OSCC has increased more than any other cancer, 2.9 fold increase in men and a 2.4 fold increase in women in the period between 1987 and 2006 Junor et al 2010 BMJ 340: c2512

3 HPV and Oropharygeal Cancer A component of OSCC have an HPV aetiology Evidence to suggest that HPV positive OSCC has a better prognosis compared to HPV negative OSCC 1 Retrospective study of Scottish patients showed prevalence of HPV positive OSCC increased from 67% to 81% in men and 50% to 85 % in women [two cohorts and ]. 2 In the above study, patients who were HPV +/p16 + had best survival, HPV- /p16- patients had worse survival. In UK no guideline-driven de-escalated management for HPV positive OSCC. Useful as prognostic indicator. 1 Ang et al (2010) New England Journal of Medicine 363: Junor et al (2012) British Journal of Cancer 106:

4 Organisational support/position National Comprehensive Cancer Network (USA) College of American Pathologists Scottish Intercollegiate Guideline Network Under Prognostic Factors: HPV infection Six studies were identified.five showed that for oropharyngeal tumours, HPV infection was associated with younger age, absence of additional risk factors (such as smoking and alcohol consumption), high proliferation indices, high grade, basaloid subtype, better response to radiotherapy and a better survival In patients that fall into the above category HPV subtyping may be appropriate although this is outwith the remit of most pathology departments at present. Unlike HPV testing for cervical disease management, which is increasingly organised & routine in UK and beyond. Testing for OPSCC is a developing area.

5 Local Provision Scottish HPV Reference Lab : varied remit includes Immunisation Surveillance testing Testing for Scottish Cervical Screening Programme QA R and D & Also currently funded to perform up to 200 HPV tests per year to help guide individual management (gynae and non gyane)

6 Local Test/Service Specimen FFPE section from relevant block Issues with previous assay (line blot), stopped receiving samples due to high invalid rate New assay validated internally service re-initiated August this year Luminex PCR based test delineates 24 HPV types. Detects HPV L1 gene Used for National HPV Surveillance Demonstrates consistent good performance WHO LabNet EQA scheme

7 Optimal Test? No commercially available FDA approved tests for determination of HPV status in head and neck tumours. Some debate as to optimal test choice Literature can tend towards the justification of a particular in-house technique Gold standards for HPV detection vary: qrt E6/E7 PCR (HPV16 E6*1) suggested* *Smeets et al Int J Cancer 2007; 121 (11)

8 Test Choice Optimal test needs to be effective on alcohol preserved tissue fragments and FFPE tissue samples. Not overly technical Common methods to characterise OSCC as HPV pos/neg P16 INK4a, HPV In Situ Hybridisation (ISH), PCR based detection. - All have been shown to correlate to improved clinical outcomes as independent prognostic markers

9 p16 p16 Advantages Disadvantages Less affected by specimen/na degradations Cellular marker - not specific for HPV infection* Cheaper than PCR Subjective interpretation and scoring schemes** Doesn t require molecular facilities, easily performed in routine pathology lab. ** Singhi & Westra Cancer 2010; 116 ( ): Positive = strong and diffuse nuclear and cytoplasmic staining >70% of tumour Schache et al Clin Cancer Res 2011; 17 (19); : Positive = As Above Smeets et al Int J Cancer (11) : Positive = Any detectable staining Jordan et al Am J Surg Pathol Vol : Positive = >35% staining

10 In Situ In Situ Advantages Disadvantages Cheaper than PCR Tend to be HPV 16 orientated Doesn t require molecular facilities Subjective interpretation Can be affected by specimen/na degradation

11 PCR based techniques PCR Advantages Disadvantages Sensitive & objective Requires Zoned pre and post amplification facilities Analytically specific, can provide info on type Affected by NA degradation If RT PCR technical gold standard. More expensive than IHC and p16

