Cervical cancer prevention update

L. Stewart Massad, M.D.

Dept. of Obstetrics & Gynecology

Washington University School of Medicine

St. Louis, MO

Disclosures

• I have no financial relationships with companies that sell HPV assays or vaccines

• I have accepted honoraria from ASCCP and SGO for speaking/organizing and for review of enduring materials sponsored in turn by Merck, GSK, Hologic, Roche, and Qiagen

• I will not discuss tests or medications not approved by the US FDA but will name unique proprietary tests

• I have accepted payment from attorneys in cases alleging missed cervical cancer (defendant & plaintiff)

Objectives

• At the conclusion of this session, participants should be able to:

Choose among screening alternatives, including cotesting vs primary HPV testing

Use HPV genotyping if it alters managementCounsel patients on nonavalent HPV vaccinationUse p16 testing in Pap/biopsy diagnosis

Cervical screening options

• Endorsed by ASC/ASCCP/ASCP and USPSTF in 2011– Start at 21yo with cytology alone

– Continue q3y with cytology alone

– Option for cotesting q5y beginning 30yo• Preferred by ASC, acceptable by USPSTF

– Stop at 65yo after neg screens, at hyst for benign condition, when life expectancy limited

USPSTF ACS/ASCCP/ASCP

When to start? 21yo 21yo

How often? Q3y PapsQ5y cotests ages 30-64

Q3y Paps ages 21-29Q5y cotest ages 30-64 preferred Q3y Paps remain an option

When to stop? 65yo if adequate prior screens

65yo if 3 neg Paps or 2 neg cotestsAfter hyst for benign disease

Screening options

Dillner J et al. BMJ 2008;337:a1754

5y CIN3+ risk after -cotest = 1y risk after -PapCotesting preferred to cytology

New screening option 2015

• Primary HPV screening– Begin at 25yo

– Continue no more often than q3y

– Stop at age 65yo

– FDA approved 2014

– Endorsed by SGO, ASCCP Feb 2015

– Being studied by ACOG, ACS, othersHuh W et al. Gynecol Oncol 2015;136:178-82

Primary HPV screening:Evidence base

• ATHENA trial– Used Roche cobas HPV test– Tests for 16/18/other pooled (31, 33, 35, 39,

45, 51, 52, 56, 58, 59, 66, 68)

• Screened 42,209 women >24yo with HPV and Pap 2008-2009

• Followed up to 3y

Wright TC et al. Gynecol Oncol 2015;136,189-97

Primary HPV screening:Evidence base

• Colposcopy for abnormal Pap (2,603) or HPV+ (5712) + random 1038 NILM/HPV-– Biopsy of all lesions– Random biopsy if no lesion– ECC if unsatisfactory colposcopy

• Off study if CIN2+: assessed 3y performance

• If no CIN2+, annual cotesting

• Colposcopy at exit (refused by 319 of 4663)

Cumulative incidence, verification bias adjusted

Wright TC et al. Gynecol Oncol 2015;136,189-97

CIN2+ CIN3+

HPV16+

HPV18+

Other HPV+

HPV-

Primary HPV screening:ATHENA evidence base

• HPV+ rate fell w/age (21% 25-29, 12% 30-39)

• In 25-29yo, 36% of CIN2+, 34% CIN3+– >50% had neg Pap—led FDA to approve for 25+– No cancers

• Strategies compared to maximize sensitivity, minimizes number of colposcopies

• Proprietary algorithm provided optimal balance

Primary HPV screening algorithm

Huh W et al. JLGTD 2015;19:91-96.

Primary HPV screening:Advantages

• Tests for the cause of cervical cancer

• More sensitive than cytology alone

• Sensitivity close to cotesting

• Includes genotyping (16/18/other)

• Defined management algorithm

• Cuts number of tests by half vs cotest

Dillner J et al. BMJ 2008;337:a1754

5y CIN3+ risk after -cotest = risk after neg PapLittle difference HPV alone vs cotest

Primary HPV screening:Disadvantages

• Sensitivity (min) less than cotesting

• Complex management algorithm

• Works with only one assay platform

• Optimal test intervals unclear

• Labels many women as high risk

HPV test alone more sensitive than Pap alone

Huh W et al. JLGTD 2015;19:91-96.

HPV genotyping:When does it change management?

