Personalized Prevention Strategy for Cervical Cancer

Chen-Yang Hsu

National Taipei University of Nursing and Health Sciences2017/10/21

Progression of Cervical Cancer

Regular Pap Smear Screening

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

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

Efficacy of HPV Vaccine

6

75% vaccine efficacy,75% vaccine coverage35% reduction in Cx Ca incidence

Progression of Cervical Cancer

Vaccination

HPV DNA testing

Regular Pap Smear Screening

8

Prevention Strategies for Cervical Cancer

Surveillance of precursor lesion

HPV Vaccination Pap Smear Screening

HPV DNA Testing

Cost-effectiveness Analysis for Prevention Strategies for Cervical Cancer: Pap smear, DNA testing, HPV, Vaccination

Annual Pap smear [+] Triennial Pap smear [+] Pap smear every 3 year+ HPV test [+] Pap smear every 5 year+ HPV test [+] Pap smear triennially + 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.

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

Personalized Cervical Cancer Prevention: Risk-based Strategies

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Public Health Genetics and Cervical Cancer Prevention Strategies

LaboratoryResearch

TranslationalResearch

ClinicalResearch

PopulationResearch

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

Healthy Women

CIN1, HPV-

CIN2/3, HPV-

HPVInfection

CIN1, HPV+

CIN2/3, HPV+

Invasive Carcinoma

Polymorphism Gene

CD28 rs3116496IFNG: rs2430561

Pre-miR: rs11134527LAMB3 rs2566

DAN Repairing SNPs

IFNG: rs11177074POLN rs17132382TMC: rs9893818….

DNA Methylation

CCNA1C13ORF18

SFRPDAPK

HIC-1…

Repairing SNPs

DUT: rs3784621GTF2H4: rs2894054OAS3: rs12302655SULF1: rs4737999

Risk Score

Effect Size of Genetic Markers on Cervical Cancer ProgressionMarkers RR Proportion in the general

population (%) ReferenceMarkers 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)

0.730.86

17.8 47.6

Zhou et al. 2010

LAMB3 rs2566 (TT)LAMB3 rs2566 (CT)

1.591.57

10.2 46.3

Zhou et al. 2010

CASP8 -652 6N del/delCASP8 -652 6N del/ins

0.530.75

10.3 39.8

Sun et al. 2007

DUT rs3784621 (CC)DUT rs3784621 (CT)

1.541.33

11.4 43.5

Wang et al. 2010

GTF2H4 rs2894054 (AA)GTF2H4 rs2894054 (AG)

0.110.57

2.1224.2

Wang et al. 2010

SULF1 rs4737999 (AA)SULF1 rs4737999 (AG)

0.590.59

7.7638.4

Wang et al. 2010

Markers on Persistent HPV InfectionIFNG rs11177074 (CC)IFNG rs11177074 (CT)

1.801.78

0.258.71 Wang et al. 2010

POLN rs17132382 (TT)POLN rs17132382 (CT)

2.161.35

3.8827.4

Wang et al. 2010

TMC8 rs9893818 (AA) 2.47 5.10 Wang et al. 2010

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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

Women with Positive HPVTransition 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 30Time (years)

Case ACase BCase C

Case SNP DNA MethylationA Pre-miR-218: rs11134527 (AA) C13ORF18, DAPKB LAMB3: rs2566(CT); Pre-miR-218: rs11134527 (AA) DAPK, HIC-1, RAR-betaC LAMB3: rs2566(CT)

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 30Time (years)

Case DCase ECase 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)

Risk of Cervical Cancer by Percentile for Risk Score

Percentile Life-time Risk (%) RR10 0.113 0.3220 0.216 0.4230 0.237 0.5640 0.533 0.7450 0.751 1.0060 0.767 1.3070 1.078 1.8680 1.685 3.0490 2.488 9.53

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

Conclusion1) 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

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http://www.taiwan.net.tw/m1.aspx?sNo=0001090