HPV€¦ · • HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers...
Transcript of HPV€¦ · • HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers...
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HPV
an evolving understanding of
an ancient and established virus
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Audrey P Garrett, MD, MPH
PEACEHEALTH CME DINNER SERIESFEBRUARY 12, 2015
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Disclosures‐1
• Merck– Speaker Panel for Gardasil
• Hologic– Speaker Panel for Cervista and Thin Prep
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Disclosures‐2
Parent
Gynecologic Oncologist
VaccineEnthusiast
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Objectives
• Epidemiology of HPV
• Role of HPV in oncogenesis
• Identify changes and controversies in cervical cancer screening recommendations
• Exciting future directions
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HPV
EPIDEMIOLOGY
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Could YOU have HPV?
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YES… if you have…
• a cervix
• a vagina
• a penis
• tonsils
• a throat
• an anus
• ever had sex
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HPV is Ubiquitous
• 85% have come in contact with it• The majority “clear it”• More common in smokers• More transmissible female to male• Resides in epithelial layer
– Basal layer required for replication
• Conserved in mammals– Across time and geography
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JAMA 2007, 297 (8) 813‐819
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JAMA 2007, 297 (8) 813‐819
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• Over 100 types identified2
• 30−40 anogenital2,3
– 15−20 oncogenic2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 584
• HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers worldwide5
– Nononcogenic types include: 6, 11, 40, 42, 43, 44, 544
• HPV 6 and 11 account for 90% of external genital warts3
Human Papillomavirus (HPV) Is a Cause of Cervical Cancer
1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076. 2. Schiffman M. Arch Pathol Lab Med. 2003;127:930–934.
3. Wiley DJ. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N. N Engl J Med. 2003;348:518–527.
5. Smith J, et al. Int J Cancer. 2007;121:621-632.
Nonenveloped double-stranded DNA virus1
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Smith J, et al. Int J Cancer. 2007;121:621-632.
16 alone
16 + 18
+ 35
+ 31
+ 33
+ 45
+ 52
+ 58
+ 59
54.7%
76.4%
83.7%
87.6%
91.0%
93.6%
94.2%
94.4%
94.5%
CumulativePrevalence
IncrementalPrevalence
> 75% of Squamous Cancers in the United States Are Caused by HPV 16/18
HPV
Typ
es
Proportion of Cancers Associated with HPV Types
Why Are HPV 16/18 Important?
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HPV Facts: Most common STD in the U.S.
Approximately 20 million Americans are currently infected.1
•Estimated incidence of new cases 6 million per year1
•80% sexually active adults in U.S. infected w/ at least one HPV type by age 501
•Peak prevalence during adolescence and young adulthood
– Among sexually active 15‐24 year olds:• 74% new infections occur in this age group2• ~9.2 million currently infected2
1. Centers for Disease Control & Prevention, Rockville MD: CDC National Prevention Information Network; 20092. Weinstock H, et al. Perspect Sex Reprod Health. 2004;36:6-10.
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US Cervical Cancer Statistics• Approximately 12,710 new cases/year1
• Approximately 4,290 deaths/year1
• Approximately 10 million cases of HPV infectionwithout cytologic abnormalities2
• Approximately 1 million cases CIN 12
• Approximately 300,000−700,000 cases of CIN2/3
• Direct cost of prevention and treatment of cervical cancer is $6 billion annually in the US
1. CA: A Cancer J for Clinicians 2011.2. Parkin et al. Int J Cancer. 1993;54:594-606.
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33,000 cancer cases annually
CDC Info
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HPV in Laryngeal Cancers
PLoS One 2014 Dec 29, 9(12)
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Internationally
• 530,000 cases of cervical cancer– 230,000 deaths
• 30,000 cases of anal cancer– more female than male
• oropharyngeal cancer– new area of tabulation
• >600,000 cancer cases – >300,000 deaths
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HPV
ONCOGENESIS
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HPV in Cancer: History
• 1935 Francis Peyton Rous– caused skin cancer in rabbit
• 1972 Stefania Jablonska– identified HPV 5 in skin cancer
• 1976 Harald zur Hausen– hypothesized HPV cause of cervical cancer
• 1983 HPV 16• 1984 HPV 18• 2008 Nobel Prize in Medicine
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How does HPV do it?
• interferes with the normal work of the cell– invades epithelium– evades “surveillance”– integrates into host genome
• E6– interrupts important work of p53
• E7– interrupts important work of RB
• Able to create immortal cell lines– HeLa cells: HPV 18
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HPV enters the epithelium
• trauma of intercourse– micro‐abrasions
– coexisting infections
• “dry” intercourse
• anal intercourse
• areas of metaplasia/ transition
• oropharyngeal trauma
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Papillomaviruses are absolutely species specific and tissue specific.
Stanley M A Clin. Microbiol. Rev. 2012;25:215-222
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Smith J, et al. Int J Cancer. 2007;121:621-632.
16 alone
16 + 18
+ 35
+ 31
+ 33
+ 45
+ 52
+ 58
+ 59
54.7%
76.4%
83.7%
87.6%
91.0%
93.6%
94.2%
94.4%
94.5%
CumulativePrevalence
IncrementalPrevalence
> 75% of Squamous Cancers in the United States Are Caused by HPV 16/18
HPV
Typ
es
Proportion of Cancers Associated with HPV Types
Why Are HPV 16/18 Important?
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HPV
SCREENING
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Enter the Pap Smear
• Georgios Papanikolaou (1883‐1962)• 1920s describing the normal vagina• 1928 presented his findings• 1943 published his findings• 1965 ACS recommended screening• 1999 reflex HPV testing • 2009 co‐testing HPV and cytology• 2014 HPV primary testing
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Limitations of Cytology
• Epidemiology– changing face of the disease
• Anatomy– screens ectocervix reliably but not endocervix
• Labor Intensive– limitations on cyto‐technologist work force
• Cost
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2003 ACOG Guidelines2003 ACOG Guidelines
First screen three years after first
intercourse or by age 21
ACOG News Release July 31, 2003; ACOG Practice Bulletin Number 45, August 2003.
Annual pelvic exam AND
annual cytology
30 Years 30 Years21-29 Years21-29 Years< 21 Years< 21 Years HysterectomyHysterectomy
• If for benign reasons,
discontinue screening.
• If CIN2 or CIN3, discontinue
screening after 3 consecutive
negative vaginal cytology tests.
Screen every 2 to 3 years after
testing negative on 3 consecutive annual cervical
cytology tests, or screened every 3
years after cervical cytology
and an FDA-approved HPV DNA tests for high-risk HPV
strains are both negative.
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2009 ACOG Guidelines2009 ACOG Guidelines
No routine speculum exam or cytology; STD
testing and counseling on safe sex and
contraception as needed
Annual pelvic exam AND cytologya
OR cytology plus HPV testing (if both are negative,
rescreen in 3 years)
aFrequency of screening can be decreased to 2-3 years after 3 normal test results if no history of CIN 2/3, no immuno-supression, HIV-negative, and no history of DES in utero.
bHistory of cervical cancer or DES in utero, HIV-positive, immunosuppression, or other risk factors for acquiring STDs.ACOG Practice Bulletin No. 109. Obstet Gynecol. 2009;114:1409-1420.
