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


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

http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.asp

https://seer.cancer.gov/statfacts/html/cervix.html


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


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)


ICC incidence by age and race

Rositch AF, et al., Cancer 2014;


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


WhiteBlack

Percent difference: 78%


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


WhiteBlack



The black-white disparity increased 44%

after correction.

Beavis and Rositch, Cancer 2017


Results: Trends in Mortality Rates

Year APC

Uncorrected 2000-12 -2.24%

Corrected 2000-12 -3.57%


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


% o

f Can

cers

Incremental Contributions of HPV Types to cervical cancer


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


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)



Dalstein(2003)Giuliano(2002)

Bory(2002)Nobbenhuis(2001)



Trottier(2008)Trottier(2008)Insinga(2007)Winer(2005)Shew(2005)

Cuschieri(2005)Munoz(2004)Molano(2003)


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


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)





Bae(2009)Lai(2008)

Goodman(2008)Trottier(2008)Trottier(2008)



Dalstein(2003)Giuliano(2002)

Bory(2002)Nobbenhuis(2001)



Trottier(2008)Trottier(2008)Insinga(2007)Winer(2005)Shew(2005)

Cuschieri(2005)Munoz(2004)Molano(2003)


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


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


https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2

New draft screening guidelines


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


HPV DNA testing more reproducible and sensitive


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%


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


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


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.


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


THANK YOU!Feel free to contact me with questions: [email protected]

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