Cervical Cancer Screening

Past… PRESENT…Future

Audrey P. Garrett, MD, MPH Women’s Health Symposium

September 7, 2012

Disclosure

• On Speaker bureau for Merck for Gardasil • On Speaker bureau for Hologic for Cervista

Objectives

• Review basis for new guidelines • Review platforms for new guidelines • Review guidelines • Convince of the rationale for use of HPV

testing in cervical cancer screening • Review strategies for discussing test results

with patients

Cervical Cancer

• 500,000 cases annually – 250,000 deaths annually

• Most common cause of cancer death • >80% occur in developing countries • 95% have never had a pap smear

Cervical Cancer: USA

• 12,200 cases annually • 4210 deaths 2010 • >60% have had no recent pap

– 83% population report screening in past year

• Death rate decreasing 4%/year – Decreased 70% since 1955

Cervical Cancer Hero • George Papanicolau: 1883-1962

Mary (wife/ MA)

Cervical Cancer Screening

• 1928 first cancer diagnosis by pap • 1941 paper presented • 1965 American Cancer Society

– Annual pap smear screening

Cervical Cancer Hero: Harald zur Hausen: Nobel Prize in Medicine, 2008

Understanding HPV: timeline

• 1973 zur Hausen hypothesis • 1983 HPV 16 isolated by Southern Blot • 1998 HPV test commercially available • 2001 vaccine trials started • 2006 HPV vaccines commercially available • 2006 HPV testing incorporated into screening • 2009 genotyping available and endorsed • 2011 4 FDA approved HPV testing platforms

http://www.qiagen.com/

HPV testing platforms

• 1998 Digene HC 2 (Qiagen) – Nucleic acid hybridization with signal amplification

using chemiluminescence • Hologic

– Invader technology, first to offer genotyping • Genprobe

– Qualitative detection of E6/E7 viral mRNA • Cobas/Roche

– PCR, uses single throughput technology

BY MIKAELA CONLEY @MIKAELACONLEY FOLLOW ON TWITTER

MAR 15, 2012 12:41PM NEW GUIDELINES DISCOURAGE YEARLY PAP TESTS

March 14, 2012

BY MIKAELA CONLEY @MIKAELACONLEY FOLLOW ON TWITTER

MAR 15, 2012 12:41PM NEW GUIDELINES DISCOURAGE YEARLY PAP TESTS

Public Health Concept: Screening Test

Screening Test

• Cervical cancer was common – 26,000 deaths/yr in early 20th century – 300,000 cases/yr of CIN3 now

• Lengthy pre-invasive process • Testing available

– Cervix accessible – Test inexpensive and “easy”

• Therapeutic intervention

Screening Test • Efficacy of test dependent on epidemiology

– Prevalence – Incidence

• Heavily pre-screened populations – Decrease prevalence – Stable incidence – Smaller incident lesions (lead time bias)

• Altered epidemiology of target lesion

Cervical Cancer and HPV

• HPV is ubiquitous • 100 subtypes identified • 40 predilection for ano-genital mucosa • 15 high risk sub-types • HPV 16, 18 most virulent and persistent

– 50% high grade dysplasias – 70-80% invasive cervical cancers

Cervical Cancer and HPV Biologic Plausibility

• HPV interacts with host genome – E6 and E7 interact P53 and RB

• Archival slides demonstrate presence • Prospective studies link HPV and dysplasia • 99% cervical cancers test positive • Vaccine data demonstrates efficacy

CaCx screening and HPV

• Pap swipes the ectocervix – Can miss endocervical lesions – Can miss very small lesions

• HPV represents risk of disease – Much stronger negative predictive value – Allows us to focus on those at risk – Allows us to reassure those at less risk

Neg HPV test offers better protection over years than negative Pap test

• Joint European Cohort Study • HPV vs conventional pap in 6 countries • N= 24,295

Dillner, BMJ, 2008

3 yrs 4 yrs 5 yrs 6 yrs

pap 0.51% 0.69% 0.83% 0.97%

HPV 0.12% 0.19% 0.25% 0.27%

Cervical Cancer: HPV

Cervical Cancer: Prevention

• Pap test: – 20% false negative rate – Compensate with frequent paps – 1 in 5 will have an abnormal pap

• Pap test 2012: – Changing epidemiology – Better testing available – Changing recommendations

Cervical Cancer Prevention: Get with the times…

“This dial phone has always worked for me…” “My patients would never be able to understand a more modern test…”

Cervical Cancer Prevention: HPV

• HPV testing is more sensitive and specific – 3 successive paps at 20% false neg: 3/1000 – Pap and HPV at 3 yrs: 1/1000

• HPV is highly predictive of disease – If HPV 16 pos, 17% risk at 10 yrs – If HPV 16/18 neg, <4% risk at 10 yrs

• HPV testing can decrease mortality from cervical cancer – NEJM Apr, 2009

Cervical Cancer: HPV

How much protection do we lose by not doing Pap tests every year?