Annual pelvic exam AND biannual cytology
30-64 Years30-64 Years21-29 Years21-29 Years< 21 Years< 21 Years ≥ 65 Years≥ 65 Years
Annual pelvic exam AND consider
discontinuing cytology at 65 or 70 years of age if patient has had 3 or more normal test results in a
row, no abnormal test results in 10 years, and
lacks other risk factorsb
STD = Sexually transmitted disease
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USPSTF and ACS/ASCCP/ASCPUSPSTF and ACS/ASCCP/ASCP
2012 Cervical Cancer Screening Guidelines2012 Cervical Cancer Screening Guidelines
• No routine speculum exam or
cytology regardless of age
of onset of intercourse or
other risk factors.
• STD testing and counseling on safe
sex and contraception as
needed.
• Annual pelvic exam AND
screening with
• Cytology and HPV testing (“co-testing”) every 5 years (preferred)
OR
• Cytology alone every 3 years
(acceptable) is recommended.
Saslow D, Solomon D, Lawson HW et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012 Apr;137(4):516-42.
• Annual pelvic exam
AND
• Screening with cytology alone every 3 years is recommended
30-65 Years30-65 Years21-29 Years21-29 Years< 21 Years< 21 Years > 65 Years> 65 Years
• Women with three
consecutive negative
cytology tests
OR
• Two consecutive
negative co-tests within the last 10 years and with the most
recent test in the past 5 years
AND
• No history of CIN2+ within the
last 20 years
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Risk Stratification with HPV Types 16 and 18 in Women ≥ 30 Years of Age with Negative Cytology
HPV 16 positive
HPV 18 positive
Non‐HPV 16/18 positive
HPV‐negative
In women ≥ 30 years of age, 10‐year cumulative incidence of ≥ CIN 3 was 20% and 18% for HPV 16 and 18, respectively
Khan MJ, et al. J Natl Cancer Inst. 2005;87(14):1072-1079.
Follow‐up Time (Years)
Cumulative Incide
nce Ra
te of
≥CIN 3 (%
)
0
5
10
15
20
25
0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95
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Changing Epidemiology
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CONTROVERSY
• April, 2014: Cobas HPV test approved for primary HPV screening
• January, 2015 SGO and ASCCP issue statements
• Common ground: Screening, by any modality, decreases cervical cancer
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SCREENING
• Public Health mechanism
• For the asymptomatic patient
• Cost to patient and society
• Balance benefit versus harm
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Hormuzd Katki, PhD
• Equal management of equal risks
• Don’t change risk thresholds for action
• Risk is a combination of immediate risk and future risk– 1000 women with LSIL pap
• 24 (2.4%) have CIN3+ at colpo
• 29 (2.9%) have CIN3+ over next 5 years
• cumulative risk 5.3%
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What do we have at PeaceHealth?
• Thin Prep pap smear– liquid based cytology
• Cobas HPV test– HPV and genotyping
• Computer assisted cytology imaging– backed up by protocolized review
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Risk Stratification with HPV Types 16 and 18 in Women ≥ 30 Years of Age with Negative Cytology
HPV 16 positive
HPV 18 positive
Non‐HPV 16/18 positive
HPV‐negative
In women ≥ 30 years of age, 10‐year cumulative incidence of ≥ CIN 3 was 20% and 18% for HPV 16 and 18, respectively
Khan MJ, et al. J Natl Cancer Inst. 2005;87(14):1072-1079.
Follow‐up Time (Years)
Cumulative Incide
nce Ra
te of
≥CIN 3 (%
)
0
5
10
15
20
25
0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95
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Cervical Cancer Prevention:Get with the times…
“This dial phone has always worked for me…”
“My patients would never be able to understand a more modern test…”
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Papanicolau to zur Hausen
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HPV
FUTURE DIRECTIONS
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Vaccines
• Gardasil 4 (Merck) FDA approved 2006– 6,11,16,18
• Cervarix (GSK) approved 2009– 16,18
• Gardasil 9 (Merck) FDA approved 2014– 6,11,16,18,31,33,45,52,58
• Vaccines are controversial
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Vaccine Efficacy
• 99‐100% immunogenicity
• 92‐99% efficacy
• Decrease CIN3 17‐33%
• Decrease colposcopy by 10%
• Decrease treatment by 25%
• Impeccable safety record
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Vaccine Eligibility
• Gardasil 4 and Cervarix – Girls 9‐26
– Boys 9‐26
– Safety data exists for the “older woman”
• Gardasil 9– Girls 9‐26
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HPV adjunctive testing
• Primary testing– controversial
• Cotesting– here to stay
• Enhanced HPV testing– Aptima test (Hologic) tests for mRNA
• Testing intervals– 3 lifetime screening tests?
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Oropharyngeal Cancers
• 20‐40% are HPV positive
• HPV 16
• Better prognosis
• Decreased morbidity from scaled back treatment regimens
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The Future
• Vaccines prevent cervical cancer
• Therapeutic “vaccines” eliminate any remaining HPV
• Cervical cancer goes the way of small pox– ? (and measles?)
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The Future: Retirement??
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Past . Present. Future.
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Cervical Cancer Prevention:Get with the times…
“This dial phone has always worked for me…”
“My patients would never be able to understand a more modern test…”
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Learning Objectives
At the conclusion of this presentation, you will be able to:•Describe the epidemiology and disease progression of cervical cancer
•Identify women at risk for cervical abnormalities and manage them in accordance with professional guidelines
•Understand the roles of cytology testing, high-risk HPV testing, and HPV genotyping in assessing risk of cervical disease, now and in the future
HPV = Human papillomavirus
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Incidence of Cervical Cancer Epidemiology History of Screening
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US Cervical Cancer Statistics
• Approximately 12,710 new cases/year1
• Approximately 4,290 deaths/year1
• Approximately 10 million cases of HPV infectionwithout cytologic abnormalities2
• Approximately 1 million cases CIN 12
• Approximately 300,000−700,000 cases of CIN2/32
1. CA: A Cancer J for Clinicians 2011.2. Parkin et al. Int J Cancer. 1993;54:594-606.
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2006Gardasil®
HPV Vaccine
2006ThinPrep®
Receives Glandular Indication
2003ThinPrep®
Imaging System
1996ThinPrep®
Pap Test
1999Hybrid Capture® 2
HPV Test
2009Cervista® HPV HR Test and
Cervista® HPV 16/18 Genotyping Test
1941Pap Smear
1990s 2000s1940s
1999SurePath® Pap
Test
2009Cervarix®
HPV Vaccine
1. zur Hausen H. Cancer Res. 1976;36:794.
1970sResearch by Harald zur Hausen linking
HPV to cervical cancer1
Major Advances in Cervical Cancer Screening
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Screening Has Dramatically Reduced Cervical Cancer Incidence
http://www.cancer.gov/aboutnci/servingpeople/snapshots/cervical.pdf
US Cervical Cancer Incidence* US Cervical Cancer Mortality*
* Insufficient data available for time trend analysis for American Indians/Alaskan Natives. ** Incidence and mortality data not available before 1992.
WhitesHispanicsAfrican Americans**Asians/Pacific Islanders**
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• Over 100 types identified2
• 30−40 anogenital2,3
– 15−20 oncogenic2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 584
– HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers worldwide5
– Nononcogenic types include: 6, 11, 40, 42, 43, 44, 544
– HPV 6 and 11 account for 90% of external genital warts3
Human Papillomavirus (HPV) Is a Cause of Cervical Cancer
1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076. 2. Schiffman M. Arch Pathol Lab Med. 2003;127:930–934.
