20171021 Personalized Prevention Strategy for Cervical Cancer

1. Personalized Prevention Strategy
for Cervical Cancer
Chen-Yang Hsu
National Taipei University of Nursing and Health Sciences
2017/10/21

2. Progression of Cervical Cancer
Regular Pap Smear Screening

3. 3
Triennial Pap smear screening targeting women aged 30-69 is recommended
Given the 61% coverage rate, the efficacy of
incidence reduction by 29% and
mortality reduction by 50%
was estimated.

4. 4

5. 5
1982 HPV/Cx Ca link reported
2006-1 FDA approved first HPV vaccine (type 6, 11, 16, 18)
2009-10 FDA approved 2nd HPV vaccine (type 16, 18)
2011-10 CDC recommends HPV vaccine for boys
2014-12 FDA approved 9 strain vaccine
2015-7 Single dose may be enough (Lancet oncology)
1990 Experimental studies on HPV and Cx Ca evolved
1991 First vaccine developed
1999 HPV is the necessary factor for Cx Ca

6. Efficacy of HPV Vaccine
6
75% vaccine efficacy,
75% vaccine coverage
35% reduction in Cx Ca incidence

7. Progression of Cervical Cancer
Vaccination
HPV DNA testing
Regular Pap Smear Screening

8. 8
Prevention Strategies for Cervical Cancer
Surveillance of precursor lesion
HPV Vaccination Pap Smear
Screening
HPV DNA Testing

9. Cost-effectiveness Analysis for Prevention
Strategies for Cervical Cancer:
Pap smear, DNA testing, HPV, Vaccination
AnnualPapsmear
[+]
TriennialPapsmear
[+]
Papsmearevery 3year+HPV test
[+]
Papsmearevery 5year+HPV test
[+]
Papsmeartriennially +Vaccination
[+]
Chen MK, Hung HF, Duffy SW, Yen AMF, Chen HH*. Cost-Effectiveness Analysis for Pap Smear Screening
and Human Papillomavirus DNA Testing and Vaccination. J Eval Clin Pract. 2011;17(6):1050-8.

10. Cost-effectiveness Analysis for
Cervical Cancer Prevention
Chen MK, et al.: Cost-Effectiveness Analysis for Pap Smear Screening and Human Papillomavirus DNA Testing and Vaccination. J Eval Clin Pract. 2011;17(6):1050-8.
Vaccination + Pap Smear

11. Personalized Cervical Cancer
Prevention: Risk-based Strategies
11

12. Public Health Genetics and
Cervical Cancer Prevention Strategies
Laboratory
Research
Translational
Research
Clinical
Research
Population
Research
Public
Health
• The application of advances in human genetics and molecular
biotechnology to improve public health and prevent disease
• The impact of genetics on the art and science of promoting health and
preventing disease through the organized efforts of society
• The effective translation of genome-based knowledge and
technologies for benefit of population health

13. Healthy
Women
CIN1,
HPV-
CIN2/3,
HPV-
HPV
Infection
CIN1,
HPV+
CIN2/3,
HPV+
Invasive
Carcinoma
Polymorphism
Gene
CD28 rs3116496
IFNG: rs2430561
Pre-miR: rs11134527
LAMB3 rs2566
DAN Repairing
SNPs
IFNG: rs11177074
POLN rs17132382
TMC: rs9893818….
DNA
Methylation
CCNA1
C13ORF18
SFRP
DAPK
HIC-1…
Repairing
SNPs
DUT: rs3784621
GTF2H4: rs2894054
OAS3: rs12302655
SULF1: rs4737999
Risk Score

14. Effect Size of Genetic Markers on Cervical Cancer Progression
Markers RR
Proportion in the general
population (%) Reference
Markers on Occurrence of Cervical Cancer Lesions
CD28+17 (TT) INFG+874 (AA) 0.78 23.6 Ivansson et al. 2010
Pre-mir-218 rs11134527 (GG)
Pre-mir-218 rs11134527 (AA)
0.73
0.86
17.8
47.6
Zhou et al. 2010
LAMB3 rs2566 (TT)
LAMB3 rs2566 (CT)
1.59
1.57
10.2
46.3
Zhou et al. 2010
CASP8 -652 6N del/del
CASP8 -652 6N del/ins
0.53
0.75
10.3
39.8
Sun et al. 2007
DUT rs3784621 (CC)
DUT rs3784621 (CT)
1.54
1.33
11.4
43.5
Wang et al. 2010
GTF2H4 rs2894054 (AA)
GTF2H4 rs2894054 (AG)
0.11
0.57
2.12
24.2
Wang et al. 2010
SULF1 rs4737999 (AA)
SULF1 rs4737999 (AG)
0.59
0.59
7.76
38.4
Wang et al. 2010
Markers on Persistent HPV Infection
IFNG rs11177074 (CC)
IFNG rs11177074 (CT)
1.80
1.78
0.25
8.71 Wang et al. 2010
POLN rs17132382 (TT)
POLN rs17132382 (CT)
2.16
1.35
3.88
27.4
Wang et al. 2010
TMC8 rs9893818 (AA) 2.47 5.10 Wang et al. 2010