• Percentage reduction in rate of invasive cacx in cohort of women aged 35-64 with different frequencies of screening – Next pap 1 year: 93.5%

• 30 paps required over 30 years – Next pap 2 years: 92.5%

• 15 paps over 30 years – Next pap 3 years: 90.8%

• 10 paps over 30 years – Next pap 5 years: 83.6%

• 6 paps required over 30 years – 3 well timed paps in a lifetime

• South Africa: 95% reduction in cacx mortality

IARC BMJ 293: 1986

How many cancers do we prevent:

• Assuming at least 3 consecutive neg paps • Cancers prevented by doing annual pap rather

than Q 3 yr – Age 30-44: 3/100,000 women – Age 45-59: 1/100,000 women

• Additional testing necessary to find each cancer – Age 30-44: 69,665 paps plus 3861 colpos – Age 45-59: 209,324 paps plus 11,502 colpos

Sawaya et al, NEJM, 2003

Rate of progression CIN3-> CA

• Increases with age – 80: 10% per year – 20-24: 0.5% per year – Adolescents: negligible

Moscicki, Cox, et al, JLGTD, 2010

Cervical Cancer Screening: ASCCP/ACOG guidelines

• No paps under 21 – Controversial but Public Health based – Difference between pap and pelvic exam – STD screens if sexually active

• HPV testing not useful under 21 – High prevalence – 90% infections resolve

Cervical Cancer Screening: ASCCP/USPSTF guidelines

• Primary cytology screening 21-29

– Triennial screening – REFLEX HPV testing for ASCUS

• Women 30-65: lengthened intervals – Triennial screening with cytology – Cotesting every FIVE years – CANNOT risk assess without HPV

Cervical Cancer Screening: Women over 30

• Cytology with HPV testing

– Pap NIL, HR HPV neg: retest 5 yrs

• Pap abnormal, regardless of HPV – Triage appropriately

Cervical Cancer Screening: Women over 30

• Pap normal, HR HPV positive

– Repeat both 12 months • If HPV persistently positive, colpo

• Pap normal, HR HPV positive – Immediate reflex to HPV 16/18

• If positive, colpo • If negative, repeat

Cervical Cancer Screening: Women over 30

• Cytology with HPV testing

– May require alteration/ attention to req – May require patient education – May require EMR tickler system – Does NOT mean that patient does not need

annual exam – This is the stronger test

Cervical Cancer Screening: “other” guidelines

• Women over 65 – If adequate prior testing, cessation of screening

• Women who have had hysterectomy – If for non-HPV related causes, no screening

• Women who have had vaccination – Routine screening

• Women with new sexual partners – Routine screening

Cervical Cancer Screening: “higher risk women”

• Immunocompromise – HIV – Transplant recipient

• DES exposure in utero • Women with symptoms

– Aka not SCREENING

• Women with prior HPV related disease/treatment

The Changing Landscape of Cervical Cancer Screening

• New epidemiology – Understanding other HPV strains

• New vaccines – To cover that new understanding

• New recommendations – To accommodate that new

understanding

Cervical Cancer: Vaccines GARDASIL (Merck)

16, 18, 6, 11 2006 for girls 9-26, 2009 for boys 9-26 2010 gained indication for anal cancer

Cervarix (GSK) 16,18

2009 for girls 9-26 34% of eligible patients are vaccinated

ACOG recommends documenting vaccine status at each visit

Risk Stratification with HPV Types 16 and 18 in Women ≥ 30 Years of Age with Negative Cytology

HPV 16 positive HPV 18 positive Non-HPV 16/18 positive HPV-negative

In women ≥ 30 years of age, 10-year cumulative incidence of ≥ CIN 3 was 20% and 18% for HPV 16/18, respectively

Khan MJ, et al. J Natl Cancer Inst. 2005;87(14):1072-1079.

Follow-up Time (Years)

Cum

ulat

ive

Inci

denc

e Ra

te o

f ≥

CIN

3 (%

)

0

5

10

15

20

25

0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95

Smith J, et al. Int J Cancer. 2007;121:621-632.

16 alone

16 + 18

+ 35

+ 31

+ 33

+ 45

+ 52

+ 58

+ 59

54.7%

76.4%

83.7%

87.6%

91.0%

93.6%

94.2%

94.4%

94.5%

Cumulative Prevalence Incremental Prevalence

> 75% of Squamous Cancers in the United States Are Caused by HPV 16/18

HPV

Type

s

Proportion of Cancers Associated with HPV Types

Why Are HPV 16/18 Important?