1. 2nd WORLD GYNECOLOGIC CANCER CONFERENCE
HPV GENOTYPING WITH REFLEX PAP CYTOLOGY FOR PRIMARY CERVICAL CANCER SCREENING
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, Quebec, Canada

2. HPV and Pap JGH
18 June 2018
DISCLOSURES
PATHOLOGY PANELIST IN HPV SCREENING AND VACCINE CLINICAL TRIALS BY
BD,
ROCHE,
ROCHE/VENTANA,
HOFFMAN LA ROCHE, CANADA
HOLOGIC ( GEN-PROBE ),
MERCK
Alex Ferenczy, MD, Professor of Pathology and Obstetrics & Gynecology, McGill University and Jewish General Hospital 2

3. BACKROUND PERSISTENT HR-HPV TYPES CAUSE CXCA AND PRECURSORS
HPV and Pap JGH
18 June 2018
BACKROUND
PERSISTENT HR-HPV TYPES CAUSE
CXCA AND PRECURSORS
WORLD DATA SHOW HPV TESTING THE IDEAL CXCA SCREENING TEST ( Schiffman et al,JNCI,2011:103 ) :
- detects 50% more CxCa/precursors vs Pap cytology
- low incidence at re-testing
- allows increased screening intervals:
annual to 3 to 5 years ( Khan et al, Lancet Onc,2011: 12 )
________________________________________________ _
Alex Ferenczy, MD, Professor of Pathology and Obstetrics & Gynecology, McGill University and Jewish General Hospital 3

4. RISK OF PRECANCERS/CANCERS (HSIL/CIN3 +) IN HPV vs PAP NEGATIVES AT 3 YEARS
11 EUROPEAN AND 3 US STUDIES ( Tota et al. IJC,2016 )
SUBJECTS STUDIED : 1,
CIN3 IN HPV(-) : 0.3% vs 0.78% PAP(-)
CXCA IN HPV(-) : 0.01% vs 0.02% PAP (-)
1 HPV(-) TEST= 2 (–) PAP TESTS

5. OTHER ADVANTAGES OF HPV TESTING
CAN BE USED FOR SELF-TESTING
META-ANALYSIS OF 36 SELF-TESTING STUDIES ( ) :
- BETTER THAN PAP TEST
- NEARLY AS SENSITIVE ( 88%)/SPECIFIC ( 96%) vs
HEALTH CARE PROVIDERS’ HPV SAMPLES
CAN INCREASE ATTANDANCE BY 30%
( Arbyn et al. Lancet Oncol ; 15 )

6. IDEAL SCREENING TEST IN THE POST-VACCINE ERA
EXPECT 90% DROP IN PRECANCERS WITH 9vHPV (GARDASIL 9)
( Smith et al. Pediatrics,2015:135 )
NEED HIGHLY SENSITIVE TEST TO DETECT THE RARE PRE-CANCERS (Franco et al.Arch Med Res,2009:40)
NEED HIGH PPV ( who goes to colpo)

7. GENOTYPING BECAUSE CANCER/PRECAN-CER RISK DIFFERS BY HPV GENOTYPES
ABSOLUTE RISK OF PROGRESSION TO HSIL(CIN3) in 30+yrs BY HPV TYPES (KPNC – Lancet Oncol 2011:12/PORTLAND STUDIES- J Clin Microbiol 2015:53)
LATEST DEVELOPMENT IN HPV SCREENING TESTS FOR CERVICAL CANCER AND PRECURSORS
GENOTYPING BECAUSE CANCER/PRECAN-CER RISK DIFFERS BY HPV GENOTYPES
( Wentzensen et al. Lancet Oncol.2013:14 )

8. THE FIRST US/FDA APPROVED HPV GENOTYPING TEST USES COBAS 4800
REAL TIME PCR assay
DETECTS 14 HPV TYPES 16 and 18 individually and 12 others:
31,33,35,39,45,51,52,56,58,59,66,68
( Stoler et al: AJCP,2012:137)
APPROVAL BASED ON THE ATHENA CLINICAL TRIAL ( Wright et al. Gyn Oncol,2015:136 )