3. Wiley DJ. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N. N Engl J Med. 2003;348:518–527.
5. Smith J, et al. Int J Cancer. 2007;121:621-632.
Nonenveloped double-stranded DNA virus1
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HPV Facts: Most common STD in the U.S.
Approximately 20 million Americans are currently infected.1
•Estimated incidence of new cases 6 million per year1
•80% sexually active adults in U.S. infected w/ at least one HPV type by age 501
•Peak prevalence during adolescence and young adulthood
– Among sexually active 15-24 year olds:–74% new infections occur in this age group2
–~9.2 million currently infected2
1. Centers for Disease Control & Prevention, Rockville MD: CDC National Prevention Information Network; 20092. Weinstock H, et al. Perspect Sex Reprod Health. 2004;36:6-10.
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Progression from HPV infection to Cervical Cancer
CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases. 11th ed. 2009.
1-5 years
Progression to cervical cancer may take up to decades
Persistent Infection
HPV Clearance
Within 12 months
HR = High riskCIN = Cervical intraepithelial neoplasia
HR HPV InfectionHR HPV Infection
CIN 1/2CIN 1/2
CIN 2/3CIN 2/3
Cervical CancerCervical Cancer
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Conventional Cervical Cytology (Papanicolaou Smear)
Dr. George N. Papanicolaou1883-1962
• First paper published in 1941
• Screening began in the 1950s
• Responsible for a >80% reduction in the incidence of invasive cervical cancer and mortality in the United States since 19501
1 Herrero R. Monogr NCI 1996; 21:1-6
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Conventional Smear•Majority of cells discarded
•Nonrepresentative transfer of cells
•Clumping and overlapping of cells
•Obscuring material
ThinPrep Pap Test•Virtually all of sample is collected
•Randomized, representative transfer of cells
•Even distribution of cells
•Minimizes obscuring material
ThinPrep® Liquid-based Cytology: Mitigates Sampling Error and Improves Preservation
Source: Hutchinson ML, et al. Am J Clin Pathol. 1994;101:215-219.
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FDA-ApprovedLiquid-based Cytology Technologies
1. ThinPrep 2000 System, Part No. 04141-001 Rev. D.00 [package insert]. Cytyc Corporation; 20072. AutoCyte/SurePath Package Insert: SurePath Collection Product Insert, Doc. No. 779-10001-03 Rev C [package insert]. Burlington:
TriPath Imaging, Inc.; 2008 3. http://www.accessdata.fda.gov/cdrh_docs/pdf9/K091724.pdf
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PreservCyt ® Is Widely Used for Molecular Testing
The ThinPrep ® sample collection medium, PreservCyt, was used in many large-scale clinical trials:
Trial Methodology N
ARTISTIC (2009)1
Randomized trial of cytology vs cotesting over 3 years 24510
ALTS (2000)2 Monitoring of women with LSIL & ASC-US over 2 years 5060
NTCC (2010)3 Study of HPV testing in combination with LBC or alone 47369
FOCAL (2010)4 Randomized trial of HPV with cytology triage over 4 years 6150
ATHENA5 Multi-center study to assess HPV testing compared to LBC 47208
CERVISTA HPV HR6
Multi-center prospective study to evaluate performance for screening patients with ASC-US cytology results
1312
CERVISTA HPV 16/187
Multi-center prospective study to evaluate performance for screening patients with ASC-US cytology results
1312
1. Kitchener HC et al . Health Technol Assess 2009; 13:51 (ARTISTIC). 2. Solomon D, et al. J Natl Cancer Inst. 2001; 93:293-299 (ALTS).
3. Ronco et al . Lancet Oncol 2010; 11:249-257 (NTCC).4. Ogilvie et al. BMC Cancer 2010; 10:1-11 (FOCAL).
5. . Stoler H, Wright T, Sharma A, et al. Am J Clin Pathol. 2011; 135:468-475 (ATHENA).6. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).
7. Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc; 2009 (P/N 15-3101).
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ACOG Practice Bulletin 109:
Cervical Cancer Screening
No routine speculum exam or
cytology; STD testing and
counseling on safe sex and
contraception as needed
Annual pelvic exam AND cytologya
OR cytology plus HPV testing (if both are negative,
rescreen in 3 years)
aFrequency of screening can be decreased to 2-3 years after 3 normal test results if no history of CIN 2/3, no immuno-supression, HIV-negative, and no history of DES in utero.
bHistory of cervical cancer or DES in utero, HIV-positive, immunosuppression, or other risk factors for acquiring STDs.ACOG Practice Bulletin No. 109. Obstet Gynecol. 2009;114:1409-1420.
Annual pelvic exam AND biannual
cytology
30-64 Years21-29 Years< 21 Years ≥ 65 Years
Annual pelvic exam AND consider discontinuing
cytology at 65 or 70 years of age if patient has had 3
or more normal test results in a row, no
abnormal test results in
10 years, and lacks other risk factorsb
STD = Sexually transmitted disease
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Advantages of HPV Screening
• HPV testing is more sensitive than cytology • HPV testing has a high negative predictive
value • For women 30 and older, a negative Pap and
HPV test would allow for a patient to extend to a 3-year screening interval2
1. Bulkmans NWJ, Berkhof J, Rozendaal L, et al. Lancet 2007; 370:1764-72.2. J Clin Oncol May 2011 vol. 29 no. 15_suppl 1508
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HPV DNA Testing Increases Sensitivity of Screening1
Screening Method
Detection of Histologically Proven High-grade Lesion
Sensitivity %1
(95% CI)Specificity %1
(95% CI)
Conventional cytology68.1
(55.4-79.2)95.3
(94.5-96.2)
Liquid-based cytologya 87.8(80.3-93.3)
93.1(92.4-93.8)
HPV DNA testb 100(96.4-100)
85.6(84.7-86.5)
1. Clavel C, et al. Br J Cancer. 2001;89:1616-1623.
a. Liquid-based cytology performed using the ThinPrep Pap Testb. HR HPV testing performed using hc2
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FDA-Approved Indications for Use: HPV HR Screening
Indications for use:1-3
• To screen patients with ASC-US Pap results• To be used adjunctively with cervical
cytology to screen women 30 and older for the absence or presence of high-risk HPV types
1. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).2. Roche Molecular Systems, Inc. Cobas® HPV Test for In Vitro Diagnostic Use Package Insert. Branchburg, NJ, 2011.3. Digene Corporation. Digene Hybrid Capture® 2 High-Risk HPV DNA Test® Package Insert. Gaithersburg, MD, 2007.
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The ASC-US/LSIL Triage Study for Cervical Cancer (ALTS)
• Organized and funded by the National Cancer Institute
• Included more than 5000 women
• Began in November 1996 and concluded at the end of 2000
• Found that HPV testing identified 96% of the women with ASC-US who had a precancerous lesion
• The authors concluded that HPV testing is a viable and cost-effective option for the management of ASC-US
Solomon D, et al. J Natl Cancer Inst. 2001;93:293-299
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ALTS Performance by Modality
*For detection of CIN 2+ Adapted from Table 5, Solomon D, et al. J Natl Cancer Inst. 2001;93:293-299.
