Natural History of HPV Infections 15/06/2015. Squamous cell carcinoma Adenocarcinoma

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Gerard Newman
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14,670 5796 United States/ Canada 17,165 8124 Central America 48,328 21,402 South America 59,929 29,814 Europe

330 Australia/ New Zealand Squamous cell carcinoma Adenocarcinoma Adenosquamous Clear cell Glassy cell Small cell

1 14, United States/ Canada 17, Central America 48,328 21,402 South America 59,929 29,814 Europe 78,896 61,670 Africa 157,759 86,708 Southcentral Asia 61,132 31,314 Eastern Asia 42,538 22,594 Southeast Asia 1, Australia/ New Zealand Squamous cell carcinoma Adenocarcinoma Adenosquamous Clear cell Glassy cell Small cell Carcinosarcoma (MMMT) 1. Ferlay J et al IARC Press; Natural History of HPV Infections Wright and Schiffman (2003) NEJM 1

HPV Prevalence (%) 25 20 15 10 5 0 20 Cervical Cancer 18 16 14 12 10 8 HPV 6 4 2 0 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 >65 Age (years) Sources: NCI SEER Data, 1990-94; Melkert

6 57 14.6 69.7 North America/ Europe 17 67.6 Northern Africa 25.7 52.5 South Asia HPV Type 16 18 45 31 33 52 58 Others Central/South America de Sanjose et al.

2 HPV Prevalence (%) Cervical Cancer HPV >65 Age (years) Sources: NCI SEER Data, ; Melkert et al., Int J Canc 53:919. CvCx Cases/100,000 HPV Type Negative ,000 Odds Ratio (95% CI*) Muñoz N et al. N Engl J Med. 2003;348: North America/ Europe Northern Africa South Asia HPV Type Others Central/South America de Sanjose et al., Lancet Infect Dis 2007;7(7):453 9 Smith et al., Int J Cancer 2007;121(3): Castellsague et al., J Natl Cancer Inst 2006;98(5): HPV 16 positive Risk for CIN 3+ 35% 25% 15% 32.5 % 39.5 % Any high-risk HPV(+) other than HPV % 8.4% 9.5% 0.0% ASC-US LSIL ASC-US LSIL Castle P et al J Natl Cancer Inst 2005;97:

LIQUID-BAED CYTOLOGY VS. CONVENTIONAL PAP SMEARS.

WITH COMPLETE GOLD STANDARD VERIFICATIONAND ONE RCT Liquid-based

1 (46.3-67.2) 97.0 (93.8-98.6) LSIL+ 79.1 (70.1-86.0) 78.8 (69.8-85.

8) Conventional cytology HSIL+ 55.2 (45.5-64.7) 96.7 (95.6-97.

grade disease than a Pap test Clavel C, et al.

3 LIQUID-BAED CYTOLOGY VS. CONVENTIONAL PAP SMEARS. POOLED ABSOLUTE SENSITIVITY AND SPECIFICITY FOR CIN2+ OF 8 STUDIES WITH COMPLETE GOLD STANDARD VERIFICATIONAND ONE RCT Liquid-based cytology SENSITIVITY (%) (95% CI) SPECIFICITY (%) (95% CI HSIL ( ) 97.0 ( ) LSIL ( ) 78.8 ( ) ASC-US ( ) 64.6 ( ) Conventional cytology HSIL ( ) 96.7 ( ) LSIL ( ) 81.2 ( ) ASC-US ( ) 71.3 ( ) High-Risk HPV DNA Testing is more sensitive in detecting high grade disease than a Pap test Clavel C, et al. Brit J Cancer, 2001;89: A positive high-risk HPV result is an objective risk indicator for the development of high-grade disease and cancer Lorincz A., Richart, R. Arch Pathol Lab Med, 2003;127:

Has the potential to prevent the majority of HPV induced cancers HPV 16/18 causes

End Point by Lesion Type HPV 6/11/16/18 CIN GARDASIL * (n=2,241) Placebo *

100% 81 100 CIN 3 0 17 100% 76 100 AIS 0 6 100% 15 100 Sydney morning herald

CUZICK et al Over 60,000 women in analysis All North American and European

parallel Combined Results # Screened: >60,000: HC2 + Cytology Age: Cases: 30-60

100 90 80 70 60 50 40 30 20 10 0 100 96.8 96.1 97.2 97.5 96.1 93.7 93.9 79.1 79.