12 Head to head comparison of HPV methods (n=48 cases) Technical study - examined different detection methods on paraffin embedded OPSCC biopsies Gold standard E6/E7 detection in fresh material derived from the same biopsies (12/48) HPV Test Sensitivity* DNA qpcr HPV PCR HPV ISH P16 IHC P16 IHC and ISH P16 IHC and HPV PCR *Relative to gold standard Specificity* Conclusion Optimal method combined p16 + molecular test Adapted from Robinson et al Head and Neck Pathol (2012) 6: S83-S90 & Smeets et al Int J Cancer 2007; 121 (11)

13 Does performing > 1 test provide better insight into prognosis. Pos Molecular test Neg P16 Pos Best (a)? (b) Neg? Worst (d)

14 Three Class Hypothesis Proposed by Weinberger et al (2006) Clin Oncol 24: HPV+ve/ P16+ve HPV-active Class-III HPV+ve/p16-ve HPV inactive Class II HPV-ve/p16-ve HPV negative Class I

15 Weinberger et al 2006 Pos Molecular Neg P16 Pos 18 Class 3 Neg 29 Class Class 1 5 year disease free survival Class 1 15% Class 2 13% Class 3 75% Extrapolation: Knowledge of HPV status doesn t add value to prognosis if p16 performed.

16 Junor et al 2012 Looked at 2 cohorts : and Pos Molecular Neg P16 Pos 77 Class 3 Neg 56 Class Class 1

17 100 Percent survival p= HPV+ve p16+ve cohort 1 HPV+ve p16+ve cohort 2 HPV+ve p16-ve cohort 1 HPV+ve p16-ve cohort 2 HPV-ve p16-ve cohort 1 HPV-ve p16-ve cohort Survival (years) HPV positive p16 neg may represent a clinical entity that may respond more favourably to chemoradiotherpy,

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19 (1) UK HPV Prevalence study. CI Terry Jones, University of Liverpool Investigation into prevalence of HPV-related OPSCC - is gender and/or age biased and it is increasing with time? 11 sites collecting over 10 year period: 01/01/ /12/2011 Comprehensive approach to testing: HPV PCR & typing, p16, ISH Centralised HPV testing Cardiff & Edinburgh 1,750 samples in total Only data recorded for analysis will be anatomical site, year of diagnosis and patient sex and age at presentation.

20 (2) RTOG* 1016 Principal Investigator: Andy Trotti, MD & Maura Gillison Phase III RCT of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer Will different arms result in comparable 5-year overall survival (1ry) Impact on morbidity/toxicity (2ry) Test = p16 Target accrual 706 patients * Radiation therapy oncology group

21 (3) DeESCALaTE* Principal Investigator: Prof Hisham Mehanna (Warwick) V similar in design & outcomes to RTOG Target accrual 304 patients End date Feb 2017 * Determination of Epidermal growth factor receptor inhibitor (cetuximab) versus Standard Chemotherapy (cisplatin) early And Late Toxicity Events in Human Papillomavirus positive oropharyngeal squamous cell carcinoma. calate

22 (4) PREDICTR-HNC Observational cohort study Assessment of biomarkers: HPV, p16, EGFR and Bcl-2, CA-9 1,400 samples, relating biomarker status to 3 year outcome End date 21/04/2014. Open to sites in England To develop and validate biomarker prognostic (PC) and treatment response classifiers (TRC) to inform selection of patients most likely to respond to chemoradiotherapy or surgery.

23 Going Forward Local, National and International studies should provide evidence based insight into using HPV testing/associated biomarkers for prognosis and management of OPSCC. The international head and neck oncology community should work together to clearly define the minimum requirements for assigning a diagnosis of HPV related OSCC in order to ensure consistent reporting of this emerging and increasingly prevalent disease. Make the most out of characterised material (linked to outcome data) as a pathway to timely, additional research

24 Outstanding questions Do we need to look at sites beyond the oropharynx Identification of further targets for therapy Why the increase in HPV associated OSCC what is known of HPV acquisition/prevalence in the general population What will be the impact of the national immunisation programme on OSCC