Management Modality* Sensitivity % Referral % PPV % NPV %
Colposcopy 100 100 11 100
HPV 96 56 20 99
Cytology ASC-US+ 85 59 17 96
Cytology LSIL+ 59 26 26 94
Cytology HSIL+ 35 8 58 92
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Management of Women With ASC-US
HPV DNA Testing*Preferred if liquid-based cytology or
co-collection availableRepeat Cytologyat 6 & 12 months
ColposcopyEndocervical sampling preferred in women with no lesions, and those with unsatisfactory colposcopy
Both Tests Negative
≥ASC(on either result)
Routine Screening
HPV Positive*(managed in same manner as
women with LSIL)
HPV Negative
Repeat Cytologyat 12 months
ASCCP. ASCCP Clinical Update. ASCCP: Hagerstown, MD; 2009.
*Test only for high-risk (oncogenic) types of HPVASC = atypical squamous cellsLSIL = low-grade squamous intraepithelial lesion
ASC-US
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Risk Stratification with HPV Types 16 and 18 in Women ≥ 30 Years of Age with Negative Cytology
HPV 16 positive
HPV 18 positive
Non‐HPV 16/18 positive
HPV‐negative
In women ≥ 30 years of age, 10‐year cumulative incidence of ≥ CIN 3 was 20% and 18% for HPV 16 and 18, respectively
Khan MJ, et al. J Natl Cancer Inst. 2005;87(14):1072-1079.
Follow‐up Time (Years)
Cumulative Incide
nce Ra
te of
≥CIN 3 (%
)
0
5
10
15
20
25
0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95
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Rationale for Co-Testing
1 out of 6 women (15%) who are HPV positive and Pap negative will develop ASC-US+ within 5 years1
1. Castle, et al. CANCER. Nov 15, 2002:95(1).
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Large Population-based Survey Demonstrates HPV Prevalence Varies with Age
NHANES, a survey of noninstitutionalized civilian women in the United States published in 2007, shows an overall HPV prevalence of 26.8%
Dunne EF, et al. JAMA. 2007;297:813-819.NHANES = National Health and Nutrition Examination SurveyData based on self-collected patient samples.
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Why HPV Test Women 30 and Older?
1. Sellors et al. CMAJ. 2000;163:503.2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
High-risk HPV types
Cancer
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In 812,598 cotests from Kaiser in Northern California:1
• Overall HPV positive rate was lower than epidemiological studies have suggested
• Concerns about excessive numbers of positive HPV tests among women ≥30 years were not validated
Carcinogenic HPV testing has proven greater reproducibility and greater sensitivity for detection of CIN
3 and cancer than cytology alone1
Cotesting Increases Sensitivity of Screening
1. Castle PE, et al. Obstet Gynecol. 2009;113:595–600.
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Co-Testing in Women 30 Years and Older
HPV (-) HPV (+)
Routine ScreeningNot before 3 years Repeat BOTH Tests
at 12 months
Manage per ASCCP Guideline
Both Negative Cytology Negative HPV (+)
Cytology Abnormal Any HPV Result
ColposcopyRoutine Screeningat 3 years
ASCCP. ASCCP Clinical Update. ASCCP: Hagerstown, MD; 2009.
Cytology Negative
*Test only for high-risk (oncogenic) types of HPV
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Smith J, et al. Int J Cancer. 2007;121:621-632.
16 alone
16 + 18
+ 35
+ 31
+ 33
+ 45
+ 52
+ 58
+ 59
54.7%
76.4%
83.7%
87.6%
91.0%
93.6%
94.2%
94.4%
94.5%
CumulativePrevalence
IncrementalPrevalence
> 75% of Squamous Cancers in the United States Are Caused by HPV 16/18
HP
V Ty
pes
Proportion of Cancers Associated with HPV Types
Why Are HPV 16/18 Important?
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HPV 16/18 Link to Cervical Adenocarcinoma
Castellsague X, et al. J Natl Cancer Inst. 2006;98:303-315.
43%
32%
8%
HPV 16 HPV 18 Multiple Types
HPV DNA was detected in 93% of patients with cervical adenocarcinoma
≈ 75%
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Risk Stratification with HPV Types 16 and 18 in Women ≥ 30 Years of Age with Negative Cytology
HPV 16 positive
HPV 18 positive
Non‐HPV 16/18 positive
HPV‐negative
In women ≥ 30 years of age, 10‐year cumulative incidence of ≥ CIN 3 was 20% and 18% for HPV 16 and 18, respectively
Khan MJ, et al. J Natl Cancer Inst. 2005;87(14):1072-1079.
Follow‐up Time (Years)
Cumulative Incide
nce Ra
te of
≥CIN 3 (%
)
0
5
10
15
20
25
0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95
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ASCCP Genotyping Algorithm
ASCCP. ASCCP Clinical Update. ASCCP: Hagerstown, MD; 2009.
Use of HPV Genotyping to Manage HPV HRa Positive Cytology Negative Women 30 Years and Older
HPV 16/18 Positive HPV 16/18 Negative
Both Negative
Cytology Negative,HPV Positive
Cytology Abnormal,Any HPV Result
Repeat BOTH Tests at 12
MonthsColposcopy
Routine Screening at 3 Years Colposcopy Manage per
ASCCP Guidelines
HR HPV Positive,Cytology Negative
a Test that detects any of the 14 HR (oncogenic) types of HPV.
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Utilization of 16/18 Genotyping Algorithm in Women 30 and Older
• The addition of 30+ co-testing and 16/18 genotyping allows selection of the patients most in need of management
• Limits colposcopy exams to those most at risk• Reduce the time to colposcopy exam by 1 year for women most at risk
Cervista® HPV HR :7% positive1
Cervista® HPV 16/18: 80% negative1
Cervista® HPV 16/18: 20% positive1
10,000 co-tested women > 30 with negative cytology
140Colposcopy
560Repeat testing in 1
year
700
Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc; 2009 (P/N 15-3100).
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What Is the Clinical Utility of HPV Genotyping?
Meijer CJ, et al. Gynecol Oncol. 2006;103:12-7.
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“My patient is not at risk
• HPV is ubiquitous virus• Risk assessment does not work
– HIV– Hep B– HPV vaccination
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“My patient is not at risk”
• Wife of Korean WHO Chief• 4J school teachers• Librarians, nurses• The girl next door• Anesthesiologists• Social workers
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Product Overview
• Cervista ® HPV HR is an FDA-approved test that screens for the presence of 14 high-risk HPV types
• 100% detection of CIN3+1,2 and 99.1% NPV for CIN2+
• First FDA-approved HPV screening test with an internal control
• Reduces patient callbacks– Limits QNS (only 2-ml sample volume required)– <1% indeterminate rate– No equivocal zone for interpretation
• Minimizes the risk of unnecessary colposcopies due to cross-reactivity with common low-risk HPV types
1. 100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%).2. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).
QNS=Quantity Not Sufficient
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Invader® Chemistry
• Structure-specific recognition and cleavage with Cleavase® enzyme
• Signal amplification
• Isothermal reactions
• Fluorescence detection
ProbeRepeating Process
Amplifies SignalCleavase®
Enzyme
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Cervista® HPV HR: The Benefits of an Internal Control
• Cervista HPV measures human histone 2 gene (HIST2H2BE) for each reaction
• An internal control is needed for several purposes:– Assess cellular adequacy– Detect interfering substances– Serve as a processing control
Johnson LR, et al. Am J Clin Pathol. 2008;130:401-408.
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Reduced Patient Callbacks and Retesting: Cervista® HPV HR Compared with hc2®
• Low sample volume requirement (2 mL) increases likelihood of sample availability for further testing
• Provides clear results without an equivocal (gray) zone
• Low overall indeterminate rate (0.57%) reduces need for patient callbacks
1. Einstein MH, et al. Gynecol Oncol. 2010. doi: 10.1016/j.ygyno.2010.04.013.2. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).
