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

Transcription

1 What are the implications of HPV in the biology of Head and Neck Cancer? Raquel Ajub Moyses Friday, August 2nd, 2013

2 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.

3 Overview HPV structure Infection Carcinogenesis Implications clinical presentation diagnosis prognosis / response to treatment follow up Prevention Immunotherapy Other treatment strategies

4 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

5 Head and Neck Pathol, 2012 Int J Cancer Biochem J, 2013 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

6 HPV structure Head and Neck Pathol, 2012 Biochem J, 2013

7 Vaccine, 2006 Head and Neck Pathol, 2012 Infection 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

8 Annual Rev Pathol Head and Neck Pathol, 2012 Infection 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

9 Infection 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 Head and Neck Pathol, 2012

10 Biochem J, 2013 Otolaryngol Clin N Am, 2013 Production of E6 and E7 Carcinogenesis 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

11 Carcinogenesis 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 Otolaryngol Clin N Am, 2013

12 Clinical presentation Tonsils and Base of Tongue Other sites Implications 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 Otolaryngol Clin N Am, 2013

13 Clinical presentation Implications 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! Otolaryngol Clin N Am, 2013

14 Implications Clinical presentation Risk factors/epidemiological profile Whites Younger Men Multiple orogenital sexual partners Non-smokers High social economic status Marijuana? Otolaryngol Clin N Am, 2013 N Engl J Med 2007

15 Diagnosis Implications WHY? HOW? WHEN?

16 Diagnosis Why? Implications 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 2 nd primary metastatic disease to lungs treatment strategies? posttreatment surveillance? AJCC cancer staging manual, 2011 College of American Pathologists; Cancer 2010 Clin Cancer Res 2003 Clin Cancer Res 2007 Am J Surg Pathol 2009 Hum Pathol 2010

17 Diagnosis How? Morphology Implications Otolaryngol Clin N Am, 2012

18 Diagnosis How? Implications 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 Otolaryngol Clin N Am, 2012

19 Implications Diagnosis How? 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) Otolaryngol Clin N Am, 2012

20 Diagnosis How? Implications Otolaryngol Clin N Am, 2012

21 Diagnosis When? not for non-op sites compulsory in research ethical implications Implications

22 Prev med 2011 NEJM, 2010 JCO, 2011 Semin Radiat Oncol Survival Implications 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

23 Implications NEJM, 2010

24 Implications NEJM, 2010

25 Implications NEJM, 2010

26 Why better outcomes? Implications 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 J Natl Cancer Inst J Clin Oncol. 2006

27 Follow up Recurrences Implications Semin Radiat Oncol. 2012

28 Follow up Second primary tumors Implications Cancer, 2013

29 Follow up Implications Distant Metastasis Similar rates, different natural courses: May occur after long survival Disseminating phenotype Prolonged survival after salvage for DM Oral Oncology, 2013

30 Follow up Distant Metastasis Implications Oral Oncology, 2013

31 Sexual Habits - Moralism? Prevention

32 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

33 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

34 HPV Vaccines Prevention 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?

35 Prevention

36 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 Otolaryngol Clin N Am, 2012

37 Immune response Immunotherapy 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) Otolaryngol Clin N Am, 2012

38 Immune response Immunotherapy 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 Otolaryngol Clin N Am, 2012

39 Immunotherapy Preventive vs Therapeutic vaccines Otolaryngol Clin N Am, 2012

40 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 Otolaryngol Clin N Am, 2012

41 Immunotherapy

42 Immunotherapy

43 N Engl J Med 2010 Eur J Cancer 2010 Otolaryngol Clin N Am, 2012 Other Strategies 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

44 Other Strategies

45 Immunotherapy

46 N Engl J Med 2010 Eur J Cancer 2010 Otolaryngol Clin N Am, 2012 Other Strategies 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

47 Other Strategies COX-2 inhibitor COX-2 enzyme overexpressed in HPV-related precancerous cervical lesions and recurrent respiratory papillomas Gynecol Oncol 2007 Mol Med, 2007

48 Other Strategies COX-2 inhibitor COX-2 enzyme overexpressed in HPV-related precancerous cervical lesions and recurrent respiratory papillomas Gynecol Oncol 2007 Mol Med, 2007

49 Other Strategies

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