1. CERVICAL CANCER PREVENTION : SEVEN DECADES OF MILESTONE ACHIEVEMENTS
2ND WORLD GYNECOLOGIC CANCER CONFERENCE
OCTOBER 17-18, 2016, ROME, ITALY
ALEX FERENCZY,MD
PROFESSOR OF PATHOLOGY AND OBSTETRICS AND GYNECOLOGY
MCGILL UNIVERSITY AND JEWISH GENERAL HOSPITAL
MONTREAL,QUBEC,CANADA

2. DISCLOSURES
PATHOLOGY PANELIST IN PROSPECTIVE CERVICAL CANCER SCREENING AND VACCINE CLINICAL TRIALS: BD
ROCHE
VENTANA/ROCHE
CEPHEID
HOLOGIC ( GENE-PROBE )
INOVIO
MERCK

3. CERVICAL CANCER-THE GLOBAL BURDEN
SECOND MOST COMMON in DC’s
/yr ( mean age-47 )
/die/yr
80% in DC’s
(Forman et al. Vaccine (supl -5)2012: 30)

4. MILESTONE I - PAP CYTOLOGY
INTRODUCED IN THE 50’S
REDUCED CXCA RATES BY 50%
SECONDARY PREVENTION
DRAWBACKS :
LOW SENSITIVITY-MISSES 50%
MUST BE FREQUENTLY REPEATED
COST-INEFFECTIVE
( Tota et al. Prev Med,2016 in press )

5. MILESTONE II- HPV - CERVICAL CANCER CONNECTION
DISCOVERED IN THE 80’S BY MATHIAS DURST AND HERALD zur HAUSEN,FREIBURG,GERMANY
NOBEL PRICE /2008
SPECTRUM OF HPV -RELATED CANCERS :
____________________________
Cervix %
Anus %
Vagina- 70%
Vulva - 40%
Penis %
ENT %
( Walboomers et al. J Path,1999,189 )

6. MILESTONE III-HPV TESTING
MOLECULAR TECHNOLOGY
Introduced in the 90’s
Detects up to 50% more precancers/cancers vs Pap
Low incidence at re- testing:
% decrease in cxca rates ( Ronco al.Lancet,2015:383,2014,Tota et al. Prev Med 2016 in press )
Increased screening intervals,safely,longer window..
( Dillner et al.BMJ,2010: 341 ) 1 (–) HPV = 4 (–) PAP’S

7. MILESTONE IV: HPV GENOTYPING
PROGRESSION RISK TO PRECANCER/CANCER DIFFERS BY HPV TYPES
AS PER KPNC, PORTLAND,ATHENA, EUROPEAN STUDIES (Ronco et al. Lancet 2014:383, Wright et al.Gyn Oncol 2015:136 )
HPV-16/18 HIGHEST RISK TO PROGRESSION
GENOTYPING IMPROVES SPECIFICITY AND PPV

8. FIRST US/FDA-APPROVED HPV PRIMARY SCREENING STRATEGY in 25+ yrs*
INCORPORATES GENOTYPING FOR TYPES 16 AND 18 INDIVIDUALLY AND REFLEX PAP CYTOLOGY FOR 12 OTHERS (COBAS 4800) ( Wright et al.Gyn Onc 2015: 136 ) :
- HPV 16/ COLPOSCOPY
- OTHERS PAP IN 1 YEAR: -Slow progression ( Kjaer et al. JNCI,2010:102 )
- IF PAP + TO COLPO
- IF PAP – HPV/PAP IN 1 YR
- BOTH – FOLLOW AT 3 YR INTERVALS
* BASED ATHENA’S FINDINGS : SAFER THAN PAP ALONE
EFFICIENT AS CO-TESTING

