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 and Gynecology University of South Carolina School of Medicine Columbia, SC, USA

Disclosures No Commercial COI

Objectives At the end of the session, the participant will be able to: Review key evidence regarding HPV primary screening for cervical cancer

1950 1955 1960 1965 1970 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 How Well Did the Old Guidelines Work? 18 16 14 12 10 8 6 4 2 Cancer of the Cervix Uteri Incidence Death 0 http://seer.cancer.gov/archive/csr/1975_2006/results_merged/topic_annualrates.pdf http://www.glowm.com/section_view/heading/epidemiologic Aspects of Uterine Cervix Cancer/item/225

History of Cervical Cancer Cases Cause Kaiser Sweden (US) No recent screen 56% 64% Pap detection failure 32% 24% Failure of follow-up 13% 11% Between 1/4 and 1/3 of cancers due to Pap test Failure Leyden WA, et al. J Natl Cancer Inst. 2005 May 4;97(9):675-83. Andrae B, et al.. J Natl Cancer Inst. 2008 May 7;100(9):622-9.

HPV 16 HPV 18 HPV 26 HPV 30 HPV 31 HPV 33 HPV 34 HPV 35 HPV 39 HPV 39 HPV 42 HPV 44 HPV 45 HPV 51 HPV 52 HPV 53 HPV 56 HPV 58 HPV 59 HPV 61 HPV 66 HPV 67 HPV 68 HPV 68 HPV 69 HPV 70 HPV 73 Invasive Cervical Ca HPV Genotypes 100% 80% 60% 40% 20% 0% Europe North America Central South Africa Asia Oceania Values <1% recorded as 0 Modified from de Sanjose S, et al. Lancet Oncol. 2010 Nov;11(11):1048-56.

10 Year Cumulative Risk of CIN 3+ in Women >30 Yrs with NILM Cytology Kaiser Portland Percent Developing CIN 3+ 25 20 15 16 18 hr Other Neg >20,000 women enrolled and followed 10 5 0 0 4.5 15 27 39 51 63 75 87 99 111 119 Months of Follow-up Kahn MJ, et al. J Natl Cancer Inst. 2005 20;97(14):1072-9.

What are the worldwide data on effectiveness of HPV primary screening for cervical cancer?

Meta-analysis 7-European Trials Objective- Data on the long term predictive value of cytology and HPV testing for development of CIN3+ Multinational cohort study 7 primary HPV screening studies Germany (Hannover & Tubingen), Sweden, Denmark, UK, France, and Spain 24,295 women attending cervical screening who had at least one cervical cytology or histopathology follow-up Dillner J, et al. BMJ. 2008 Oct 13;337:a1754.

Incidence of CIN3+ per 10,000 Cumulative incidence rate for CIN3+ for women according to baseline test results in seven European countries 4000 3000 Cytology+/HPV+ 2000 1000 Cytology-/HPV+ 0 0 12 24 36 48 60 72 Time since intake (months) Cytology+/HPV- Cytology-/HPV- Modified from Dillner J, et al. BMJ. 2008 Oct 13;337:a1754.

Incidence of CIN3+ per 10,000 Cumulative incidence rate for CIN3+ for women according to -baseline test results, excluding Denmark &Tübingen 100 80 Negative predictive value 60 40 Cytology-/HPV- Cytology- HPV- 20 0 0 12 24 36 48 60 72 Time since intake (months) Modified from Dillner J, et al. BMJ. 2008 Oct 13;337:a1754.

Incidence of CIN3+ per 10,000 Cumulative incidence rate for CIN3+ for women according to baseline test results, excluding Denmark &Tübingen 2500 2000 Positive predictive value Cytology+ 1500 HPV+ 1000 500 0 0 12 24 36 48 60 72 Time since intake (months) Cytology- HPV- Modified from Dillner J, et al. BMJ. 2008 Oct 13;337:a1754.

Kaiser N. California Study Assessed 5-year cumulative incidence of CIN3 for 331,818 women aged 30 yrs HPV test and cytology samples were collected, and colposcopically directed biopsies when taken Shows how screening will work in a realworld setting What does cytology really add? Katki HA, et al. Lancet Oncol, 2011. 12(7): 663-72.

Cumulative Incidence of CIN 3+ Kaiser Study HPV & Pap Jointly 14 12 10 Cytology+/HPV+ 8 6 4 2 0 Cytology-/HPV+ Cytology+/HPV- 0 1 3 5 Years Cytology-/HPV- Katki HA, et al. Lancet Oncol, 2011. 12(7): 663-72.

Cumulative Incidence of CIN 3+ Kaiser Study HPV & Pap Jointly after 2nd Co-test 6 5 4 Cytology+/HPV+ 3 2 1 0 Cytology-/HPV+ Cytology+/HPV- 0 1 3 5 Years Cytology-/HPV- Katki HA, et al. Lancet Oncol, 2011. 12(7): 663-72.

Ronco: Efficacy of HPV-based Screening - 4 European Trials Ronco et al analyzed follow-up data from 4 published randomized controlled screening trials of HPV-based screening NTCC (Italy), ARTISTIC (United Kingdom), Swedescreen (Sweden), and POBASCAM (Netherlands) Over 176,000 women liquid based or conventional Pap PCR assay or HC-2 Ronco G, et al. Lancet, 2014. 383(9916): p. 524-32.

