Ai Ling TanGynaecological OncologistAscot Clinic/ADHB

NCSP UPDATE & PRIMARY HPV SCREENING

NCSP annual monitoring report 2010-11

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 <50% compared to European 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

NormalCervix

Mild Cytologic and/orHistologic Abnormalities

PrecancerCervicalCancer

HPV=human papillomavirus.Schiffman M, Kjaer SK. J Natl Cancer Inst Monogr. 2003;(31):14-19.

HPV

Progression

RegressionClearance

Infection InvasionHPV- Infecte

d Cervix

Primary prevention

Secondary prevention

Triage strategies with HPV testing, P16INK4a, others

HPV

Test

CvC

x Cases/100,000

0

5

10

15

20

25

15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 >65

Age (years)

HP

V P

reva

len

ce (

%)

0

2

4

6

8

10

12

14

16

18

20

HPV

Cervical Cancer

Sources: NCI SEER Data, 1990-94; Melkert et al., 1993. 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

16

18

45

31

33

HPV Type

52

Others

Prevalence of HPV Types in Cervical Cancer

58

57

12.6

69.7

14.6

67.6

1752.5

25.7

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

Cytology

HPV DNA

Biomarkers

[p16/Ki67]

HPV mRNA

NO

WF

UT

UR

EChanging Cervical Screening

Cytology versus HPV testing

Subjective Objective

HPV DNA testsCobas 4800 HPV [Roche]

Digene HC-2 [Qiagen]Cervista HPV HR

[Hologic]Cervista HPV16/18

[Hologic]

FDA approved HPV tests[for clinical use]

HPV RNA testsAptima 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

Women > 30 years ASCUS / LSIL

HrHPV reflex test

Repeat cytology at 12 months

HrHPV negative

Refer to colposcopyReturn to 3 yearly

screening

HrHPV positive

Cytology > ASC-US Cytology negative

HPV Testing Guidance 1

Triage of women 30 years and over with ASC-US or LSIL(who have not had an abnormal smear within the last 5 years)

Refer to colposcopy

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;97:1066-71

35%

7.5%

32.5%

39.5%

8.4% 9.5%

ASC-US LSIL LSILASC-US

Post treatment HPV testing

• Substitutes for annual smears for life

SMEAR + HPVNEGATIVE

SMEAR +HPV NEGATIVE

NORMAL SCREENING

+

Cancer Res; November 1 2006

Test of cure studyIf 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;89:1616-1623

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: 959-968.

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

207 125 33 365 313 183 38 534Cases:

Se

ns

itiv

ity

(%

)

Cuzick et al. Int J Cancer, April 2006

Dillner et al 2008 BMJ

www.canserforum.com (Cuzick et al, 2006)

Performance characteristics:cytology and HPV testing[meta analysis]

Cumulative incidence of Cancer in women with negative entry test

  3.5 years 5.5 years

Experimental arm (HPV-based)

4.6 per 105 (1.1 – 12.1)

8.7 per 105 (3.3 – 18.6)

Control arm (cytology based)

15.4 per 105 (7.9 – 27.0)

36.0 per 105 (23.2 – 53.5)

Rate ratio was 0.30 (0.15 – 0.60)

Guglielmo Ronco et al Lancet 2014;383:524-532

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 screeningKitchener 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

Sensitivity Specificity

HPV (primarily HC2) 96% 92%

CYTOLOGY 53% 96%

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

Automated, Objective, Very Sensitive Test

Quality controlMedico-legal

Cytology reserved for 6-10% of women

High qualityFewer, more focused cyto-screenersAvoids triage of HPV negative ASCUS/LSIL

Longer screening interval

CostConvenience

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%]

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POTENTIAL NEW SCREENING ALGORITHM

Use of HPV TESTING as the primary screening test and of CYTOLOGY to triage HPV positive women

WOMEN AGED 35 - 64 YEARSHPV TEST

Negative Positive

Normal orASCUS

≥ LSIL

Cytology Negative

HPV Negative

Cytology ≥

LSILHPV Positive & Cytology < LSIL

HPV Negative & CytologyASCUS

CYTOLOGY

COLPOSCOPYHPV & CYTOLOGYat 6 – 12 months

COLPOSCOPYNORMAL

5 YEAR RECALLHPV & CYTOLOGYat 6 – 12 months

NORMAL 5 YEAR RECALL

HC2=Hybrid Capture 2 HPV Test.Khan M. et al. J Natl Cancer Inst. 2005;97:1072-1079.

Cumulative Incidence of CIN 3+ in 20,512 Women: 10-year Follow-up

0

5

10

15

20

4.5 15.0 27.0 39.0 51.0 63.0 75.0 87.0 99.0111.0119.5Follow-up time (months)

Cu

mu

lati

ve in

cid

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ate

(%

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Positive for HPV 16

Positive for HPV 18

Positive for non-HPV 16/18oncogenic types in HC2Oncogenic HPV negative

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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 35 - 64 YEARSHPV TEST

Negative Positive

</= LSIL > LSIL

Negative

Positive

NORMAL 5 YEAR RECALL

CYTOLOGY

COLPOSCOPY3 – 5 YEAR

RECALL

COLPOSCOPYHPV 16/18 Typing

Screening Age….

P Sasieni BMJ 2009

High incidence hpv and CINLow 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 screeningIncidence HPV in young women

Age HrHPV Pos Cyto Pos

> 35 5.8% 2.5%

< 35 13% 3.6%

< 25 34 – 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