What are the implications of HPV in the biology of Head...

What are the implications of HPV in the biology of Head and Neck

Cancer?

Raquel Ajub Moyses

Friday, August 2nd, 2013

Disclosure

Raquel Ajub Moyses has no significant financial

relationship with any commercial or proprietary entity that

produces healthcare-related products and/or services

relevant to the content of this presentation.

Overview

• HPV structure • Infection • Carcinogenesis • Implications

• clinical presentation • diagnosis • prognosis / response to treatment • follow up

• Prevention • Immunotherapy • Other treatment strategies

HPV structure

• Small, nonenveloped DNA viruses

• more than 200 subtypes

• 30 suptypes: muccosal and genital

• Low risk: 6,11,42,43,44

• High risk: 16, 18, 31, 33, 35, 45, 51, 52, 56

Virology 2004 Proc Natl Acad Sci U S A. 1994

HPV structure

• Double-stranded genome encodes

• 6 early proteins (E1, E2, E4, E5, E7) • 2 late proteins (L1 and L2)

•Virus DNA in host cell: •Episomal (extrachromosomal)

•Integrated

•Mixed forms of both

• Once integrated: selective growth advantage

for the affected cells

Head and Neck Pathol, 2012 Int J Cancer. 2002

Biochem J, 2013

HPV structure

Head and Neck Pathol, 2012 Biochem J, 2013

Infection

Vaccine, 2006 Head and Neck Pathol, 2012

• Trauma or erosion – infection of undifferentiated basal cells of epithelia • E1 and E2 proteins expressed • infected cell migrates toward the superficial layers • E6 and E7 oncogenes expressed - retain the differentiating host keratinocyte in a state favorable for amplification of viral genome • granular epithelial layer - L1 and L2 (capsid proteins) expressed and encapsulate the newly synthesized viral genomes

Infection

Annual Rev Pathol. 2009 Head and Neck Pathol, 2012

Affinity for tonsillar crypts • patches of stratified squamous nonkeratinizing epithelium • patches of reticulated epithelium (porous BM)

•intimate contact between effector cells of immune responses

•facilitate direct transport of antigens

•synthesize secretory component continually

•contain a pool of immunoglobulins

Infection

Head and Neck Pathol, 2012

HPV infections • Cleared by the immune system • Latent infections of the basal cell layer - low viral copy numbers

•maintained indefinitely •injury or immunosuppression induces active infection

• Integration of viral DNA into host genome: strong predictor of risk of progression to neoplastic disease

Carcinogenesis

Biochem J, 2013 Otolaryngol Clin N Am, 2013

Production of E6 and E7 • E6: degradation of p53 – prevents apoptosis • E7: inactivation of Retinoblastoma family tumor suppressor proteins (pRb, p130, p107) – cell cycle progression ---- compensatory overexpression of p16 proteins

Carcinogenesis

Otolaryngol Clin N Am, 2013

Production of E5 • enhances EGFR pathway activation

•blocks ATPase and aids in recycling of EGFR and its expression on the cellular surface

•Enhances cell proliferation through downregulation of tumor suppressor p21/27

Implications


Clinical presentation • Tonsils and Base of Tongue • Other sites

• May affect mucosa outside the oropharyngeal lymphoepithelium under rare

circumstances.

• Laboratory methodology (PCR), amount of HPV signal is below biologic

significance - simple infection without cancer transformation.

• Misclassification of site

Implications


Clinical presentation

• early occult lesions – crypts

• late symptoms, reffered otalgia

• rare pre-cancerous lesions (also ≠ from cervix)

• no field cancerization (multifocal lesions)

• large interval between presentation and diagnosis – BOT palpation!

Implications

Otolaryngol Clin N Am, 2013 N Engl J Med 2007

Clinical presentation • Risk factors/epidemiological profile

•Whites •Younger •Men •Multiple orogenital sexual partners •Non-smokers •High social economic status •Marijuana?

Implications Diagnosis

• WHY?

• HOW?

• WHEN?

Implications

AJCC cancer staging manual, 2011 College of American Pathologists; 2011.

Cancer 2010 Clin Cancer Res 2003 Clin Cancer Res 2007

Am J Surg Pathol 2009 Hum Pathol 2010

Diagnosis • Why?

• Powerful biomarker for prediction of prognosis • College of American Pathologists & American Joint Committee on Cancer

•routine HPV testing: standard pathologic evaluation of resected oropharyngeal squamous cell carcinomas for the purpose of molecular tumor staging

• Help in difficult diagnostic dilemmas • Finding occult primary tumor • differentiate 2nd primary – metastatic disease to lungs • treatment strategies? • posttreatment surveillance?

Implications Diagnosis • How?