3. Solomon D, et al. J Natl Cancer Inst. 2001;93(4):293-299.
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Cervista® Clinical Performance Summary ASC-US Cytology
Central Histology Result Cervista® HPV HR Test
≥ CIN 2
Sensitivity (95% CI) 92.8% (84.1-96.9)
Specificity (95% CI) 44.2% (41.5-46.9)
NPV (95% CI) 99.1% (98.1-99.6)
PPV (95% CI) 8.3% (7.6-8.9)
≥ CIN 3
Sensitivity (95% CI) 100% (85.1-100)
Specificity (95% CI) 43% (40.3-45.7)
NPV (95% CI) 100% (99.4-100)
PPV (95% CI) 2.9% (2.4-3.0)
Source: Table 2 in Einstein MH et al, Gynecologic Oncology, 2010
5% rate of CIN2+
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ACOG Practice Bulletin 99:CIN3 is the Most Significant Clinical Target
• Although not all CIN3 lesions will progress to cancer, it is generally considered to be a cancer precursor– CIN3 prevalence peaks between ages 25 years
and 30 years– Progression to cancer usually takes at least a
decade or longer
• The significance of CIN2 is less clear– The risk of progression to CIN3 or cancer appears greater
for women with CIN2 than for women with CIN1– However, up to 40% of women with CIN2 will have
regression of their lesions without therapy
ACOG Practice Bulletin No. 99. Obstet Gynecol. 2008;112(6):1419-1444.CIN = Cervical Intraepithelial Neoplasia
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CIN3+ Sensitivity and Negative Predictive Value of FDA-Approved HR HPV Tests
Test Sensitivity for CIN3+ NPV
Cervista® HPV HR 100% (85.1%-100%)1,4
100% (99.4%-100%)1,3
Roche cobas® 93.5% (82.5%-97.8%)5
99.7% (99.2%-99.9%)5
hc2 (ALTS trial)* 96%2 95%2
1. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).2. Solomon D, Schiffman M, Tarone R, et al. J Natl Cancer Inst. 2001 Feb 21;93(4):293-9.
3. 100% ≥ CIN3 NPV in ASC-US: 95% CI (99.4% - 100%). 4. 100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%)
5. Stoler H, Wright T, Sharma A, et al. Am J Clin Pathol. 2011 135:468-475.*Data are percentages and involve 95% confidence intervals.
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Technology
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FDA-Approved HPV Tests
Cervista® HPV1 Hybrid Capture 2®2 cobas® 4800 HPV3
Approval 2009 1999 2011
Indications for use • ASC-US reflex • ≥ 30 adjunct testing
• ASC-US reflex • ≥ 30 adjunct testing
• ASC-US reflex • ≥ 30 adjunct testing
Approved specimen types
PreservCyt® Solution •PreservCyt® Solution•Sample Transfer Medium
PreservCyt® Solution
HPV types detected 14 high-risk types 13 high-risk types 14 high-risk types
Genotyping (IVD) 16/18 genotyping None (ASR only) 16/18 genotyping
Technology Signal amplification utilizing Invader®
Chemistry
In vitro nucleic acid hybridization assay with signal amplification and chemiluminescence
Multi-channel real-time PCR
1. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).2. Digene Corporation. Digene Hybrid Capture® 2 High-Risk HPV DNA Test® Package Insert. Gaithersburg, MD, 2007.3. Roche Molecular Systems, Inc. Cobas® HPV Test for In Vitro Diagnostic Use Package Insert. Branchburg, NJ, 2011.
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SHENCCAST II Study Overview
• First independent clinical study evaluating performance of Cervista® HPV HR and hc2® in the same patient population
• 8435 patients in final analysis– 3 sites in rural Guangdong Province as well as “inner-city” Shenzhen– 25-59 years of age, mean 38.8
• Physician obtains a direct cervical sample:– Cytology – Computer-assisted detection using the I2 Imager– hc2® assay– Cervista HPV assay– MALDI-TOF assay
• Patients positive for high-risk HPV and/or cytology ≥ ASC-US were recalled, underwent colposcopy and biopsy
Belinson JL. Am J Clin Pathol. 2011 May;135(5):790-5.
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Does Cervical Screening Remain the Standard of Care in a Post-Vaccine World?
Yes!
Vaccine does not protect against every HPV type.It only covers 4 types—6,11, (low risk) 16,18 (high risk)
Vaccination will prevent most future pre-invasive disease and cancer, but does not treat active pre-invasive disease
Routine screening continues to be recommended by societies such as ASCCP, ACOG, SGO, American Family Practice Association
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What Is the future of cervical cancer screening?
• Cytology primary with: – HPV DNA co-test or triage?– Other biomarker triage (p16, Ki67, etc)?
• HPV primary with: – Cytology triage?– HPV genotyping triage?– Other biomarker triage? – Re-test at specified interval?
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Conclusions
• The incidence and prevalence of cervical cancer has dramatically declined as a result of screening --although more than 4000 women in the United States will die from it each year.
• Today, advances in screening technologies have enabled clinicians to effectively and efficiently identify women at greatest risk for developing cervical cancer.
• Guidelines, including ACOG and ASCCP, have incorporated the use of cytology, HPV testing, and HPV genotyping to identify and treat those women most likely to develop cervical cancer.
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Questions?
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The Importance of FDA Approvals
Why should I use an FDA‐approved test?•Increased lab and healthcare provider confidence•Established technology supported by data•Adherence to professional guidelines
A Premarket Approval submission must provide valid scientificevidence collected from human clinical trials showing that the device is safe and effective for its intended use. Products that
receive Premarket Approval are “FDA approved.”1
Nygaard I. Obstet Gynecol. 2008;111(1):4-6.
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CDC STD Testing Recommendations
CDC recommends testing at least 80% of women aged 15‐25 years for chlamydia
CDC Fact Sheet: Human Papillomavirus. April 2008.CDC Fact Sheet: Chlamydia. December 2007. CDC Fact Sheet: Gonorrhea. December 2007.
CDC = Centers for Disease ControlSTD = sexually transmitted disease
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Two‐period, retrospective analysis of ≈ 2 million specimens showed with the ThinPrep Pap Test:•Improvement was statistically significanta
•Significant decrease in false-negative proportion
•233% improvement in the HSIL detection in high-risk cases
•Decrease in ASC-US to SIL ratio
Large, Retrospective Study Confirms Superiority of ThinPrep® Pap Test
aAfter authors’ correcting for selection bias.ASC-US = Abnormal squamous cells of undetermined significanceSIL = Squamous intraepithelial lesionsHSIL = High-grade squamous intraepithelial lesions
HSIL Detection–Period 2
233% Increase in Detection
SIL Detection–Period 1
162%Increase in Detection
Limaye A, et al. Arch Pathol La Med. 2003;127:200-204.
