Ai Ling Tan Gynaecological Oncologist Ascot Clinic/ADHB NCSP UPDATE & PRIMARY HPV SCREENING

NCSP annual monitoring report Since 2005 cancer rates stable

Coverage rates by age

Coverage rates by ethnicity

Ethnic Disparities=WORK REQUIRED!! Participation, retention and follow up of abnormalities 3 year coverage – Maori, Pacific Island and Asian women 77% Adjustment for hysterectomies, coverage goal is 75% Incidence and mortality rates in European women is 30% lower

Changes to the Standards 2013

Future direction of NCSP Challenges Improve coverage Achieve equity in coverage and incidence Implement the Parliamentary review report recommendations Accurate electronic colposcopy data transfer Linkage to immunisation register 2015 Audit cycle

The Sun is setting on the Pap Smear

Wright and Schiffman (2003) NEJM Natural History of HPV Infections

Natural History of Cervical Carcinogenesis Normal Cervix Mild Cytologic and/or Histologic Abnormalities Precancer CervicalCancer HPV=human papillomavirus. Schiffman M, Kjaer SK. J Natl Cancer Inst Monogr. 2003;(31): HPV Progression RegressionClearance InfectionInvasion HPV- Infected Cervix Primary prevention Secondary prevention Triage strategies with HPV testing, P16 INK4a, others HPV Test

CvCx Cases/100, >65 Age (years) HPV Prevalence (%) HPV Cervical Cancer Sources: NCI SEER Data, ; Melkert et al., Int J Canc 53:919. Relationship of Age to HPV Prevalence and Incidence of Cervical Cancer

Central/South America Northern Africa North America/ Europe South Asia HPV Type 52 Others Prevalence of HPV Types in Cervical Cancer

HPV is detectable in over 90% of cervical cancers in NZ

Cytology HPV DNA Biomarkers [p16/Ki67] HPV mRNA NOW FUTURE Changing Cervical Screening

Cytology versus HPV testing Subjective Objective

HPV DNA tests Cobas 4800 HPV [Roche] Digene HC-2 [Qiagen] Cervista HPV HR [Hologic] Cervista HPV16/18 [Hologic] HPV DNA tests Cobas 4800 HPV [Roche] Digene HC-2 [Qiagen] Cervista HPV HR [Hologic] Cervista HPV16/18 [Hologic] FDA approved HPV tests [for clinical use] HPV RNA tests Aptima HPV assay [Hologic/ GenProbe] HPV RNA tests Aptima HPV assay [Hologic/ GenProbe]

Introduction of HPV testing Triage of low grade smears Test of cure post LLETZ Historical test of cure Primary HPV screening

HPV triage of ASCUS/LSIL

Risk for CIN 3+ 25% 15% 0.0% HPV 16 positive Any high-risk HPV(+) other than HPV 16 Castle P et al J Natl Cancer Inst 2005;97: % 7.5% 32.5 % 39.5 % 8.4% 9.5% ASC-USLSIL ASC-US

Post treatment HPV testing Substitutes for annual smears for life SMEAR + HPV NEGATIVE SMEAR +HPV NEGATIVE NORMAL SCREENING +

Cancer Res; November

Test of cure study If cytology and HPV testing are negative at six months then the risk of CIN 2+ over the next two years was less than 0.5% Kitchener et al Lancet Onc 2009 HPV testing using HC2 is the most sensitive test of cure and is superior to either cytology or colposcopy Paraskevaidis et al Cancer Treat Rev, 2004 The addition of cytology to HPV testing improves the sensitivity of sampling. The optimum time for the double test (cytology and HC2) is probably at 18–24 months Coupe et al BJOG, 2007

Post Treatment

Previous Treatment

Why change now? High-Risk HPV DNA Testing is more sensitive in detecting high grade disease than a Pap test Clavel C, et al. Brit J Cancer, 2001;89: A positive high-risk HPV result is an objective risk indicator for the development of high-grade disease and cancer Screening is less effective with reduced prevalence Lorincz A., Richart, R. Arch Pathol Lab Med, 2003;127:

HPV Vaccination

Confidence in new test with longer screening interval

Over 60,000 women in analysis All North American and European studies where cytology is used as the primary screen and where HR HPV was run in parallel

Comparison of HPV DNA vs Cytology: Europe / USA Combined Results  # Screened:>60,000: HC2 + Cytology  Age:30-60 (majority) CIN 3+CIN 2+ HPV DNA Cytology Cases: Sensitivity (%) Cuzick et al. Int J Cancer, April 2006

Dillner et al 2008 BMJ (Cuzick et al, 2006) Performance characteristics: cytology and HPV testing [meta analysis]

