Epidemiology and natural history of HPV cervical cancer ... · Cervical cancer is the 4thmost...
Transcript of Epidemiology and natural history of HPV cervical cancer ... · Cervical cancer is the 4thmost...
© 2008, Johns Hopkins University. All rights reserved.
Epidemiology and natural history
of HPV cervical cancer:
New opportunities for prevention
Anne F. Rositch, PhD, MSPH
Assistant Professor
Department of Epidemiology
Johns Hopkins Bloomberg School of Public Health
Sidney Kimmel Comprehensive Cancer Center
© 2008, Johns Hopkins University. All rights reserved.
Cervical CancerCervical cancer is the 4th most common cancer in women worldwide
528,000 new cases and 266,000 deaths globally (2012)12,820 new cases and 4,210 deaths in the US (2017)
GLOBOCAN 2012: http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.aspSEER cancer report 2017: https://seer.cancer.gov/statfacts/html/cervix.html
Estimated Cervical Cancer Incidence Worldwide in 2012
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Global age-specific incidence of cervical cancer
010
2030
4050
6070
8090
100
Inci
denc
e pe
r 100
,000
wom
en
0-14 15-44 45-54 55-64 65+
Age(yrs)
Africa Continent Asia Continent Americas Continent
Europe Continent Oceania Continent
The Americas
ICO HPV Information Center; Rositch AF, et al., Cancer 2014; 120(13), 2032-2038
© 2008, Johns Hopkins University. All rights reserved.
Hysterectomy-corrected ICC incidence0
1020
3040
5060
70
Ann
ual i
ncid
ence
per
100
,000
wom
en
20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Age(yrs)
Uncorrected Corrected
40-44 65-69
Age-standardized rate Uncorrected:
11.7 per 100,000(11.5, 11.8 )Corrected:
18.6 per 100,000 (18.3, 18.9)
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ICC incidence by age and race
Rositch AF, et al., Cancer 2014;
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Age-standardized mortality rates, 2002-2012
6
3.2 5.70
2
4
6
8
10
1
Ann
ual M
orta
lity
per 1
00,0
0 w
omen
Uncorrected Corrected
WhiteBlack
Percent difference: 78%
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Age-standardized mortality rates
73.2 5.7 4.7 10.1
0
2
4
6
8
10
1
Ann
ual M
orta
lity
per 1
00,0
0 w
omen
Uncorrected Corrected
WhiteBlack
Percent difference: 78%
Percent difference: 115%
The black-white disparity increased 44%
after correction.
Beavis and Rositch, Cancer 2017
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Results: Trends in Mortality Rates
Year APC
Uncorrected 2000-12 -2.24%
Corrected 2000-12 -3.57%
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High risk HPV infection is necessary, but not sufficient for development of invasive cervical cancer
More than 100 genotypes identified which infect human epithelium, ~50 which specifically infect the anogenital tract
Approximately 14-18 are high risk (HR-HPV) or oncogenic.– HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59,
66, 68, 73, and 82
Remaining HPV types are not associated with cancer (low risk or non-oncogenic), but can cause low grade cervical abnormalities or benign proliferative warts (esp HPV 6 and 11)
HPV infections and cervical cancer
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% o
f Can
cers
Incremental Contributions of HPV Types to cervical cancer
© 2008, Johns Hopkins University. All rights reserved.
Working Model of Cervical Carcinogenesis
Normalcervix
HPV infection PersistenceHigh-grade Precancer
(HSIL/ CIN2-3)Invasion
•Immune suppression
•HIV
•renal transplant
•HLA
•viral type(?)
•viral load (?)
•viral variants (?)
•viral type
•viral load (?)
•viral variants
•parity
•smoking
•inflammation
•Hormones/OC
•sexual behavior
•partner sex history
•Innate immunity•Antibody•Cytotoxic T-cell (CTL) response
“Loss of detection”Median duration: 8-11 months
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Most HPV infections are “transient”
Rositch et al, Int J Cancer. 2013; 133(6): 1271–1285.