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In Routine Use, ThinPrep® Pap TestConsistently Increases HSIL Detection
Published Peer‐reviewed Literature Direct‐to‐Vial
TPPT = ThinPrep Pap TestCP = Conventional Pap aBased on odds ratio
Author, Date Journal% Increase
from CP Smear# of TPPT Samples
Bolick et al, 1998 Acta Cytol 173% 10,694
Papillo et al, 1998 Acta Cytol 55% 8,574
Diaz-Rosario et al, 1999
Arch Pathol Lab Med 103% 56,339
Guidos et al, 1999 Diagn Cytopathol 233% 9,583
Yeoh et al, 1999 Hong Kong Med J 28% 16,541
Ferris et al, 2000 J Fam Pract 119% 992
Weintraub et al, 2000
Diagn Cytopathol 244%a 39,455
Limaye et al, 2003 Arch Pathol Lab Med 233% 166,619
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Improved HSIL Detection with ThinPrep® Pap Test
HSIL DetectionMedian Laboratory
Reporting Ratep Value
Conventional 0.3
p = 0.05ThinPrep Pap Test 0.6
SurePath 0.3
Eversole GM, et al. Arch Pathol Lab Med. 2010; 134:331-335.
A recently published survey of 679 laboratories by the College of American Pathologists found a statistically significant
increase in HSIL detection with ThinPrep Pap Test
An increase in HSIL detection of this magnitude yields an additional 3 HSIL cases per 1,000 patients
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Meta-analyses of SIL Detection
Improved Detection with ThinPrep® Pap Test vs. Conventional Smear
AnalysisEvaluation of All Available
LiteratureQuantitative Analysis of 24 Published Studies
Meta-analysis of 25 Published Studies
Scope 37,449 TP samples 35,172 patients 221,864 TP samples
Conclusions
ThinPrep has greater sensitivity for ASC-US, LSIL, and HSIL compared with conventional Pap and similar specificity
ThinPrep is superior to conventional Pap for evaluating LSIL and HSIL, and is more sensitive and more specific
ThinPrep led to improved sample adequacy and improved diagnosis if LSIL and HSIL
SourceKlinkhamer P, et al. Cancer Cytopath. 2003;99:263-271.
Abulafia O, et al. Gynecol Oncol. 2003;90:137-144.
Bernstein S, et al. Am J Obstet Gynecol. 2001;185:308-317.
TP = ThinPrep
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Detecting Glandular Abnormalities
Combined adenocarcinoma = Cervical and endometrial adenocarcinomaAGUS = Atypical glandular cells of undetermined significance
p < 0.001
p < 0.001p < 0.002
Study Findings:• Increased sensitivity for all adenocarcinoma• Reduced false‐negative rate by 52%• Reduced AGUS
Schorge JO, et al. Cancer Cytopathol. 2002;96(6):338-343.
ThinPrep® Pap Test vs. Conventional Smear
Per
cent
(%)
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Prevalence of HR HPV in Cervical Cancer Specimens
• Analysis of 932 specimens from women in 22 countries indicated 99.7% prevalence of HPV DNA in cervical cancers1
• Meta-analysis of worldwide publications has documented HR HPV DNA in 87.3% of 14,595 invasive cervical cancers and 84.9% of 7,094 high-grade cervical lesions2
Walboomers JM, et al. J Pathol. 1999;189:12-19. Clifford GM, et al. Br J Cancer. 2003;88:63-73.
Persistent HR HPV infection is a necessary precursor for the vast majority of cervical cancers
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Prevalence• Age
• Race
• Sexual history
• Geography
• Screening sensitivity (clinic type)
• History of abnormal cytology
Specificity• Age (higher specificity is
found in women ≥ 30 years of age)
• Presence of disease (≥ CIN 2) in the tested population
• Cross-reactivity to untargeted HPV
Population Heterogeneity Influences HPV Prevalence
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Emerging Data Demonstrate Prevalence Within Expected Range for Cervista® HPV HR
Study NILM ASC-US
Chehak, et al.CVS. 2010.7
12.8% (2,039/15,878)
47.5%(837/1,763)
Recently presented data support the prevalence found with Cervista HPV HR in NILM and ASC‐US populations and are in
line with previously published literature1‐6
1. Sherman M, et al. J Natl Cancer Inst. 2003;93(1):46-52.2. Schiffman M, et al. JAMA. 2000;283(1):87-93.
3. Wright T, et al. JAMA. 2000;283(1)81-86.4. Belinson J, et al. Gynecol Oncol. 2001;83:439-444.
5. Bory JP. Int J Cancer. 2002;102:519-525.6. Petry KU, et al. Br J Cancer. 2003;88:1570-1577.
7. Chehak L, et al. CVS. 2010.
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Clinical Performance Summary forCervista® HPV HR
Einstein MH, et al. Gynecol Oncol.2010. doi: 10.1016/j.ygyno.2010.04.013.
Trial Endpoint ≥ CIN 2 95% CI ≥ CIN 3 95% CI
Sensitivity92.8%(64/69)
84.1-96.9100%
(22/22)85.1-100.0
Specificity44.2%
(558/1,263)41.5-46.9
43% (563/1,310)
40.3-45.7
NPV99.1%
(558/563)98.1-99.6
100% (563/563)
99.4-100.0
PPV = Positive predictive value NPV = Negative predictive value
Compared with Colposcopy/Central Histology Results
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Phylogenetic Tree Basis of Cervista® HPV HR Test Design
Los Alamos National Laboratory. Human papillomaviruses: a compilation and analysis of nucleic acid and amino acid sequences. 1997. Available at: http://hpv-web.lanl.gov/.
HPV Group HPV Types
A5/A6 51, 56, 66
A718, 39, 45, 59,
68
A916, 31, 33, 35,
52, 58
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Analytical Performance of Cervista®
HPV HR• Analytical sensitivity
– ≤ 5,000 copies per reaction
• Analytical specificity– No cross-reactivity to low-risk HPV types (1a, 6, 11, 42, 43, 44, 53) detected when
tested up to 1 x 107 copies/reaction– No cross-reactivity to 17 organisms that may be present in the cervical specimen
• Reproducibility– 16 samples were subjected to 15 measurements: 3 sites × 5 days × 1 run/day
– 208/210 (99%) for positive expected results – 30/30 (100%) for negative expected results
• Precision – At 5,000 copies/reaction, the plasmid DNA samples yielded 97.2% (1,143/1,176) of
expected positive results
• Interfering substance testing– No interference by substances that could be present in the sample with the
exception of high levels of antifungal cream and contraceptive jelly
Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).
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Invader® HPV Reagents Show High Analytical Concordance
Analyte Specific Reagent (ASR). Analytical and performance characteristics are not established.Data based on independent assessments using laboratory-developed tests with ASRs. Analytical and performance characteristics are not established.aAn additional discordant sample (Invader-negative, HC2-positive) was positive for HPV 53 by PCR. While considered “probably high-risk” by IARC, it is not recommended for inclusion in HR assays.bSamples tested with both Invader and HC2 methods; 5,788 samples were part of the study.
Study Citation SamplesConcordant
SamplesDiscordant Samples
Discordance Resolution in
Agreement with Invader®
Discordance Resolution in
Agreement with HC2®
Resolution Method
North Shore-Long Island Jewish Health System Laboratories1
821 TP673/821 (81.97%)
148/821(18%)
60/84(71%)
24/84(29%)
PCR
Cedars-Sinai Medical Center2 133 SP
115/133 (86.6%)
12/133(9%)
8/12(67%)
4/12(33%)
Roche HPV Linear Array
CompuNet Clinical Laboratories3 87 TP
71/87 (81.6%)
16/87(18%)
11/11(100%)
0/11a
(0%)PCR
Regional Medical Laboratory4 207 SPb 188/207
(90.8%)19/207
(9%)12/18(67%)
6/18(33%)
PCR
1. Ginocchio CC, et al. J Clin Microbiol. 2008;46(5):1641-1646.2. Wong AK, et al. J Clin Microbiol. 2008;46(3):869-875.
3. Schutzbank TE, et al. J Clin Microbiol. 2007;45(12):4067-4069. 4. Johnson LR, et al. Am J Clin Pathol. 2008;130:401-408.