7 <35 35-49 50+ All <35 35-49 50+ All CIN 3+ CIN 2+ HPV DNA Cytology HPV

4 Has the potential to prevent the majority of HPV induced cancers HPV 16/18 causes 70% Prior to exposure Vaccination rate 55% Impact on screening program? End Point by Lesion Type HPV 6/11/16/18 CIN GARDASIL * (n=2,241) Placebo * Vaccine (n=2,258) Efficacy CI % CIN % CIN % CIN % AIS % Sydney morning herald Garland SM et al. New Engl J Med. 2007;356: CUZICK et al Over 60,000 women in analysis All North American and European studies where cytology is used as the primary screen and where HR HPV was run in parallel Combined Results # Screened: >60,000: HC2 + Cytology Age: Cases: (majority) Sensitivity Specificity Sensitivity (%) < All < All CIN 3+ CIN 2+ HPV DNA Cytology HPV (primarily HC2) 96% 92% CYTOLOGY 53% 96% Management Problems Similar positive predictive value for CIN3 detection BUT Too many women with HPV positive normal smears Cuzick et al. Int J Cancer, April

LBC + HPV vslbc alone over 2 screening rounds 24510 women age 20-64 Primary outcome: Detection of CIN3+ in 2 nd round LBC + HPV = Significantly lower detection rate of CIN3+ in 2 nd round but effect

5 LBC + HPV vslbc alone over 2 screening rounds women age Primary outcome: Detection of CIN3+ in 2 nd round LBC + HPV = Significantly lower detection rate of CIN3+ in 2 nd round but effect was small Over the 2 rounds co-testing did not detect a higher rate of CIN2 or 3 than LBC alone Kitchener et al Lancet Onc 2009 Cumultativerates of CIN2 + 3 correlated with baseline HPV status and cytology Baseline status Abnormal cytology 20.5% HPV Positive 20.12% Normal cytology 1.41% HPV Negative 0.87% >50 yo HPV Negative 0.16% Cumulative HSIL Negative HPV confers greater protection over a longer period than negative cytology Could extent screening intervals if HPV negative (up to 10 years if >50) Kitchener et al EurJ Cancer 2011 Italy - NTCC Netherlands - POBASCAM Sweden - Swedescreen England - ARTISTIC women aged years RCT to HPV-based (experimental arm) or cytology based (control arm) screening GuglielmoRonco et al Lancet 2014;383: years 5.5 years Experimental arm 4.6 per 10 5 (1.1 (HPV-based) 12.1) Control arm 15.4 per 10 5 (7.9 (cytology based) 27.0) Rate ratio was 0.30 ( ) 8.7 per 10 5 ( ) 36.0 per 10 5 ( ) HPV-based screening provides 60 70% greater protection against invasive cervical carcinomas compared with cytology. GuglielmoRoncoet al Lancet 2014;383: Roncoet al Lancet

ADVANTAGES OF USING HPV TESTING AS THE SOLE PRIMARY SCREENING TEST Automated, Objective, Very Sensitive Test Quality control Medico-legal Cytology reserved for 6-10% of women High quality Fewer, more

6 ADVANTAGES OF USING HPV TESTING AS THE SOLE PRIMARY SCREENING TEST Automated, Objective, Very Sensitive Test Quality control Medico-legal Cytology reserved for 6-10% of women High quality Fewer, more focused cyto-screeners Avoids triage of HPV negative ASCUS/LSIL Longer screening interval Cost Convenience More expensive Less specific Incidence HPV in young women Age HrHPV Pos Cyto Pos > % 2.5% < 35 13% 3.6% < % Immediate colposcopy Identified CIN3+ Colp Referrals 100% HPV triage 96% 56% Repeat cytology 44% 8% Using 30 as age cut off reduced identification to 94% and referrals to 31% In women < 30, 65% would have been referred for colp Am J Obstet Gynecol 2003;188: Use of HPV testing alone as primary screening test will yield too many positives Would generate too many colposcopy referrals Not practical <30 as prevalence too high Triage further with use of cytology Possible alternative triage with genotyping 6

Can be used alone for women 25 years or older Netherlands proposed primary HPV screening in 2016 Screening Invitation, at age

Hr-HPV positive, reflex cytology Nl cytology Repeat cytology after 6 months Normal cytology No response, may respond or

7 Can be used alone for women 25 years or older Netherlands proposed primary HPV screening in 2016 Screening Invitation, at age 30, 35, 40, 50, 60 `(if HPV pos at 40/50/60, than also at age 45, 55, and 65 HPV neg Hr-HPV screening Next screening round Hr-HPV positive, reflex cytology Nl cytology Repeat cytology after 6 months Normal cytology No response, may respond or askforselfsampleat reminder >Ascus Colposcopy Non responder P Sasieni BMJ 2009;339:b2968 High incidence hpvand CIN. Low risk of cancer. Spontaneous regression Potential harm intervention Impact of HPV vaccination Recommendations announced in April 2014 To commence 2016 Kitchener et al EurJ Cancer 2011 Current Australian Screening Program Commence at Age 18 2-yearly pap smears Ceased at Age 70 7

5 yearly cervical screening HPV test with partial genotyping Reflex liquid-based cytology (LBC) triage 25 to 69 years of age Exit test at 70 Primary HPV screening more sensitive

8 5 yearly cervical screening HPV test with partial genotyping Reflex liquid-based cytology (LBC) triage 25 to 69 years of age Exit test at 70 Primary HPV screening more sensitive Negative HPV test confers greater protection Longer screening intervals Raise screening age Need to triage with cytology +/- genotyping Need to raise vaccination rates to be most effective 8

HPV Primary Screening in the United States

IFCPC 15th World Congress May 2014, London, UK. HPV Primary Screening in the United States E.J. Mayeaux, Jr., M.D. Professor and Chairman Department of Family and Preventive Medicine Professor of Obstetrics