15. 15
Methylation Effect on Transition of Cervical Neoplasm
Marker Methylation
Frequency (%)
Relative Risk
Reference
Normal  LSIL LSIL HSIL HSIL  Cx Ca
CCNA1 4.9% 42.1 - - Yang et al. 2009
C13ORF18 2.9% 67.7 - - Yang et al. 2009
SFRP 4.4% 3.92 1.06 18.4 Chung et al. 2009
DAPK 27% 2.11 3.44 0.97 Kim et al. 2010
HIC-1 24% 2.72 1.66 0.99 Kim et al. 2010
HIN-1 9.8% 2.13 1.57 1.35 Kim et al. 2010
MGMT 2.4% 1.29 4.07 2.47 Kim et al. 2010
RAR-beta 4.9% 3.58 4.35 1.32 Kim et al. 2010
RASSF1A 4.9% 2.77 2.31 1.27 Kim et al. 2010
SHP-1 4.9% 6.38 1.42 1.02 Kim et al. 2010
Twist 7.3% 1.80 4.54 0.79 Kim et al. 2010

16. Women with Positive HPV
Transition probabiity from Cervical Cancer-free to Cervical Cancer
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0 5 10 15 20 25 30
Time (years)
Case A
Case B
Case C
Case SNP DNA Methylation
A Pre-miR-218: rs11134527 (AA) C13ORF18, DAPK
B LAMB3: rs2566(CT); Pre-miR-218: rs11134527 (AA) DAPK, HIC-1, RAR-beta
C LAMB3: rs2566(CT)

17. Women with Negative HPV
Transition probabiity from free of Cervical Cancer to Cervical Cancer
0
0.01
0.02
0.03
0.04
0.05
0.06
0 5 10 15 20 25 30
Time (years)
Case D
Case E
Case F
Case SNP DNA Methylation
D IFNG: rs11177074 (CC or CT) , Pre-miR-218: rs11134527
(AG), LAMB3: rs2566(CT)
DAPK
E POLN: rs17132382 (CT) , LAMB3: rs2566(CT), CD28:
rs3116496 (TT); IFNG rs2430561 (AA)
DAPK
F CD28: rs3116496 (TT); IFNG rs2430561 (AA)

18. Risk of Cervical Cancer by Percentile for Risk Score
Percentile Life-time Risk (%) RR
10 0.113 0.32
20 0.216 0.42
30 0.237 0.56
40 0.533 0.74
50 0.751 1.00
60 0.767 1.30
70 1.078 1.86
80 1.685 3.04
90 2.488 9.53

19. Screening
Strategy
Risk Score
<20% 20-40% 40-60% 60-80% >80%
HPV testing HPV testing HPV testing HPV testing HPV testing
- + - + - + - + - +
HPV vaccination + Pap Smear screening by interscreening interval
1 yr 0.32 0.28 0.15 0.19 0.21 0.20 0.24 0.23 0.29 0.30
3 yr 0.32 0.29 0.24 0.21 0.26 0.23 0.26 0.25 0.36 0.32
5 yr 0.39 0.34 0.27 0.20 0.25 0.24 0.28 0.26 0.36 0.32
Pap Smear screening by interscreening interval
1 yr 0.37 0.31 0.33 0.28 0.35 0.35 0.44 0.40 0.42 0.44
3 yr 0.45 0.35 0.35 0.33 0.40 0.33 0.46 0.46 0.51 0.45
5 yr 0.44 0.42 0.43 0.41 0.42 0.39 0.50 0.46 0.54 0.48
HPV
Vaccination
0.94 0.96 0.55 0.61 0.57 0.58 0.64 0.58 0.73 0.70
Baseline (lacking of any Intervention (baseline): RR=1.00
Simulated Cohort with 300,000 Taiwan women from birth

20. Conclusion
1) HPV vaccination in combination with triennial screening would be cost-
effective if vaccination cost can be reduced
2) Genetic and methylation markers can be used to stratify population into
a series of risk levels
3) Triennial Pap smear along can reach the efficacy of reducing cervical
cancer incidence by 55-65% for low- median- risk women
4) HPV vaccination in combination with Pap smear is required for high risk
women
20
http://www.taiwan.net.tw/m1.aspx?sNo=0001090