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Prim
ary Re
action
Second
ary Re
action
(Sim
ultane
ous)
Signal amplification is typically ≈ 107
per molecule of target sequence
Summary of the Invader® Chemistry Reactions
Cervista® HPV Core Technology
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Invader Chemistry Biplex Reaction
F2
C
G
A
A
C
C
Invader®Oligo
Probe Probe
FRET Cassette 1 FRET Cassette 2
Released 5´ Flap
Cleavage Site
Human DNA‐specific Target HPV‐specific Targets
Cleavage Site
Invader®Oligo
Released 5´ Flap
CleavageSite
CleavageSite
A
T
F1 Q F2 Q
F1
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ThinPrep® Pap Test Provides Specificity to the Co-testing Model
Belinson J, et al. Gynecol Oncol. 2001;83:439-444.Clavel C, et al. Br J Cancer. 2001;84(12):1616-1623.
NPV PPV
Belinson et al1
ThinPrep Pap Test cytology for ≥ HSIL 99.0% 61.0%
HPV direct test for ≥ HSIL 99.8% 23.0%
Clavel et al2
ThinPrep Pap Test cytology for HSIL in women > 30
99.8% 15.1%
HR HPV for HSIL in women > 30 100.0% 8.7%
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ASCCP. ASCCP Clinical Update. ASCCP: Hagerstown, MD; 2009.
Use of HPV Genotyping to Manage HPV HRa‐Positive, Cytology‐Negative Women 30 Years and Older
HPV 16/18 Positive HPV 16/18 Negative
Both NegativeCytology Negative,
HPV-PositiveCytology Abnormal,
Any HPV Result
HR HPV Positive,Cytology Negative
Repeat BOTH tests at 12 months
Colposcopy
Routine Screening at 3 Years
ColposcopyManage per ASCCP
Guidelines
ASCCP = American Society for Colposcopy and Cervical PathologyaTest that detects any of the 14 HR (oncogenic) types of HPV.
ASCCP Algorithm for HPV GenotypingFor Resolution of Discordant Results in Reflex Testing Women ≥ 30 Years
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Cost-effectiveness and Clinical Utility of HPV Testing
• For women with ASC-US:– Triage based on a positive HR HPV test detected
more ≥ CIN 3 cases and was less costly than immediate colposcopy or conservative management1
– HPV testing was highly sensitive for detecting ≥ CIN 3 with dramatically fewer referrals for older women2
Kulasingam SL, et al. J Natl Cancer Inst. 2006;98(2):92-100.Sherman ME, et al. J Natl Cancer Inst. 2002;94(2):102-107.
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Risk of ≥ CIN 2 with Different Cervista® HPV 16/18 Genotyping Outcomes
Among Women with Positive Cervista®
HPV HR and ASC‐US Cytology
Cervista HPV 16/18 Result Risk of ≥ CIN 2 95% CI
HPV 16 and/or 18 Positive17.1%
(44/257)13.0%-22.2%
HPV 16 and 18 Negative4.0%
(20/500)2.6%-6.1%
Prevalence of CIN 2 or greater: 5.3%Einstein MH, et al. Gynecol Oncol. 2010. doi: 10.1016/j.ygyno.2010.04.013.
Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc; 2009 (P/N 15-3101).
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Risk of ≥ CIN3 with Different Cervista® HPV 16/18 Outcomes
Einstein MH, et al. Gynecol Oncol. 2010. doi: 10.1016/j.ygyno.2010.04.013.Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).Prevalence of CIN 3 or greater: 1.7%
Among Women with Positive Cervista®
HPV HR and ASC‐US Cytology
Cervista HPV 16/18 Result Risk of ≥ CIN 3 95% CI
HPV 16 and/or 18 Positive6.6%
(17/257)4.2%-10.3%
HPV 16 and 18 Negative1.0%
(5/500)0.4%-2.3%
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Clinical Performance Summary of the Cervista® HPV 16/18 Genotyping Test
Trial Endpoint ≥ CIN 2 95% CI ≥ CIN 3 95% CI
Sensitivity68.8%
(44/64)56.6-78.8
77.3%(17/22)
56.6-89.9
Specificity69.3%
(480/693)65.7-72.6
67.3%(495/735)
63.9-70.6
NPV 96.0%93.9-97.4
99.0% 97.7-99.6
Compared with Colposcopy/Central Histology Results
Einstein MH, et al. Gynecol Oncol.2010. doi: 10.1016/j.ygyno.2010.04.013.
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Cervista® HPV 16/18 Test Design
• Cervista HPV 16/18 Genotyping Test individually identifies and differentiates HR types 16 and 18 – Identifies the 2 most highly oncogenic and
persistent HR HPV types known to cause high-grade cervical neoplasia
– Uses the same technology as Cervista HPV HR, and the test may be run from the same 2-mL specimen
Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).
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Cervista® HPV 16/18 Test Indications
Indications for usea:
• In women ≥ 30 years the Cervista HPV 16/18 test can be used adjunctively with the Cervista HPV HR test in combination with cervical cytology to assess the presence or absence of HR HPV types 16/18.
• To be used adjunctively with the Cervista HPV HR test in patients with ASC-US cervical cytology results to assess the presence or absence of HR HPV types 16/18. The results of this test are not intended to prevent women from proceeding to colposcopy.
aCervista HPV 16/18 Genotyping Test results should not be used as the sole basis for clinical assessment and treatment of patients. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).
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Society Statements on HPV Genotyping
SGO– “HPV typing for the most common types of the disease –
HPV 16 and HPV 18 is also now available for clinical use. SGO believes that HPV testing and typing should be viewed as important, additional diagnostic and screening tools.”
– SGO did note the following caveats:• These tests should not replace other cervical cancer screening
methods, including regular Pap tests and gynecologic examinations• HPV testing and HPV typing should not be used as a prescreening tool
for HPV vaccinationACOG
– DNA tests specific for HPV 16 and HPV 18 can be used as an adjunct in women with negative Pap test results, but who have tested positive for HR HPV by an assay testing for 13 or 14 HR types
SGO. Statement Regarding the Role of HPV Testing and HPV Typing inCervical Cancer Prevention and Detection. March 2009.
ACOG Committee Opinion No. 431. Obstet Gynecol. 2009;113(5):1190-1193.
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Analytical Performance of Cervista® HPV 16/18 Genotyping
• Analytical Sensitivity– Approximately 1,250 copies per reaction
• Analytical Specificity– No cross-reactivity to low-risk HPV types (1, 6, 11, 42, 43, 44, 53) detected when
tested up to 1 x 107 copies/rxn– No cross-reactivity to HPV types 35, 39, 45, 51, 52, 58, 59, 66, 67, 68, 70 detected
when tested up to 1 x 107 copies/rxn– No cross-reactivity to HPV type 31 detected when tested up to 1 x 106 copies/rxn – No cross-reactivity to 17 organisms that may be present in the cervical specimen
• Reproducibility– 16 samples were subjected to 15 measurements: 3 sites × 5 days × 1 run/day– 100% agreement for positive and negative expected results
• Accuracy – 94.1% (177/188) positive agreement (95% CI: 89.8%-96.7%)– 85.7% (460/537) negative agreement (95% CI: 89.8%-96.7%)
• Interfering Substance Testing– No interference by substances that could be present in the sample with the
exception of high levels of antifungal cream and contraceptive jelly
Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3101).MISC-00510-001 Rev 003
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Adenocarcinoma Increasing, Invasive Squamous Cell Decreasing
Per 10
0,00
0 Wom
en
Invasive Squamous Cell Carcinoma
InvasiveAdenocarcinoma
Adapted from Wang SS, et al. Cancer. 2004;100(5):1035-1044.
