Cancers Linked to HPV Presenter: Chuck Lynch 2014 Iowa Cancer Summit Cancers Linked to HPV Presenter: Chuck Lynch

During this presentation I will mention Gardasil and Cervarix, the two HPV vaccines currently approved by the FDA; I have no commercially vested interest in either of vaccines

Overview Human papillomavirus (HPV) Cancer sites associated with HPV Cervical cancer and HPV Head and neck cancer and HPV Prevention and control

Human Papillomaviruses (HPV) ds DNA viruses- Papillomaviridae family >130 known HPV genotypes > 40 genital HPV genotypes 15 HPV genotypes associated with high cancer risk (high-risk HPV genotypes) HPV-16 most common

HPV Infection One of the most common sexually transmitted infections worldwide 1 Estimated 14 million newly infected annually in U.S. 2 Most people who become infected do not know they have it 1 About 79 million persons in U.S. are infected 2 HPV cleared from body in 90% of infected people within two years – no health-related problems 1 Remaining 10% have persistent infection 1 Within 30 years, about half develop cancer 1Zandberg DP et al. Ca Cancer J Clin 2013. 2http://www.immunize.org/letter/recommend_hpv_vaccination.pdf)

Human Papillomavirus (HPV) HPV-related cancers are defined as cancers at specific anatomic sites with specific cellular types in which HPV DNA is frequently found and include the back of the oral cavity and tonsils, anus, penis, cervix, vagina, and vulva Necessary, but not sufficient, cause of these cancers HPV-16 infection is the single most common high-risk type in most regions of the world, including Iowa Estimated 70% of cervical cancers caused by types 16 and 18 In Iowa between 2006 and 2011, there were 2100 cancers diagnosed at HPV-related sites; 75% of these were likely caused by HPV infection. Use slide text

Schiffman M et al. Lancet, 2007. HPV Biology Schiffman M et al. Lancet, 2007.

HPV-Attributable Cancer Cases per Year, U. S HPV-Attributable Cancer Cases per Year, U.S., 2006-2010 CDC HPV Study Site Definitions Annually, about 33,000 new cases of cancer are found in parts of the body where human papillomavirus (HPV) is often found. HPV causes about 26,700 (81%) of these cancers HPV-related 91% 72% 63% 91% 72% 91% 75% 69% http://www.cdc.gov/cancer/hpv/statistics/cases.htm

Age and Year of Diagnosis Age-adjusted incidence rates (number of cases) of HPV-related cancers@ among females, year and age of diagnoses, Iowa (Rates are per 100,000 and age-adjusted to the 2000 U.S. standard population) Age and Year of Diagnosis Cervix Vagina Vulva Anus Oropharynx** <60 1988-93 9.3 (593) 0.1 (7) 0.8 (48) 0.3 (16) 0.5 (32) 2006-11 6.4+ (448) 0.2 (13) 1.5+ (117) 1.3+ (105) 0.7 (59) 60+ 15.0 (289) 1.9 (39) 7.9 (159) 3.4 (66) 4.3 (82) 7.8+ (154) 1.5 (31) 8.1 (176) 5.2 (105) 4.4 (88) Probably caused by HPVŧ 91% 75%  69% 91%^ 72%^ @ Cases are invasive, microscopically-confirmed, squamous cell carcinomas except for cervical cancer where adenocarcinomas are also included. **Oropharynx subsites include base of tongue, tonsil, lingual and palatine tonsils, oropharynx, pharynx, and Waldeyer ring. +Rate is significantly different (p < 0.05) from corresponding 1988-93 rate. ŧData source: http://www.cdc.gov/cancer/hpv/statistics/cases.htm; ^Percent is for males and females combined.

