The Impact of HPV Vaccination and the Future of Cervical Cancer Screening

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1 UICC Word Cancer Congress 2016 Latest Evidence and Tools for Effective National Cervical Cancer Screening Programs Paris, November 3, 2016 The Impact of HPV Vaccination and the Future of Cervical Cancer Screening Joseph E. Tota, PhD US National Cancer Institute Division of Cancer Epidemiology and Genetics Rockville, Maryland, USA

2 HPV Vaccination Cervical cancer is caused by infection with a group of high risk HPV infections (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59). Two first generation vaccines target oncogenic types 16 and 18; responsible for ~70% of cervical cancer cases. New nonavalent vaccine (Gardsil-9) is successful and targets oncogenic types 16, 18, 31, 33, 45, 52, and 58; responsible for ~90% of cervical cancer cases. School-based HPV vaccination a success in many high-income countries.

3 Brotherton et al. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet 2011; 377: High-Grade Cervical Lesions (per 100)

4 Changes in the prevalence of HPV infections between the prevaccination and postvaccination periods in girls aged 1319 yrs (Drolet et al. Lancet ID 2015;15:565-80) ~65% reduction ~30% reduction

5 Cervical cancer prevention activities are inherently a single process (Tota et al., Curr Oncol 2014)

6 Loss of Pap screening performance due to vaccination As successive cohorts of girls and young women are vaccinated and enter screening age: Reduction in prevalence of cytological abnormalities End result: decrease in positive predictive value of cytology

7 Predictive value (%) PPV NPV Prevalence (%) Influence of prevalence of cervical lesions on the positive predictive value (PPV) and negative predictive value (NPV) of cytology as a primary screening test. Sensitivity and specificity held constant at 70% and 98%, respectively. Gray bands: 95% credibility intervals around median values for 1000 simulations using each of the parameter combinations in hypothetical populations of 10,000 women. (Franco et al., Arch Med Res 2009)

8 Key reasons to immediately introduce HPV as primary technology in cervical cancer screening More sensitive in detecting high-grade precancerous lesions. HPV infection occurs upstream in the carcinogenic pathway, providing longer reassurance against CIN3+ supporting extended intervals. More effective in detecting adenocarcinoma precursor lesions. May reduce income/regional disparities and improve screening coverage among non-responders via self-sampling. May be more cost-effective. Performance of HPV testing is expected to be less adversely affected as a consequence of reduced lesion prevalence due to HPV vaccination.

9 There is urgency to change the screening paradigm now but how will screening perform in the future? Gardasil 9 and its successors will be game changers as disruptive technologies to screening. Even HPV testing may eventually lose its clinical utility in identifying disease that has become so rare relative to (false) positive findings. Cervical cancer screening is not devoid of immediate and long term risks for women s reproductive health. Today, such risks are far outweighed by the benefits of screening. Question: Will that balance change in the future?

10 Variable Specificity: 90%, 95%, 97%, or 99% Sensitivity is assumed constant at 99% Risk management band for clinical decision Positive predictive value of a future cervical cancer screening test following reductions in precancerous lesion prevalence post-hpv vaccination. The horizontal broken lines indicates today s 2% and 10% risk thresholds of a pre-existing lesion to guide clinical decision regarding immediate colposcopy referral (> 10%), repeat screening in the short-term (2%-10%), or continue low-intensity screening of averagerisk women (< 2%). (El-Zein et al., J Clin Virol 2016)

11 Wilson & Jungner s classic screening criteria 1) The condition should be an important health problem. 2) There should be a treatment for the condition. 3) Facilities for diagnosis and treatment should be available. 4) There should be a latent stage of the disease. 5) There should be a test or examination for the condition. 6) The test should be acceptable to the population. 7) The natural history of the disease should be adequately understood. 8) There should be an agreed policy on whom to treat. 9) The total cost of finding a case should be economically balanced in relation to medical expenditure as a whole. 10) Case-finding should be a continuous process, not just a "once and for all project. Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968.

12 Andermann et al. s Synthesis of emerging screening criteria proposed over the past 40 years Screening programme should respond to a recognized need. Objectives of screening should be defined at the outset. There should be a defined target population. There should be scientific evidence of screening programme effectiveness. Program should integrate education, testing, clinical services and program management. There should be quality assurance, with mechanisms to minimize potential screening risks. Program should ensure informed choice, confidentiality and respect for autonomy. Program should promote equity and access to screening for entire target population. Program evaluation should be planned from the outset. Overall benefits of screening should outweigh the harm. Andermann A, Blancquaert I, Beauchamp S, Déry V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ. 2008;86:

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15 Conclusions HPV vaccination is working as intended. The rarity of precancerous lesions will have a negative impact on the performance of cervical cancer screening. Incorporation of molecular HPV testing in screening will help in the immediate future. As the prevalence of precancerous lesions falls in fully vaccinated screening cohorts the ratio of benefits to harms from screening will also fall dramatically. Analogy with other cancers helps to define benchmarks for society s tolerance of risk.

16 Thank you for your attention!

17 Fulfillment of Wilson & Jungner s Screening Criteria for Various Cancers Cervix Vulva Vagina Ovary Breast Oral (mouth) Anal Colorectal Melanoma Lung Prostate Thyroid Men Women Men Women Incidence Survival Natural history of condition adequately understood /- Recognizable latent/early symptomatic stage exists /- +/ /- Suitable test or examination available / Test acceptable to population Accepted treatment for disease exists Facilities for diagnosis and treatment available Yes (conditional on availability of secondary and tertiary care facilities) Agreed policy on whom to treat as patients /- + + Potential harms of undergoing screening Cost-effectiveness ++?? +/- +/ /- +/- Case-finding a continuing process Yes (conditional on risk group or antecedents) Tota, Isidean, Franco (in preparation)

18 Risk of CIN2+/CIN3+ and invasive cervical cancer following negative HPV, cytology or both tests reveals HPV testing is much safer than cytology and that there is almost no additional benefit from co-testing compared with HPV testing alone Population/Study (Author, Year) 7 European studies (Dillner, 2008) N Negative Test at Baseline 24,295 Cytology HPV Cytology & HPV 3-y CIN y CIN y CIN2+ 3-y CIN y CIN y Cancer 5-y Cancer KPNC (Katki, 2011) 331,818 Cytology HPV Cytology & HPV KPNC (Gage, 2014) 1,011,092 Cytology HPV Cytology & HPV European trials (Ronco, 2014) 176,464 Cytology HPV Cytology & HPV ATHENA (Wright, 2015) 42,209 Cytology HPV Cytology & HPV CCCaST (Isidean, 2016) 10,154 Cytology HPV Cytology & HPV

19 Positive predictive value (%) Prevalence =40% Prevalence =5% The PPV of Pap cytology will improve greatly when it is used for triaging HPV positive women Situation in an averagerisk area today: PPV of Pap cytology is adequate Prevalence =10% Prevalence =1% Situation in a high risk area today: PPV of Pap cytology is high The PPV of Pap cytology will be very low in the postvaccination era Sensitivity (%) Joint effects of changes in sensitivity, specificity, and lesion prevalence on the PPV of cytology as a primary screening test. Blue curve: specificity=98%; red curve: specificity=95%. Gray bands: 95% credibility intervals. Three of the prevalence scenarios are intended to illustrate situations found in Pap cytology screening in different settings as well as the one anticipated post-vaccination. A 40% prevalence is shown to represent the situation found in triage, following an initially positive referral HPV test. (Franco et al., Arch Med Res 2009)