•Morphology



Gold Standard: Evidence for transcriptional activation of the viral oncoproteins E6 and E7 • recognizes the presence of HPV • discerns its tumorigenic potential Immunohistochemical probes for E6 and E7 proteins

•Difficult to get reliable probes Detection of E6/E7 mRNA

•Usually fresh frozen samples •Recently from FFPE samples – still difficult for the clinical setting



•Strategies for detection of •The actual presence of HPV DNA •Postintegration transcription of viral E6 and/or E7 messenger RNA (mRNA) •The viral oncoproteins E6 and E7 •Altered expression of cellular proteins (overexpression of the p16 protein)


Implications Diagnosis • When?

• not for non-OP sites

• compulsory in research

• ethical implications…

Implications

Prev med 2011 NEJM, 2010

JCO, 2011 Semin Radiat Oncol. 2012

Survival • Increased global and disease-free survival

• 3 years: 84% vs 57%

• 4 fold increase in median survival

• HPV+ tumors with increasing survival while HPV- estable

Implications

NEJM, 2010

Implications Why better outcomes?

• less disrupted genetic milieu in HPV+ tumors

•wild type p53

• Overstaged node metastasis? – not valid dogma of

“planned” neck dissection after non-surgical treatment when

disease stage is N2 or above

• No cancerization field

• Imunosurveillance for viral antigens?

Curr Opin Oncol. 2009 J Natl Cancer Inst. 2000

J Clin Oncol. 2006

Implications Follow up •Recurrences

Semin Radiat Oncol. 2012

Implications Follow up •Second primary tumors

Cancer, 2013

Implications Follow up •Distant Metastasis

•Similar rates, different natural courses:

•May occur after long survival

•Disseminating phenotype

•Prolonged survival after salvage for DM

Oral Oncology, 2013

Implications Follow up •Distant Metastasis

Oral Oncology, 2013

Prevention Sexual Habits - Moralism?

Prevention HPV Vaccines • Quadrivalent (Gardasil®): HPV-6, -11, -16, -18

APPROVAL: •2006: ♀ 9-26y – CA cervix, vagina and vulva •2009: ♀♂ 9-26y – genital warts •2011: anal cancer

EFFICACY • >98% if no previous contact • 50-78% if previous contact

US FDA Centers for Disease Cintrol and Prevention

Drugs, 2010 BMC Infect Dis, 2011

Prevention HPV Vaccines • Bivalente (Cervarix®): HPV-16, -18

APPROVAL: •2009: ♀– CA cérvix

EFFICACY •>97% if no previous contact •No protection agains genital warts

US FDA BMC Infect Dis, 2011

Prevention HPV Vaccines • Dificulties to be implemented:

• Parents’ misconception of stimulating sexual activity

• Costs

• Benefits will not be noted for several decades

• Change in HPV oral prevalence?

• Change in HPV+ NHC?

Prevention

Immunotherapy Importance of a functioning immune system against HPV

• Most immune-competent individuals are able to clear the infection

• Only 10% of infected individuals will develop HPV-related lesions

• Immunocompromised individuals: increased rates of HPV infections

and of HPV-related diseases


Immunotherapy Immune response

• humoral responses: Ab against L1

• weak, inconsistent, and may not protect against future

reinfection

• 30% to 50% patients with HPV-associated cancer with

detectable antibodies

•Antibody titers can persist for many years even after the

infection is cleared (useful marker for past infection rather than

current)

• Ab against E6 (HNC)


Immunotherapy Immune response

•Cell mediated

•HPV-specific CD41 and CD81 T cells

•critical in clearing established lesions

•Patients with evidence of previously cleared HPV-16 infections

have strong detectable T-cell responses to viral proteins


Immunotherapy Preventive vs Therapeutic vaccines


Immunotherapy Preventive vs Therapeutic vaccines • identification of tumor-specific antigens -specificity of the targeted immune response • E6 and E7 proteins: good model

•Viral (foreign) – more immunogenic than a self protein •Expressed by all cells infected by the virus (cancerous or not) •Cancer cell not likely to downregulate de expression, because they are necessary to maintain the malignant phenotype


Immunotherapy

Other Strategies

N Engl J Med 2010 Eur J Cancer 2010


EGFR Inhibitors •Increased EGFR expression in HPV positive tumors •Paradox:

•HPV positivity: good outcome in oropharyngeal •EGFR expression: independent risk factor for poor prognosis in HNC

Other Strategies

Immunotherapy

Other Strategies

N Engl J Med 2010 Eur J Cancer 2010


VEGF inhibitor • E6, E7: upregulation of VEGF • E5: increases VEGF expression through EGFR pathway •Paradox:

•HPV positivity: good outcome in oropharyngeal •EGFR expression: independent risk factor for poor prognosis in HNC

Other Strategies

Gynecol Oncol 2007 Mol Med, 2007

COX-2 inhibitor • COX-2 enzyme overexpressed in HPV-related precancerous cervical lesions and recurrent respiratory papillomas

Other Strategies

“Feliz serás e sábio terás sido se a morte, quando vier, não te puder tirar senão a vida.” Francisco de Quevedo

What are the implications of HPV in the biology of Head...

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