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

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

CERVICAL CANCER-THE GLOBAL BURDEN SECOND MOST COMMON in DC’s 530 000/yr ( mean age-47 ) 274 000/die/yr 80% in DC’s (Forman et al. Vaccine (supl -5)2012: 30)

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 )

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 - 99.7% Anus - 85% Vagina- 70% Vulva - 40% Penis - 47% ENT - 35% ( Walboomers et al. J Path,1999,189 )

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: - 60-70 % 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

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

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 16/18+ 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

RECENT SCREENING GUIDELINES USA/ACOG : - STANDALONE HPV PRIMARY SCREENING OF 25 + 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 )

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

HPV VACCINES 4vHPV ( 6/11/16/18 ) GARDASIL/SILGARDTM (MERCK/MSD ) licensed in 2006 2vHPV (16/18 ) CERVARIXTM ( GSK)-2007 - RCT’S OF > 50 000, 15 - 26…/45/55 yrs F 4 000, 15 - 26 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 )

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. 2015 : 22 )

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

RATIONALE FOR 9vHPV CONTRIBUTION CERVICAL LESIONS 6/11/16/18 31/33/35/45/52/58 TOTAL 9 TYPES _________________________________________________________________ - CANCER 70 % 20% 90% - PRE-CANCER 50 % 30% 80% - LOW GRADE LESIONS 35% 25% 65% ( Sanjose et al. Lancet Oncol 2010 : 11 )

9vHPV CLINICAL TRIALS Phase 2B and 3 Intl. RCT’s 14 215 ( 9 -15 M/F ) and 16-26 (F) with no or normal Pap’s From 2007 to 2013 ( Joura et al NEJM,2015: 372 )

SAFETY FINDINGS IN 9vHPV vs 4vHPV TRIALS INJECTION SITE AE’S 9vHPV 4vHPV # subjects ( < 15 days/IM ) 90% 85% 12,445 MOST MILD ( 90% ) to MODERATE ( pain,erythema,etc ) Same rates as post-licensure US safety data (VRAERS) w 80M doses SYSTEMIC AE’S 30.6% 26% 14,119 ( < 15 Days/IM ) VRAE’S 4 3 DISCONT. ------ 0.5% ---- SYNCOPE 8/100000 doses ( Garland et al. Vaccine,2015: 33 /Joura et a.NEJM ,2015:372 ) ( Joura et al.NEJM,2015: 372 )

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 )

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

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 )

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 )

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 )

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

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