1 HPV: Infections and induced cancersAnil K. Chaturvedi, PhD Multidisciplinary Approach to Oral Cancer September 9, 2016 Plymouth, MI

2 Outline HPV-positive head and neck cancer Oral HPV infectionHPV and associated cancers Etiology in head and neck cancers: oral cavity and oropharynx Global burden Oral HPV infection Transmission Population epidemiology Natural history Changing burden and prevention Primary and secondary prevention

3 Human papillomaviruses (HPV)ds DNA viruses- Papillomaviridae family >100 known HPV genotypes > 40 genital HPV genotypes 13 HPV genotypes associated with high cancer risk (high-risk/oncogenic HPV genotypes) Oncogenic potential: E6 and E7 viral oncogenes Target p53 and pRB

4 HPV attributable proportions in cancers% attributable to HPV infection % of HPV-associated cancers attributable to HPV16/18 Cervix 100 76 Anus 93 Penis 36 87 Vagina 64 88 Vulva 51 86 Oropharynx 63 95 Gillison ML et al. Cancer, 2008.

5 Etiologic role of HPV in head and neck cancersSpecific to oropharynx cancers Base of tongue, lingual tonsil, soft palate, palatine tonsil, pharyngeal wall Epithelial transition zones Low etiologic fraction in other head and neck cancers: <5% Oropharynx

6 Anatomic origin of HPV-positive oropharynx cancersCrypt epithelium: exposed basal layer—discontinuous basement membrane Ready access to underlying lymphatics Westra and Pai, Ann Rev Pathol 2009 Westra, Head Neck Pathol 2012

7 HPV attributable proportions in Oropharynx cancersCastellsague et al., JNCI 2015

8 HPV attributable proportions in Oral cavity cancersCastellsague et al., JNCI 2015

9 Sexual behaviors (Oral sex)HPV: causal model Sexual behaviors (Oral sex) Oral/OP HPV HPV+ OPC Risk: 5-10 times Risk: times D’Souza et al. NEJM, 2007

10 Oral HPV infection

11 Primary mode of transmission: Sexual activityOral sex ↑ number of sexual partners

12 Majority of infections attributable to sexual behaviors0.3% prevalence in unexposed 0.2% prevalence in unexposed 96% sexual 88% sexual Gillison, JAMA 2012 and Chaturvedi , Cancer Res 2015

13 Other modes of transmissionAuto-inoculation: HPV in finger tips Sonnex et al., STI 1999 and Winer et al., CEBP 2010 Deep-kissing: salivary transmission D’Souza et al., JID 2009 and Pickard et al., STD 2012 Correlated behaviors

14 Oral HPV in the U.S. population (NHANES 2009-2010)7% 3.5% 1% Gillison et al., JAMA 2012

15 Oral HPV prevalence by ageBimodal association First peak (25-30 years) STI pattern Second peak (55-60 years) Newly acquired? Cumulative persistence? Immune senescence reactivation? Birth cohort effect? Adjusted for gender, race, education, marital status, # partners, smoking Gillison, JAMA 2012

16 Oral HPV prevalence by gender3-5 times higher prevalence in men Gillison, JAMA 2012; Chaturvedi, Cancer Res 2015

17 Behavioral differences do not entirely explain higher oral HPV in men~18% of male excess explained by behaviors Chaturvedi , Cancer Res 2015; D’Souza, PLOS One 2014

18 Stronger associations with sexual behaviors in men vs. womenMale susceptibility to oral HPV Steeper increase Later plateau Adjusted for age, race, education, marital status, smoking Chaturvedi et al., Can Res 2015

19 Male susceptibility to oral HPVPoor immunity in men Higher female to male transmission Higher oral HPV in men Poor immune responses to other infections Low seroconversion from genital HPV infection Low antibody titers Higher oral HPV viral load in men vs. women (NHANES) Oral HPV in heterosexual vs. homosexual men and women (NHANES ) Chaturvedi et al., JID 2014

20 Incidence of oral HPV infection: ~5-10%/yearAny HPV Oncogenic HPV HPV16 Kreimer et al., Lancet 2013

21 Persistence of oral HPV infection: 90% clear in 1-2 yearsAny HPV Oncogenic HPV HPV16 Kreimer et al., Lancet 2013

22 Natural history of HPV-OPCPrevalence: ~7% Incidence: ~5-10% per year Persistence: 90% clear in 2 years Risk factors: Sexual behaviors Oral HPV infection HPV-positive oropharyngeal cancer Latency? HPV serology studies: >10 years prior to cancer Cervix model: years Precancerous state/lesion?

23 Risk factors for HPV-positive oropharynx cancerStrength of evidence Strength of association Oral HPV infection +++ 100x Sexual behaviors Younger age 1.5-2x Male gender 3-5x Smoking +/- ? Alcohol Oral hygiene Diet Host genetics

24 Burden of HPV-positive OPC~22,000 annual cases worldwide US: >70% attributable to HPV (~8,000 annual cases)

25 Burden and prevention

26 Rising burden of HPV+ OPC in the U.S.2020: Most common HPV+ cancer 2030: Most common head and neck cancer Majority among men Chaturvedi et al., JCO 2011

27 Prospects for preventionPrimary prevention: HPV vaccination >90% efficacy for prevalence 4 years after vaccination Gender neutral vaccination in countries with low coverage (<80%) in girls/women Herrero, PLOS One 2013

28 Should we screen for HPV+ OPC?Not at this time Future? Rare cancer <10 to 30 per 100,000 High NNS (~10,500) Strong risk factors—low PAFs No identifiable precursor Difficult to visualize and collect samples No risk reduction modalities Risk stratification, precursor, screening, treatment Combine with oral cavity cancers?

29 Summary: Knowns and unknownsEpidemiology Risk factors/ risk groups Oral HPV infection HPV-positive oropharyngeal cancer Site of infection? Natural history? Latency? Male excess? Precursor lesion? Risk stratification tools Secondary prevention?