9. THE ATHENA CLINICAL TRIAL
PROSPECTIVE CROSS SECTIONAL,ROUTINE PRACTICE TRIAL
yrs
BASE LINE AND FOLLOW UP PHASES
ALL LBC+/HPV COLPO
3 KEY FINDINGS CONFIRMED WORLD DATA

10. __________________________
1 - CUMULATIVE INCIDENCE OF HSIL(CIN3+) IN 25 +YRS BY BASELINE HPV TEST RESULTS
3 YR FOLLOW UP
CIN3
BASELINE HPV TYPES %
______________________________________
HPV 16+ :
HPV 18+ :
HPV 12+ :
HPV NEG:
__________________________

11. 2 - SAFETY OF HPV PRIMARY SCREENING
DURING 3YR F/U :
319 HSIL(CIN3+)
20 AIS
8 CANCER
3-YR CUMULATIVE INCIDENCE OF CIN3+ PER NEGATIVE BASELINE TEST RESULTS:
( Wright et al. Gyn.Oncol.2015:136 )

12. Strategy # CIN3+* # colpo/ CIN3+
3-PERFORMANCE FOR DETECTING CIN3+ BY SCREEENING STRATEGIES IN 25+yr olds
Strategy # CIN3+* # colpo/ CIN3+
_________________________________________
Pap alone
Combo**
HPV alone
* Crude numbers detected, ** co-testing,
2 x more colpos with HPV alone vs PAP alone

13. ATHENA’s CONCLUSIONS
1 - INCIDENCE DIFFERENTIAL OF HSIL(CIN3+) BY HPV TYPES REQUIRES GENOTYPING FOR APPROPRIATE RISK MANAGEMENT AND INCREASED SPECIFICITY
2 - AS SAFE AS PAP CYTOLOGY ALONE
3 - AS EFFICIENT AS PAP/HPV CO-TESTING

14. HPV 12 + CYTOLOGY IN 1 YR ASCUS+ NILM COLPO REPEAT HPV/PAP in 1 year
THE FIRST FDA APPROVED HPV PRIMARY SCREENING STRATEGY ( for 25+ yrs ) INCORPORATES GENOTYPING FOR HPV 16 AND 18 AND REFLEX CYTOLOGY FOR 12 OTHER HR-HPV GENOTYPES
HPV16+/ COLPO
HPV CYTOLOGY IN 1 YR
ASCUS+ NILM
COLPO REPEAT HPV/PAP
in 1 year
HPV NEGATIVES : ROUTINE SCREENING AT 3 YRS

15. LATEST ACOG GUIDELINES ( Ob/Gyn, 2016: 127 )
STANDALONE HPV TESTING FOR PRIMARY SCREENING OF 25 +YRS ACCEPTABLE ALTERNATIVE TO:
- PAP ALONE IN LOW RISK YR AT 3 YR- INTERVALS or
PAP/HPV CO-TESTING IN YR OLDS AT 5 YEAR-INTERVALS
ANNUAL PAP’S NOT RECOMMENDED
STANDALONE HPV PRIMARY SCREENING:
Mexico/2015; Turkey/2015; Italy/2015; Netherlands/2016;Sweden.2017;Scotlans/2018/19

16. HPV GENOTYPING WITH REFLEX PAP CYTOLOGY FOR PRIMARY CERVICAL CANCER SCREENING : THE CLOSE
OVERWHELMING EVIDENCE-DRIVEN SCIENCE FAVORS HPV PRIMARY CXCA SCREENING
HPV GENOTYPING WITH PAP TRIAGE BEST CURRENT SCREENING STRATEGY AS PER ATHENA
EDUCATE HEALTH CARE PROVIDERS,WOMEN AND POLICY DECISION MAKERS ON BEST MEANS OF CXCA PREVENTION, i.e morphology-vs molecular-based technology
FOR IMPLEMANTATION : MUST ESTABLISH ORGANIZED,POP-BASED, HPV SCREENING PROGRAMS USING

17. THANK YOU