1. Cervical cancer prevention update
L. Stewart Massad, M.D.
Dept. of Obstetrics & Gynecology
Washington University School of Medicine
St. Louis, MO

2. 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)

3. 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 management
Counsel patients on nonavalent HPV vaccination
Use p16 testing in Pap/biopsy diagnosis

4. 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

5. Screening options USPSTF ACS/ASCCP/ASCP When to start? 21yo How often?
Q3y Paps
Q5y cotests ages 30-64
Q3y Paps ages 21-29
Q5y cotest ages preferred
Q3y Paps remain an option
When to stop?
65yo if adequate prior screens
65yo if 3 neg Paps or 2 neg cotests
After hyst for benign disease

6. 5y CIN3+ risk after -cotest = 1y risk after -Pap
Cotesting preferred to cytology
Dillner J et al. BMJ 2008;337:a1754

7. 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, others
Huh W et al. Gynecol Oncol 2015;136:178-82

8. 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
Followed up to 3y
Wright TC et al. Gynecol Oncol 2015;136,189-97

9. 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)

10. Cumulative incidence, verification bias adjusted
CIN2+
CIN3+
HPV16+
HPV18+
Other HPV+
HPV-
Wright TC et al. Gynecol Oncol 2015;136,189-97

11. 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

12. Primary HPV screening algorithm
Huh W et al. JLGTD 2015;19:91-96.

13. 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

14. 5y CIN3+ risk after -cotest = risk after neg Pap
Little difference HPV alone vs cotest
Dillner J et al. BMJ 2008;337:a1754

15. 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

16. HPV test alone more sensitive than Pap alone
Huh W et al. JLGTD 2015;19:91-96.

17. 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%

18. Summary: Management by 5y CIN3+ Risk Thresholds
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+
risk
HPV/Cytology
result
CIN3+ risk
Immediate
colposcopy
(high-grade cytologies)
SCC
0.01%
83%
HPV+/
HSIL
0.20%
50%
48%
AGC
0.05%
34%
HPV-/
29%
ASC-H
0.12%
25%
0.17%
18%
0.21%
8.7%
3.8%
0.16%
1.1%
Immediate Colposcopy
ASC-US
6.8%
LSIL
0.77%
6.2%
0.92%
5.3%
1-year return
Pap-
3.5%
4.5%
2.7%
2.6%
0.18%
2.1%
3-year return
1.8%
0.45%
95.8%
0.26%
5-year return
92.1%
0.08%
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

19. 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 threshold
Gage J et al. Gynecol Oncol 2013 Jun;22(6):

20. Cumulative incidence of CIN3+
HPV16
HPV18
Non16/18 HRHPV
No HRHPV
Khan M J et al. JNCI J Natl Cancer Inst 2005;97:

21. Pap-/HPV16+: 3y CIN3+ risk exceeds threshold for colpo
HPV18 causes adenocarcinomas
Schiffman M et al. J Clin Micro 2015;53:52-9

22. 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

23. 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

24. 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

25. 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

26. Uses for p16 testing Triage 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

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

28. Uses for p16/Ki67 testing Triage 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

29. Costaining showed 92% sensitivity, 80% specificity for CIN2+
Brown cytoplasm=p16
Red nucleus=Ki67
Costaining showed 92% sensitivity, 80% specificity for CIN2+
Schmidt D et al. Cancer Cytopathol 119;158–66. Slide from anatomiacabra.wordpress.com/cintecplus/

30. Questions?