National Immunisation Conference 25th May 2018

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Meredith Robbins
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1 Cervical Cancer Prevention National Immunisation Conference 25th May 2018 Donal Brennan UCD Professor of Gynaecological Oncology

3 Outline Burden of cervical cancer Biology of HPV related oncogenesis Primary prevention Secondary prevention Screening The future

4 Global burden of Cervical Cancer

Burden of HPV related Cancer in Ireland 538 cases

preventable with Gardasil4 120 preventable with

5 Burden of HPV related Cancer in Ireland 538 cases per annum 73% women Cervical cancer ~ 300 pa Vulvar / anal Penile Oropharyngeal 50-70% related to HPV Male > Female 180 Deaths per annum 100 preventable with Gardasil4 120 preventable with Gardasil 9 National Cancer Registry HPV-related Cancers 2017

6 Biology of HPV related carcinogenesis

Cervical screening: A new way forward (tests of risk and

7 Cervical pre-cancer and cancer progression. Risk of regression O'Leary JJ, White C, Spillane C et al. Cervical screening: A new way forward (tests of risk and tests of disease) [version 1]. HRB Open Res 2018, 1:3 (doi: /hrbopenres )

8 Risk of progression of CIN3 to cancer McCredie et al Lancet Oncol 2008; 9:

9 Primary Prevention Smoking cessation HPV vaccination Barrier contraception

10 Is it working Impact on HPV Prevalence 98.5% Unvaccinated 86% Vaccinated Kavanagh et al Lancet Infect Dis 2017; 17:

11 Impact on CIN

12 Secondary Prevention Smear Picks up dyskaryosis Colposcopy Allows direct inspection and targeted biopsy or treatment Biopsy Provides final diagnosis CIN1-3 / invasion

14 Does screening for cervical cancer work? Australia UK Peirson et al. Systematic Reviews 2013, 2:3

15 Detecting early stage cancer a screening success 60 Stage at diagnosis Stage I Stage II Stage III Stage IV Stage Unknown Northern Ireland Republic of Ireland

16 Risks and Benefits of Screening Reduction in morbidity/mortality associated with Ca Cervix Pap smears have inherent weaknesses Low sensitivity Human error /intra-observer variability Fail to pick up adenocarcinoma Difference between a screening and diagnostic test False positive / over treatment Significant obstetric morbidity / premature labour Psychological morbidity

17 Adenocarcinoma of the cervix

18 How to improve screening accuracy Cytology Primary HPV screening + Vaccination

19 HPV screening v s cytology the data Ronco et al. Lancet 2014; 383:

20 HPV screening reduces cervical cancer mortality Sankaranarayanan et al. N Engl J Med 2009;360:

21 Potential pitfalls of HPV based screening Move from a test of disease to a test of risk High negative predictive value, low specifity and high false-positive rate Must be aware of over-treatment What to do with HPV positive/ cytology negative patients Will we have to change protocols for vaccinated women?

22 O'Leary JJ, White C, Spillane C et al. Cervical screening: A new way forward (tests of risk and tests of disease) [version 1]. HRB Open Res 2018, 1:3 (doi: /hrbopenres )

23 Primary HPV screening Benefits Increase detection of CIN2/3 5 yearly testing Reduce mortality Particularly beneficial in vaccinated cohorts May improve quality of cytology Risks False negative 15% Over treatment Additional tests required Some patients will need long term follow-up

24 Important Questions for the Future Vaccinating outside the National Program Single dose schedule Gender Neutral Vaccination Therapeutic Vaccination

25 What about the older patient? (>25) Wheeler et al Lancet Infect Dis 2016; 16:

26 VIVIANE Study Vaccinated Cohort Cumulative incidence of CIN1+ irrespective of HPV DNA in women who received the HPV 16/18 vaccine versus control Wheeler et al Lancet Infect Dis 2016; 16:

27 Single Dose Schedule CVT trial No difference in cumulative HPV incidence at 7 years in 3 dose compared to 1 dose group Safaeian JNCI J Natl Cancer Inst (2018) 110(2): djx158

28 Gender Neutral Vaccination

29 Male Vaccination? Is it cost effective? Direct effects will be small in relation to HPV related cancers A high level of female vaccination (>80%) will confer herd immunity

30 What if female coverage is lower? Brisson et al Lancet Public Health 2016; 1: e8 17

31 Therapeutic HPV vaccination E6/E7 proteins are best targets DNA vaccines are currently most advanced VGX-3100 is promising Anti HPV 16/18 DNA vaccine 50% regression of CIN2/3 at 36 weeks REVEAL trial awaited Trimble et al Lancet 2015; 386:

32 Provider Recommendation Klosky et al JCO 2017, 35,

33 Irish HCP attitude to HPV Vaccination Support for HPV Vaccination 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 80.0% 63.4% 28.4% 30.0% Pre-Campaign Post-Campaign Has children No children 100% 90% Support for HPV Vaccination 80% 70% 60% 50% 40% 30% 20% 10% 54% 45% 64% 57% Cares for HPV-related cancer patients Doesn't care for HPVrelated cancer patients 0% Pre-Campaign Post-Campaign

34 Irish HCP attitude to HPV vaccination 100% 90% Support for HPV Vaccination 80% 70% 60% 50% 40% 30% 20% * p= % * p= % 26% 13% p= % 44% Pre-campaign Post-campaign 10% 0% More likely to advise patients Less likely to advise patients No difference Maria Cheung

35 Summary Cervical cancer prevention is multi-facetted Extensive data supports a reduction of incidence and mortality from cervical cancer National coordinated screening programs are the best option HPV-based screening will improve accuracy but also has additional challenges Therapeutic vaccines may be the ultimate choice Health care providers are the most important advocates for vaccination

Goals. In the News. Primary HPV Screening 3/9/2015. Your PAP and HPV Update Primary HPV Testing- Screening Intervals- HPV Vaccine Updates-

Goals. In the News. Primary HPV Screening 3/9/2015. Your PAP and HPV Update Primary HPV Testing- Screening Intervals- HPV Vaccine Updates- Your PAP and HPV Update 2015 Connie Mao, MD University of Washington Goals Primary HPV Testing- Is it time to stop doing pap smears? Screening Intervals- Should patients have a choice? HPV Vaccine Updates-