Cumulative Detection Rate (per 100,000) Ronco: Cumulative Invasive Cervical Cancer Rates - 4 European Trials 100 All randomized women 90 80 70 60 50 Cytology Arm More cancer in cytology arm 40 30 20 HPV Testing Arm 10 0 0 2 4 6 8 Time since entry (Years) Modified from Ronco G, et al. Lancet, 2014. 383(9916): p. 524-32.

Cumulative Detection Rate (per 100,000) Ronco: Cumulative Invasive Cervical Cancer Rates - 4 European Trials 100 Women with a negative test at entry 90 80 70 60 50 40 30 20 Cytology Arm More cancer in cytology arm 10 HPV Testing Arm 0 0 2 4 6 8 Time since negative test at entry (Years) Modified from Ronco G, et al. Lancet, 2014. 383(9916): p. 524-32.

Ronco: Efficacy of HPV-based Screening - 4 European Trials After 2.5 years of follow-up Incidence of invasive cervical cancer began to increase in women initially screened with cytology compared those screened using hrhpv testing (RR 0.45, 95%CI: 0.25-0.81) There was also a better overall detection of adenocarcinoma using hrhpv testing Known problem for cytology-based screening strategies. Ronco G, et al. Lancet, 2014. 383(9916): p. 524-32.

ATHENA U.S. Based RCT Cohort of 46,887 women in US undergoing routine screening (32,260 >30 yrs) Had gynecological exam, ThinPrep Pap test, HPV testing (and genotyping) All hrhpv (+) and/or Pap (+) and a subset of hrhpv (-) / WNL underwent colposcopy Wright TC Jr, et al. Am J Clin Pathol. 2011 Oct;136(4):578-86.

ATHENA U.S. Based RTC Significantly and substantially higher 3- year cumulative incidence rate (CIR) of CIN3 and cancer (CIN3+) in women 25 years who were cytology negative at enrollment (0.78%; 95% CI 0.53 1.09) compared to women who were hrhpv negative (0.34%; 95% CI 0.10-0.65) Both cytology and hrhpv negative at enrollment = 0.30% (95% CI; 0.05-0.62). Wright TC Jr, et al. Am J Clin Pathol. 2011 Oct;136(4):578-86.

Absolute Risk of CIN in NILM Cytology ATHENA study: women >30 yrs HPV Status CIN 2+ CIN 3+ hrhpv (-) 0.9% 0.3% hrhpv (+) 6.3% 4.1% 16/18 (+) 11.7% 9.9% Other 12 hr (+) 4.7% 2.5% Wright TC, et al. Am J Clin Path. 136(4):578-586,2011.

cobas HPV Results in Pap tests from Women Dx with Cancer Number of Cases % HR HPV+ by the cobas HPV Test ATHENA 8 100 (8/8) UNM Cytology Registry 18 94.4 (17/18) Total 26 96.2 (25/26) Note: 1 sample determined to be an endometrial cancer and 1 sample with an invalid cobas HPV Test result was not included in this analysis FDA Presentation, March 12, 2014 http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/ medicaldevices/medicaldevicesadvisorycommittee/microbiologydevicespanel/ucm388683.pdf

Screening with HPV Alone It is clear from current trials that cytology adds little when HPV is used as screening test Several Netherlands, Australia, U,S. and U.K. (limited) are now adopting Problem is how to identify ("triage") which hrhpv (+) women need further evaluation Number of options for "triage" test: cytology, genotyping, hrhpv persistence, p16 immunostaining, other markers http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/ Content/ncsp-renewal

What was the U.S. FDA submission for HPV primary screening?

Proposed HPV Testing Algorithm cobas HPV Test 16 18 31 33 39 45 35 51 52 56 58 59 66 68 12 other hrhpv+ HPV Cytology HPV16/18+ NILM ASC-US Routine screening Follow-up in 12 months Colposcopy FDA Presentation, March 12, 2014 http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/ medicaldevices/medicaldevicesadvisorycommittee/microbiologydevicespanel/ucm388683.pdf

ASCCP/SGO Interim Guidance Recommendations

Interim Guidance - Concerns Potential harms of beginning primary HPV screening at age 25 years Higher number of colposcopies, Increased disease detection Is 25 years is the right age to start? If a woman initiates screening at 21 years and is re-screened at 24 years, when would she change to 1 o HPV screening? What is the best screening interval?

Issues with Primary HPV Screening Number of tests and number of women requiring work-up / follow-up Slightly reduces specificity of screen But still much better than cytology alone Will not pick-up non-hpv cancers Work-up for symptomatic individuals? Will patients give up their "Pap? Will providers?

Conclusion Primary HPV screening as safe and effective as cytology Based on ATHENA and European randomized controlled screening trials Comparisons between primary HPV screening and co-testing are less clear Literature is either not designed or underpowered to specifically address this

Interim Guidance Recs 1 o HPV screening is an important scientific and clinical advancement for cervical cancer screening Offers improved performance over cytology only screening strategies Should be considered as an alternative The use of HPV 16/18 genotyping and reflex cytology achieve a reasonable balance of tests

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