Year and Age of Diagnosis Age-adjusted incidence rates (number of cases) of HPV-related cancers@ among males, year and age of diagnoses, Iowa (Rates are per 100,000 and age-adjusted to the 2000 U.S. standard population) Year and Age of Diagnosis Anus Oropharynx* Penis <60 1988-93 0.3 (15) 1.8 (103) 0.3 (19) 2006-11 0.6+ (50) 4.2+ (367) 0.2 (19) 60+ 1.0 (14) 11.4 (164) 4.2 (57) 2.0 (32) 16.7+ (274) 4.5 (69) Probably caused by HPVŧ 91%^ 72%^ 63% @ Cases are invasive, microscopically-confirmed, squamous cell carcinomas except for cervical cancer where adenocarcinomas are also included. *Oropharynx subsites include base of tongue, tonsil, lingual and palatine tonsils, oropharynx, pharynx, and Waldeyer ring. +Rate is significantly different (p < 0.05) from corresponding 1988-93 rate. ŧData source: http://www.cdc.gov/cancer/hpv/statistics/cases.htm; ^Percent is for males and females combined.

Percent Distribution of HPV-related HNSCC in Iowa, 2006-2011 CDC HPV Study Site Definitions Males (n=811) Females (n=1296) http://cph.uiowa.edu/shri/pubs/pdf/Cancer_2014.pdf

Pap Screening Tests for Asymptomatic Female Patients Cervical Cancer (http://www.uspreventiveservicestaskforce.org/uspstf11/cervcancer/cervcancerrs.htm) Pap Screening Tests for Asymptomatic Female Patients USPSTF Recommends screening for cervical cancer in women age 21 to 65 years with cytology (Pap smear) every 3 years or, for women age 30 to 65 years who want to lengthen the screening interval, screening with a combination of cytology and human papillomavirus (HPV) testing every 5 years. Recommends against screening For women who have had a total hysterectomy for benign disease For cervical cancer in women younger than age 21 years For cervical cancer in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. For cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer For cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years Current ACS guidelines very similar

Normal Pap Smear Normal Pap Smear

Abnormal Pap Test Findings Severe dysplasia / CIN III / HSIL Mild dysplasia / CIN I / LSIL Severe dysplasia / CIN III / HSIL Moderate dysplasia / CIN II / HSIL Squamous cell carcinoma

Malignant Cervical Cancer Rates, Iowa, 1973-2010 (Rates are per 100,000 men and age-adjusted to the U.S. 2000 population.) 15% decrease in incidence between 1994 and 2006 64% decline between 1973 and 2010 40% decrease in mortality between 1994 and 2008 58% decline between 1973 and 2010

Percent of Iowa Female Population Who have had a Pap Test within the Past Three Years by Age Group and Year (http://apps.nccd.cdc.gov/brfss/) Age Group

Percent of Iowa Female Population Who have had a Pap Test within the Past Three Years by Education and Year (http://apps.nccd.cdc.gov/brfss/)

approved first vaccine (Gardasil) against HPV types 6, 11, 16 and 18. On June 8, 2006, FDA approved first vaccine (Gardasil) against HPV types 6, 11, 16 and 18.

Estimated 85% of 270,000 annual cervical cancer deaths occur in developing nations

90-95% squamous cell carcinomas Head and Neck Cancers 90-95% squamous cell carcinomas

Cancer involving tonsil Causal Evidence Strong and consistent for oropharynx Base of tongue, tonsil, pharynx Weak and inconsistent for oral cavity Cancer involving tonsil

HPV-related HNSCC Subset of HNSCCs (oropharynx) Base of tongue Lingual and palatine tonsils Pharynx Predominantly HPV-16 (95%)

Blue-shaded = HPV-related; Orange-shaded = non-HPV-related Percent Distribution of HNSCC in Iowa by HPV-related Site Status, 2006-2011 CDC HPV Study Site Definitions Blue-shaded = HPV-related; Orange-shaded = non-HPV-related http://cph.uiowa.edu/shri/pubs/pdf/Cancer_2014.pdf

Age Distribution of HNSCC in Iowa by HPV Status, 2006-2011 CDC HPV Study Site Definitions

Rising Incidence of Oropharynx Cancers in U.S. Declining incidence for oral cavity cancers Decrease in smoking Increasing incidence for oropharyngeal cancers Chaturvedi et al, JCO, 2008.