Cumulative incidence of Cancer in women with negative entry test 3.5 years5.5 years Experimental arm (HPV-based) 4.6 per 10 5 (1.1 – 12.1) 8.7 per 10 5 (3.3 – 18.6) Control arm (cytology based) 15.4 per 10 5 (7.9 – 27.0) 36.0 per 10 5 (23.2 – 53.5) Rate ratio was 0.30 (0.15 – 0.60) Guglielmo Ronco et al Lancet 2014;383: HPV-based screening provides 60 – 70% greater protection against invasive cervical carcinomas compared with cytology

Detection of cancer using HPV vs cytology Ronco et al Lancet 2014

HPV analysis – primary screening Primary screening with HPV may be effective in women over 30 Arbyn meta-analysis of 49 studies  HPV testing showed a higher sensitivity for CIN 2+ and CIN 3+ relative to cytology  HPV negative women had a significantly lower cumulative incidence of CIN 3+ in the second round of screening compared with cytology negative women

HPV analysis – primary screening Kitchener et al Eur J Cancer 2011 ARTISTIC screening trial  negative HPV test provides the same degree of ‘protection’ over two screening rounds as negative cytology for one screening round  allows screening interval to be increased to 5-6 years or longer in women over 30 Yr

Summary Management Problems Similar positive predictive value for CIN3 detection BUT Too many women with HPV positive normal smears

ADVANTAGES OF USING HPV TESTING AS THE SOLE PRIMARY SCREENING TEST ADVANTAGES OF USING HPV TESTING AS THE SOLE PRIMARY SCREENING TEST Automated, Objective, Very Sensitive Test Quality control Medico-legal Cytology reserved for 6-10% of women High quality Fewer, more focused cyto-screeners Avoids triage of HPV negative ASCUS/LSIL Longer screening interval Cost Convenience

So why not just use HPV alone? Use of HPV testing alone as primary screening test will yield too many positives Would generate too many colposcopy referrals Not practical <30 as prevalence too high Triage further with use of cytology Possible alternative triage with genotyping

Rijkaart et al. concluded that referral for cytology followed by repeat cytology led to an acceptable colposcopy referral rate [33.4% of positives] and a high negative predictive value [99.3%]

Vaccine, Vol xx Supplement x, © 2006 Elsevier Limited. All rights reserved. Chapter 03. Figure 3 POTENTIAL NEW SCREENING ALGORITHM Use of HPV TESTING as the primary screening test and of CYTOLOGY to triage HPV positive women WOMEN AGED YEARS HPV TEST Positive Normal or ASCUS ≥ ≥ LSIL Cytology Negative HPV Negative Cytology ≥ LSIL CYTOLOGY COLPOSCOPY HPV & CYTOLOGY at 6 – 12 months COLPOSCOPY NORMAL 5 YEAR RECALL HPV & CYTOLOGY at 6 – 12 months NORMAL 5 YEAR RECALL

HC2=Hybrid Capture 2 HPV Test. Khan M. et al. J Natl Cancer Inst. 2005;97: Cumulative Incidence of CIN 3+ in 20,512 Women: 10-year Follow-up Follow-up time (months) Cumulative incidence rate (%) Positive for HPV 16 Positive for HPV 18 Positive for non-HPV 16/18 oncogenic types in HC2 Oncogenic HPV negative

Vaccine, Vol xx Supplement x, © 2006 Elsevier Limited. All rights reserved. Chapter 03. Figure 4 POTENTIAL FUTURE SCREENING ALGORITHM Use of HPV TESTING as the primary screening test and of CYTOLOGY and HPV TYPING to triage HPV positive women to eliminate a ‘short follow up’ group. Triage with P16 AND MRNA may also be useful, but this is less well established WOMEN AGED YEARS HPV TEST Negative Positive </= LSIL > > LSIL Negative Positive NORMAL 5 YEAR RECALL CYTOLOGY COLPOSCOPY 3 – 5 YEAR RECALL COLPOSCOPY HPV 16/18 Typing

Screening Age…. P Sasieni BMJ 2009 High incidence hpv and CIN Low risk of cancer Spontaneous regression Impact of HPV vaccination Odds of developing cancer between screened and unscreened as a function of age

Later age of onset of screening Incidence HPV in young women AgeHrHPV PosCyto Pos > 355.8%2.5% < 3513%3.6% < 2534 – 47 %

Self Collection for the under- and never - screened women

Primary HPV Screening USA - Co-testing (Cytology and HPV testing) - Primary HPV screening with genotyping for women 25yo and older Intention to commence in 2016 Netherlands - HPV testing with reflex LBC from 30 Australia - HPV testing with partial genotyping and reflex LBC

Conclusion Primary HPV screening more sensitive Negative HPV test confers greater protection Longer screening intervals Raise screening age Need to triage with cytology +/- genotyping Need to raise vaccination rates to be most effective

A new dawn is rising……. The Era of Primary HPV Cervical Screening