9. RECENT SCREENING GUIDELINES
USA/ACOG :
- STANDALONE HPV PRIMARY SCREENING OF YRS ACCEPTABLE ALTERNATIVE Toscreen 21-65yrs PAP ALONE AT 3 YRS OR CO-TESTING AT 5 YRS (ob/gyn,2016: 127 )
EUROPE:
- HPV PRIMARY SCREENING 30-65yrs at 5-10 yr-intervals* and Pap triage of HPV+ women
- CO-TESTING NOT RECOMMENDED
- MUST HAVE ORG.POP-BASED SCREENING ROGRAMS AND INFO SYSTEMS :
- ID,INVITE,SCREENING F/U,MONITORING PARTICIPANTS( vonKarsa et al. Papillomavirus Res.20015:1 )
* 5 yr vs 3 yr increases absolute life-time cxca risk/death by 0.27%/0.06 % ( Kinney et al. Ob/Gyn 2015: 125 )

10. MILESTONE V - HPV VACCINES
INTRODUCED IN 2006
APPROVED WORLDWIDE
RECOMMENDED BY INTL.ADVISORY COMMITEES AND US/CDC,WHO,FIGO,etc
……. FOR THE PRIMARY PREVENTION OF ANOGENITAL TRACT CANCERS,PRE-CANCERS,WARTS AND PERSISTENT INFECTIONS CAUSED BY VACCINE– RELATED HPV TYPES

11. HPV VACCINES
4vHPV ( 6/11/16/18 ) GARDASIL/SILGARDTM (MERCK/MSD ) licensed in 2006
2vHPV (16/18 ) CERVARIXTM ( GSK)-2007
- RCT’S OF > , …/45/55 yrs F
4 000, yrs M, 600 MSM
NEAR 100% EFFICACY TO PREVENT AGT WARTS/PRECANCERS AND PERSISTENT HPV INFECTIONS IN NAIVES (susceptible)
50% in CATCHUPS ( naïves/non-naïves )

12. LONG TERM F/U EXPERIENCE WITH 4vHPV in NORDIC REGION ( NORWAY )
10 YEAR FOLLOW UP
1,245 M/F 9-15 YRS
IMMUNOGENICITY ABOVE SEROSTATUS CUT- OFF LEVELS ( IgG LUMINEX vs COMPETITIVE LUMINEX ASSAYS)
NO BREAKTHROUGH 6/11/16/18 CASES !
SAFETY PROFILE SIMILAR TO RCT’s AND POST - MARKETING ERA
( Nygard et al. Clin Vacc Immunol : 22 )

13. THE LATEST HPV VACCINE : 9vHPV GARDASIL 9TM (MERCK/2014)

14. RATIONALE FOR 9vHPV CONTRIBUTION
CERVICAL LESIONS /11/16/ /33/35/45/52/58 TOTAL 9 TYPES
_________________________________________________________________
- CANCER % % %
- PRE-CANCER % % %
- LOW GRADE LESIONS % % %
( Sanjose et al. Lancet Oncol 2010 : 11 )

15. 9vHPV CLINICAL TRIALS Phase 2B and 3 Intl. RCT’s
( M/F ) and (F) with no or normal Pap’s
From 2007 to 2013 ( Joura et al NEJM,2015: 372 )

16. SAFETY FINDINGS IN 9vHPV vs 4vHPV TRIALS
INJECTION SITE AE’S vHPV vHPV # subjects
( < 15 days/IM ) % % ,445
MOST MILD ( 90% ) to MODERATE ( pain,erythema,etc )
Same rates as post-licensure US safety data (VRAERS) w 80M doses
SYSTEMIC AE’S % % ,119
( < 15 Days/IM )
VRAE’S
DISCONT %
SYNCOPE / doses
( Garland et al. Vaccine,2015: 33 /Joura et a.NEJM ,2015:372 )
( Joura et al.NEJM,2015: 372 )