Increased Incidence of HPV-positive Oropharynx Cancers HPV-positive: 225% increase HPV-negative: 50% decline Overall oropharynx: 28% increase Reweighted prevalence: 70% HPV-positive in 2004 Chaturvedi et al, JCO, 2011.

Future Burden of HPV-positive OPC More OPC than cervical cancers by 2010 More HPV-positive OPC than cervical cancers by the year 2020 8600 HPV+ OPC 7700 cervical cancers Majority occurring among men (7400 cases) Chaturvedi et al, JCO, 2011.

Summary HPV-positive vs. HPV-negative HNSCCs Distinct Characteristics of HPV-positive HNSCCs Epidemiologic Predominantly among -Young individuals -Men -Never smokers? -Never drinkers? Molecular Low TP53 mutations P16 overexpression Distinct gene expression profile Clinical Better prognosis Better response to chemoradiation

Prevention and Control Screening for HPV-associated OPCs Not currently feasible Cervix / Oral Cavity Oropharynx Precursor lesions Well-defined ? Screening tests Cytology/histology Difficult to visualize/sample Treatments Available Kreimer AR et al. Can Prev Res, 2011.

Primary Prevention: HPV Vaccination High efficacy of prophylactic HPV vaccines at anogenital sites Vaccination anticipated to have equivalent efficacy in prevention of oropharynx HPV persistence, but no clinical trial data on efficacy Site Efficacy against persistent infection/ precursors Cervix 91% to 98% Anus 78% to 95% Penis 90% Vagina 100% Vulva Oropharynx ?

Primary Prevention: HPV Vaccination Vaccines licensed by FDA; cost-effective Gardasil (HPV4) targets HPV types 6, 11, 16, and 18 Cervarix (HPV2) targets HPV types 16 and 18 Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of females at age 11 or 12 years and catch-up vaccination for females aged 13 through 26 years ACIP guidance for males: HPV4 given aged 11-12 through 21 years to reduce likelihood of acquiring genital warts Use slide text

Primary Prevention: HPV Vaccination High-coverage HPV vaccination programs resulting in rapid reduction of: Genital warts Cervical cytologic abnormalities Diagnostic and therapeutic procedures Reduction in cancer rates should follow Since HPV vaccination does not protect against all cancer-causing types of HPV, vaccinated and unvaccinated women should still be screened for cervical cancer via Pap test Use slide text

Primary Prevention: HPV Vaccination In 2012, data collected in the CDC’s National Immunization Survey-Teen showed state-level HPV vaccination coverage levels for one or more doses varied widely from 39% of adolescent girls in Florida to 74% in Rhode Island Iowa’s percent was 58% Iowa’s percent for three doses was 36% Same survey showed that 21% of adolescent boys ages 13 through 17 nationwide and 19% in Iowa had received one or more doses of HPV vaccine Major medical societies recently released “Dear Colleague” letter that encourages providers to promote HPV vaccination (http://www.immunize.org/letter/recommend_hpv_vaccination.pdf) Health care advocate recommendations key to increasing this vaccination Use slide text

Conclusions HPV is a strong risk factor for a subset of HNSCCs– base of tongue, tonsil, and pharynx Recent increases in oropharynx cancers in the U.S. are caused by HPV infection; not smoking/alcohol Should recent incidence trends continue, there will be more HPV-positive oropharynx cancers than cervical cancers in the U.S. by 2020 HPV vaccines should be effective against HPV oropharyngeal cancers Health care advocates need to promote HPV vaccination Since HPV vaccination does not protect against all cancer-causing types of HPV, vaccinated and unvaccinated women should still be screened for cervical cancer via Pap test

?? ?? Questions ?? ??