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

HPV and Pap Test @ 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

BACKROUND PERSISTENT HR-HPV TYPES CAUSE CXCA AND PRECURSORS HPV and Pap Test @ 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

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 : 1,585 870 CIN3 IN HPV(-) : 0.3% vs 0.78% PAP(-) CXCA IN HPV(-) : 0.01% vs 0.02% PAP (-) 1 HPV(-) TEST= 2 (–) PAP TESTS

OTHER ADVANTAGES OF HPV TESTING CAN BE USED FOR SELF-TESTING META-ANALYSIS OF 36 SELF-TESTING STUDIES ( 154 556 ) : - 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. 2014 ; 15 )

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)

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 )

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 )

THE ATHENA CLINICAL TRIAL PROSPECTIVE CROSS SECTIONAL,ROUTINE PRACTICE TRIAL 46 887 21+yrs BASE LINE AND FOLLOW UP PHASES ALL LBC+/HPV+ COLPO 3 KEY FINDINGS CONFIRMED WORLD DATA

__________________________ 1 - CUMULATIVE INCIDENCE OF HSIL(CIN3+) IN 25 +YRS BY BASELINE HPV TEST RESULTS 3 YR FOLLOW UP CIN3 BASELINE HPV TYPES % ______________________________________ HPV 16+ : 25 HPV 18+ : 11 HPV 12+ : 5 HPV NEG: 0.3 __________________________

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 )

Strategy # CIN3+* # colpo/ CIN3+ 3-PERFORMANCE FOR DETECTING CIN3+ BY SCREEENING STRATEGIES IN 25+yr olds Strategy # CIN3+* # colpo/ CIN3+ _________________________________________ Pap alone 179 10.8 Combo** 240 12.9 HPV alone 294 12.8 * Crude numbers detected, ** co-testing, 2 x more colpos with HPV alone vs PAP alone

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

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+/18+ COLPO HPV 12 + CYTOLOGY IN 1 YR ASCUS+ NILM COLPO REPEAT HPV/PAP in 1 year HPV NEGATIVES : ROUTINE SCREENING AT 3 YRS

LATEST ACOG GUIDELINES ( Ob/Gyn, 2016: 127 ) STANDALONE HPV TESTING FOR PRIMARY SCREENING OF 25 +YRS ACCEPTABLE ALTERNATIVE TO: - PAP ALONE IN LOW RISK 21-65 YR AT 3 YR- INTERVALS or PAP/HPV CO-TESTING IN 29-65 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

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

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