Follow-up time (Months)
Est
imat
ed p
erce
nt p
ersi
sten
t
0 6 12 18 24 36
025
5075
100
Andersson-Ellstrom(1996)Bory(2002)Bulkmans(2007)Clavel(2000)Clavel(2001)Cuschieri(2004)Dalstein(2003)Farzaneh(2006)Gagnon(2004)Giuliano(2002)Hildesheim(1994)Hopman(2000)Kotloff(1998)Liaw(2001)Molano(2003)Nobbenhuis(2001)Richardson(2003)
Richardson(2003)Shew(2005)Sun(1997)Sun(1997)Sun(1997)Syrjanen(2005b)Trottier (2008)Sawaya (2008)Romanowski (2009)Bulk(2007)Bae(2009)Belinson(2009)Derchain(2008)Luyten(2009)Munoz(2009)Ralston Howe(2009)lowess estimate
Figure 2B. High Risk
Median duration (months)
0 5 10 15 20 25
Lai(2008)Goodman(2008)
Trottier(2008)Insinga(2007)Winer(2005)
Munoz(2004)Richardson(2003)Woodman(2001)
Ahdieh(2000)Ho(1998)Lai(2008)
Goodman(2008)Trottier(2008)Insinga(2007)
Mao(2006)Winer(2005)
Munoz(2004)Richardson(2003)
Molano(2003)Giuliano(2002)
Fu Xi(2002)Woodman(2001)
Ho(1998)Lai(2008)
Goodman(2008)Trottier(2008)
Shew(2005)Munoz(2004)
Richardson(2003)Molano(2003)
Giuliano(2002)Woodman(2001)
Kotloff(1998)Hildesheim(1994)
Bae(2009)Lai(2008)
Goodman(2008)Trottier(2008)Trottier(2008)
Shew(2005)Munoz(2004)
Richardson(2003)Molano(2003)
Dalstein(2003)Giuliano(2002)
Bory(2002)Nobbenhuis(2001)
Kotloff(1998)Hildesheim(1994)
Lai(2008)Goodman(2008)
Trottier(2008)Trottier(2008)Insinga(2007)Winer(2005)Shew(2005)
Cuschieri(2005)Munoz(2004)Molano(2003)
Giuliano(2002)Woodman(2001)
Ahdieh(2001)Ho(1998)
Hildesheim(1994)*
*
*
***
*
*
**
*
*
*
**
**
***
*******
*
*******
†
†
†
†
†
†
Overall
High Risk
Low Risk
Type 16
Type 18
9.8
9.3
8.4
12.4
9.8
Type(s) AuthorsWeighted
Average Median
Median duration (months)
0 5 10 15 20 25
Lai(2008)Goodman(2008)
Trottier(2008)Insinga(2007)Winer(2005)
Munoz(2004)Richardson(2003)Woodman(2001)
Ahdieh(2000)Ho(1998)Lai(2008)
Goodman(2008)Trottier(2008)Insinga(2007)
Mao(2006)Winer(2005)
Munoz(2004)Richardson(2003)
Molano(2003)Giuliano(2002)
Fu Xi(2002)Woodman(2001)
Ho(1998)Lai(2008)
Goodman(2008)Trottier(2008)
Shew(2005)Munoz(2004)
Richardson(2003)Molano(2003)
Giuliano(2002)Woodman(2001)
Kotloff(1998)Hildesheim(1994)
Bae(2009)Lai(2008)
Goodman(2008)Trottier(2008)Trottier(2008)
Shew(2005)Munoz(2004)
Richardson(2003)Molano(2003)
Dalstein(2003)Giuliano(2002)
Bory(2002)Nobbenhuis(2001)
Kotloff(1998)Hildesheim(1994)
Lai(2008)Goodman(2008)
Trottier(2008)Trottier(2008)Insinga(2007)Winer(2005)Shew(2005)
Cuschieri(2005)Munoz(2004)Molano(2003)
Giuliano(2002)Woodman(2001)
Ahdieh(2001)Ho(1998)
Hildesheim(1994)*
*
*
***
*
*
**
*
*
*
**
**
***
*******
*
*******
†
†
†
†
†
†
Overall
High Risk
Low Risk
Type 16
Type 18
9.8
9.3
8.4
12.4
9.8
Type(s) AuthorsWeighted
Average Median
© 2008, Johns Hopkins University. All rights reserved.Schiffman & Castle, NEJM, 2005
Natural History of HPV and Cervical Cancer
© 2008, Johns Hopkins University. All rights reserved.