• When 5y CIN3+ risk if HPV16+ >5%• Or when risk HPV16-/other HRHPV+ <5%

Recall risk threshold for colpo: – 5y CIN3+ risk ≥5%

Summary: Management by 5y CIN3+ Risk Thresholds

• Left side orders risks from all cytologies, banded by current management guideline

• Right side orders risks for each co-test into the risk band

• Managing cotest results by these benchmarked implicit risk thresholds ensures “Similar management of similar risks”

Katki H et al. JLGTD 2013;17:S28-S35

Benchmarking cotest risks to implicit 5-year CIN3+ cytology-only risk thresholds

 Cytology-only 5-year CIN3+ risks

(implicit risk thresholds) Cotest 5-year CIN3+ risks

Current management

based on cytology-only

Cytology result Frequency

CIN3+

riskHPV/Cytology

result FrequencyCIN3+

risk

Immediatecolposcopy(high-grade cytologies)

SCC 0.01% 83%

HPV+/ HSIL 0.20% 50%

HSIL 0.20% 48%

HPV+/ AGC 0.05% 34%

HPV-/ HSIL 0.01% 29%

HPV+/ ASC-H 0.12% 25%

ASC-H 0.17% 18%

AGC 0.21% 8.7%

HPV-/ ASC-H 0.05% 3.8%

HPV-/ AGC 0.16% 1.1%

Immediate Colposcopy

HPV+/ ASC-US 1.1% 6.8%

HPV+/ LSIL 0.77% 6.2%

LSIL 0.92% 5.3%

1-year return

HPV+/ Pap- 3.5% 4.5%

ASC-US 2.7% 2.6%

HPV-/ LSIL 0.18% 2.1%

3-year returnHPV-/ ASC-US 1.8% 0.45%

Pap- 95.8% 0.26%

5-year return HPV-/ Pap- 92.1% 0.08%

HPV genotyping:When does it change management?

• Pap-/HPV16+ has >10% 5y CIN3+ risk– Higher in ATHENA

• ASC-US/HPV+/HPV16- has >5% risk– Although risk is lower than ASC-US/HPV16+,

still crosses the benchmark threshold for colposcopy

– For women testing ASC-US/HPV+/HPV16/18- 2y CIN3+ risk = 8%

• Exceeds 5% colpo thresholdGage J et al. Gynecol Oncol 2013 Jun;22(6):1095-101

Cumulative incidence of CIN3+

Khan M J et al. JNCI J Natl Cancer Inst 2005;97:1072-1079

HPV16

HPV18

Non16/18 HRHPV

No HRHPV

Schiffman M et al. J Clin Micro 2015;53:52-9

• Pap-/HPV16+: 3y CIN3+ risk exceeds threshold for colpo• HPV18 causes adenocarcinomas

Nonavalent HPV vaccine

• Quadrivalent vaccine: 6, 11, 16, 18– Should prevent 67% of cervical cancers

• Nonavalent vaccine: These + 5 additional HPV types related to 16/18– Should prevent 90% of cervical cancers– 12-14 HPV types “high risk” carcinogenic

• Preferred vaccine for HPV-naïve women

A:CIN2+ from 5 novel HPV types, per protocol

B:CIN2=from 5 novel HPV types, mod ITT

C:CIN2+ overall, not HPV+ at T0

D: CIN2+overall, mod ITT

Joura EA et al. NEJM 2015; 372:711-23

Nonavalent HPV vaccine:Revaccinate after HPV4?

• Target population is 11-12yo– Vaccine not therapeutic: give before sexual debut

• If still sexually naïve, revaccinate

• If sexually active, benefits insignificant

Uses for p16 testing

• p16 binds to pRb to allow cell cycling

• HPV E7 gene product causes pRb degradation

• Without pRb, p16 accumulates

p16 accumulation is a marker for presence of E7 & so of HPV infection moving toward cancer

Uses for p16 testingTriage of CIN2

• Histology sections stained with immunohistochemistry to identify accumulated p16– Block p16 staining of CIN2 suggests oncogenic

potential– p16- or basal staining suggests only HPV

infection

Treat p16+ CIN2, observe p16- CIN2– Report as HSIL, LSIL

Block p16 staining (brown) reflects E7 expression, oncogenic transformation

Uses for p16/Ki67 testingTriage Pap tests

• In cotesting, how to manage HPV+/Pap- women? ASCUS/HPV+? LSIL?

• In primary HPV screening, how to manage HPV+ women?

• HPV+/p16+/Ki67+: ?neoplasia: colpo

• HPV+/p16-/Ki67-: ?nonneoplastic: obs

Not FDA approved

Schmidt D et al. Cancer Cytopathol 119;158–66. Slide from anatomiacabra.wordpress.com/cintecplus/

Brown cytoplasm=p16Red nucleus=Ki67Costaining showed 92% sensitivity, 80% specificity for CIN2+

Questions?