17. POST-LICENSURE COVERAGE (2007-2013)
13-17 YRS/USA : 1 DOSE + OF ANY VACCINE:
- 57.3% GIRLS ( > 75% Canada )
- 34.6% BOYS ( < 5% Canada)
MUST ENCOURAGE SCHOOL - BASED PROGRAMS:
- COULD REACH 90% COVERAGE = HERD IMMUNITY
ACIP/USA RECOMMENDS CO-VACCINATION at 1st MEDICAL VISIT TO INCREASE COVERAGE ( Stockley et al. MMWR: 2014:63 )
EDUCATION/INFO NEEDED AGAINST PREJUDICES ABOUT AE’s, VLP,etc
POOR UPTAKE IN US/POST-SCHOOL CATCHUPS ( 50%/1d F,8%M )
( Hollman et al.Pediatrics,2014: 168 )

18. 2015 REVISED SCHEDULES for 2vHPV,4vHPV,9vHPV ( Canada/NACI )
9-14 yrs BOYS AND GIRLS : 2 DOSES AT 6 mo INTERVALS (school-based )
15 yrs+ MALES AND FEMALES : 3 DOSES or 2 DOSES IF FIRST DOSE BEFORE 15yrs
IMMUNOCOMPROMISED MALES AND FEMALES : 3 DOSES (free for MSM < 21/USA,< 26 yrs/QC )
9vHPV INTERCHANGEABLE w 4vHPV

19. LONG TERM POPULATION IMPACT (RISK REDUCTION ) OF 9vHPV
PPP m-ITT (Naïves) (Catchups) ____________________ CERVICAL LESIONS PERSISTENT HPV INFECT’S 90% 50%—75% ABNORMAL PAP’S BX’S/LEEEP’S ( Joura et al. NEJM,2015: 372 )

20. SHORT TERM POPULATION IMPACT (4vHPV)
World: in high income countries 50%+ coverage (140M person-years experience):
68% HPV16/18 inf’s
61% warts < 19 yrs (F)
34% warts < 20yr (M)
( Drolet et al.Lancet Inf.Dis.2015 )
Australia: 40% drop in c-HSIL < 20yrs, 5 yrs > vaccination 80% drop in a-HSIL in MSM
( Donovan et al.Lancet Inf.Dis,2011 )
Canada : 40% drop in prevalence and incidence of JoRRP
( Caspisi et al. Eurogin,2015 )

21. POTENTIAL COST-EFFECTIVENESS OF 9vHPV vs 4vHPV in pre-sexuals
INCREMENTAL COST-EFFECTIVENESS/QALY GAINED*
_________________________________________________
9vHPV $ 12,205 CND
4vHPV $ 15,528 CND
( < $ 40,000/QALY threshold )
_______________________________________________________________________
Based on indiv.transmission of HPV inf./diseases, 70 yr horizon, 80% coverage of 10 yr olds F,$95CND/d, > 85% efficacy, 20 yrs to lifelong protection
( Drolet et al. Intl J Ca,2014:134 )

22. CERVICAL CANCER PREVENTION:SEVENTY YEARS OF MILESTONE ACHIVEMENTS - CONCLUSIONS
HPV-RELATED CANCERS ARE MAJOR BURDEN, IN DC’S
TIME TO CHANGE CORE CERVICAL SCREENING TECHNOLOGY FROM MORPHOLOGY (PAP) TO MOLECULAR-BASED HPV TESTING
HPV GENOTYPING BEST PRIMARY SCREENING STRATEGY FOR CANCER RISK MANAGEMENT (SECONDARY CANCER PREVENTION)
PRIMARY PREVENTION WITH MASS VACCINATION ( Gardasil-9 ) COMBINED WITH SECONDARY CANCER PREVENTION COULD REDUCE/PREVENT 90% CERVICAL AND OTHER HPV-RELATED ANO- GENITAL CANCERS AND WARTS
IMPLEMENTATION REQUIRES ORGANIZED,POP.BASED,PUBLICLY FUNDED, SCREENING AND VACCINATION PROGRAMS
HPV TESTING AND HPV( CANCER ) VACCINES,THE GREATEST BREAKTROUGHS IN AGT- CANCER/WART PREVENTION

23. THANK YOU FOR YOUR PATIENCE