Evolving Screening Guidelines
14
• Historical: annual screening with Pap smear and cytology
• 2003: American Cancer Society Guidelines begin recommending less than annual screening depending on type of test• Conventional cytology annual, LBC every 2 years; over 30
and 3 normal results every 2-3 years
• 2009: American Congress of Obstetricians & Gynecologists Guidelines recommend every 2-3 year screening• Pap every 2 years; over 30 and 3 normal results every 3
years; Co-testing every 3 years
• 2012: Guidelines from three major professional organizations: consensus on screening no more than every 3 years• Pap every 3 years; Co-testing every 5 years
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https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2
New draft screening guidelines
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Combined
Seattle
Canada
HART
Jena
Tuebingen
Hannover
French Private
French Public
0% 10% 30% 50% 70% 90% 100%
Cytology Positivity
CIN 2+
Single cytology not very sensitive or reproducible
Cuzick et al., IJC, 2006Mayrand et al., NEJM, 2007
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HPV DNA testing more reproducible and sensitive
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Time in months since intake testing
Inci
denc
e of
CIN
3+
per 1
0,00
0
cyt-
hpv-cyt-/hpv-
0 12 24 36 48 60 72 0
10
20
30
40
50
60
70
80
90
High NPV allows safe increase in screening interval
Dillner et al., BMJ, 2008
0.95%
0.28%0.22%
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HPV genotyping
Khan M et al. JNCI 2005;97:1072.
The cumulative incidence of CIN3 or greater over a 10-year period in women ages 30 and older as a function of a single HPV result at enrollment.
© 2008, Johns Hopkins University. All rights reserved.Gravitt PE, et al. Vaccine 2008;26S
normal
HR HPV
infectionpersistence CIN 2/3/cancer
HPV DNA TESTING, PAP, or VIA
HPV genotyping (persistence)HPV E6/E7 mRNA
p16
HPV integrationMethylation profile
Proliferation markersTERC gain
**Oncoprotein expression
Ultimate goal – maintain sensitivity with substantial increase in specificity
20
Challenges—cost, clinical feasibility/translation, sample types and buffers, objective vs. subjective output
© 2008, Johns Hopkins University. All rights reserved.
© 2008, Johns Hopkins University. All rights reserved.
1st generation HPV vaccines• Gardasil®, Merck Research Laboratories (MRL)
• FDA approved June 2006• Targets HPV types 16 & 18 ~70% of cervical cancer and 6 & 11
~90% of anogenital warts
• Cervarix™, GlaxoSmithKline (GSK)• FDA approved October 2009• Targets HPV types 16 & 18 ~70% of cervical cancer• Some cross-protection for HPV-31 and HPV-45
Both are safe – no risk of infection, adverse events minor--site injection pain, fainting
Neither impact pre-existing HPV16/18 (6/11) infection• Uncertain impact in women with prior exposure (seropositive)
but not currently ‘infected’ (DNA negative)—new post-tx studies are promising
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Nonavalent vaccine- current approvalIn December, 2014 the FDA approved Gardasil 9
• Nonavalent HPV vaccine: types 6, 11, 16, 18, 31, 33, 45, 52, 58
• Estimated 90% reduction of cervical cancer and similar percentage of other HPV-associated cancers
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm426485.htmSource: Guo T et al. Cancer. 2016.
© 2008, Johns Hopkins University. All rights reserved.
2-dose vaccine recommendations
Routine and catch-up age groups
• routine HPV vaccination at age 11 or 12 years but can start at age 9 years. • females through age 26
• males through age 21 (aged 22 through 26 may be vaccinated)
Dosing schedules
• If initiating vaccination before their 15th birthday, the recommended immunization schedule is 2 doses of HPV vaccine
• Else 3 doses of HPV vaccine is recommended
*One dose trials are ongoing
© 2008, Johns Hopkins University. All rights reserved.Schiffman & Castle, NEJM, 2005
Natural History and prevention strategies
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