Years
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Historical SEER Trends in North American Incidence of Cervical Adenocarcinoma
Black, USAWhite, USACanadaHispanic
Year of Birth
Cumulative Ra
te per
1,00
0 Wom
en
0
0.05
0.10
0.15
0.20
0.25
0.30
1930 1940 1950 1960
SEER = Surveillance, Epidemiology, and End Results Vizcaino AP, et al. Int J Cancer. 1998;75:536-545.
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Independent Validation of Clinical Benefits of ThinPrep® Imaging System
• A study of TIS published in 2008 compared 54,565 manually screened ThinPrep® Pap Tests with 55,547 imaged ThinPrep Pap Tests – LSIL detection increased 29% (p < 0.001)– HSIL detection increased 24% (p = 0.051)– Biopsy confirmation rate increased from 75.0% to 86.1%
(p < 0.05)– Increased positive predictive value of HSIL diagnosis (p < 0.05)
Results of surgical correlation and HPV testing validated an increase in detection rates of
ASC-H, LSIL, and HSIL, as well as increased PPV of HSIL with the ThinPrep Imaging System.
Papillo JL, et al. Diagn Cytopathol. 2008;36(3):155-160.ASC-H = Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion
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• Abnormal cells commonly have large dark nuclei because of increased amount of DNA
• To the human eye, the ThinPrep® Stain looks like a routine Pap stain
• The ThinPrep® Stain allows the Image Processor to measure DNA content
The Imaging System Identifies Areas of Interest for the Cytotechnologist
Normal
Abnormal
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ThinPrep® Imaging System Detects Glandular Lesions
• Prospective clinical study of 70 cases with AGC1: – TIS correctly identified 68 cases (97%) containing AGC in specimens
containing malignant glandular cells– Both cases not identified were “found to contain only rare
diagnostic tumor cells in the specimen”
• Retrospective analysis of 662 AGC cases with tissue follow-up2:– Verification bias-adjusted Pap screening sensitivity for “significant
neoplastic cervical disease” utilizing TIS was 93% – 86% of AGC-detected carcinomas were endometrial or ovarian in
origin
AGC = Atypical glandular cells1. Friedlander M, et al. Cancer. 2008;114:7-12.
2. Zhao C, et al. Gynecol Oncol. 2009;114(3):383-389.
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1st Review• Imager scans every
cell and cell cluster on the slide, measuring DNA content
2nd Review• Cytotechnologist reviews 22 fields containing “objects of interest”– Full slide screened if any
cells judged abnormal
Clinical benefits over manually reviewed ThinPrep® Pap Test1:
•Increased sensitivity
•Increased specificity
•Reduced false‐negative fraction
ThinPrep® Imaging System with Dual Review™
Review Scope
Image Processor
1. ThinPrep Imaging System Operation Summary and Clinical Information. Cytyc Corporation; 2003.
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Independent Study Demonstrates Improved Detection with ThinPrep® Imaging System
In a split-sample study of 55,164 women, ThinPrep Imaging System resulted in:
•Fewer unsatisfactory slides (1.8% with TIS vs. 3.1% with conventional cytology; p < 0.001)
•More slides classified as abnormal – Overall: 7.4% abnormal with TIS vs. 6.0% for conventional cytology– For ≥ CIN 1, 2.8% abnormal with TIS vs. 2.2% with conventional
cytology
•Significantly increased detection of histologic high-grade disease compared with conventional cytology
Davey E, et al. BMJ. 2007;335(7609):31.TIS = ThinPrep Imaging System
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Imaging System Focuses Slide Review
120 Fields of View 22 Fields of View
1. ThinPrep Imaging System Operation Summary and Clinical Information. Cytyc Corporation; 2003.
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•TIS more sensitive than manual screening for:–ASC‐US–Higher‐grade lesions with equivalent specificity for ASC‐US
– LSIL•Glandular malignancies not included in original studies, but data now support
ThinPrep® Imaging System Is Statistically More Sensitive Than Manual Screening
1. ThinPrep Imaging System Operation Summary and Clinical Information. Cytyc Corporation; 2003.
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Cells Are Collected in Liquid for Laboratory Processing
Sample collected
• Representative sample
• Even distribution of cells
• Minimal obscuring material
Dispersion/Collection/Transfer
LaboratoryHealthcare Provider Office
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Liquid-based Pap Technologies Have Substantially Different FDA Claims
ThinPrep® SurePath®
Year of Original FDA Approval 1996 1999
Replacement for Conventional Pap
Improved Specimen Quality
Improved HSIL Detection
Significantly More Effective Than Conventional Pap
Improved Glandular Disease Detection
Approved for Adjunctive HPV Testing (2 tests)
Approved for Adjunctive CT/NG Testing (3 tests) (1 test)
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Cervista® HPV HR hc2®
Year of FDA Approval 2009 1999
Internal Control Yes1 No
HPV Types Detected14 High-Risk Types(genotypes covered by hc2
plus HPV 66)13 High-Risk Types
Sample Size Requirement 2 mL1 4 mL
Cross-Reactivity With Common Low-Risk Types
None1 Yes3,4
IVD Genotyping Test Yes; same 2mL sample1 No (ASR only)
CIN3 Sensitivity 100% (CI: 85.1%-100%) 1,5 96.3% (CI: 91.6%-98.8%)2
Cervista® HPV HR Compared with hc2®
1. Consult package insert (http://www.cervistahpv.com/laboratory/cervistahpvhr/index.html) for full clinical details. 2. Solomon D, Schiffman M, Tarone R, et al. J Natl Cancer Inst. 2001 Feb 21;93(4):293-9.
3. Castle PE, Solomon D, Wheeler CM, et al. J Clin Microbiol. 2008 Aug;46(8):2595-604. 4. Poljak M, Marin IJ, Seme K, Vince A. J Clin Virol. 2002 Dec;25:S89-97.
5. 100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%)MISC-00977-001 Rev 001
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Cervista® HPV FDA Clinical Trial Results Compared with ALTS Data
Data are percentages and involve 95% confidence intervals.Consult package insert (http://www.cervistahpv.com/laboratory/cervistahpvhr/index.html) for full clinical details.
Solomon D, Schiffman M, Tarone R, et al. J Natl Cancer Inst. 2001 Feb 21;93(4):293-9. 100% ≥ CIN3 NPV in ASC-US: 95% CI (99.4% - 100%).
100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%)
≥CIN2 Detection
≥CIN3 Detection
≥CIN2 NPV
< 60% Colposcopy Referral Rate
Trial End‐PointCervista® HPVClinical Trial 1
93% (84.1‐96.9)
100%1,4 (85.1‐100.0)
99.1% (98.1‐99.6)
57% (All subjects)44% (Women >30)
hc2® ALTS Trial2
96%
96%
98.9%
57%
≥CIN3 NPV 100%1,3 (99.4‐100) 99.5%
MISC-00977-001 Rev 001