Cervical Cancer Disease Burden
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  • Key Point Female Population greater than 5 years will continue to increase in developing countries and will remain stagnant in developed countries Background The population of women in the world continues to increase. Predictions for the period 2000–2050 clearly indicates the expected growth of the female population (ages 15+ years) in developing countries and a stable prediction in the developed countries. By age groups, these estimates reflect for girls 10–14 years and women 15–24 years, a plateau in the developing countries and a decrease in the younger populations in developed countries, largely in the age groups 15–24 years. With these population estimates, largely attributable to the increased life expectancy in women in developing countries. Ref 1) FX Bosch, X Castellsague´ and S de Sanjose´.British Journal of Cancer (2008) 98(1), 15 – 21
  • Key Point Female population – 15yrs and older is approximately 365 million Background WHO estimates says India has a population of 365.71 millions women ages 15 years and older who are at risk of developing cervical cancer. Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
  • Key Point Incidence of cervical cancer cases in India is highest as compared to other cancers in women 15-44 yrs of age Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
  • Key Point Mortality in India due to cervical cancer is highest as compared to other cancers in women of all ages. Second most common cause is Breast Cancer. Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
  • Key Point Difference between incidence of Cervical cancer vs mortality due to cervical cancer narrows for the females between age group 15-44yrs. Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
  • Key Point HPV 16 and 18 cause approximately 77% of Invasive cervical cancer . Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
  • Key Point Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types 1 and is linked to the activity of E6 and E7 proteins. 2 Background HPV infects its host by penetrating through mucosal tears in the basal membrane. 3 In benign HPV-associated skin lesions, the HPV virus maintains its genome as episomes at low copy numbers (10 – 200 copies/cell) in the basal cells of the epithelium separate from the host cell DNA. To maintain its viral DNA as an episome, viral E1 and E2 proteins are expressed. Failure to express E1 leads to the integration of the HPV genome into the host cell chromosome. 3 Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types 1 and is c onsidered an important step in tumor progression. 2 In malignant HPV-associated skin lesions, HPV DNA integration into the host cell ’ s chromosome regularly occurs through a break in the viral genome around the E1/E2 region . Integration-mediated disruption of E2 may trigger uncontrolled expression of E6 and E7, resulting in cellular transformation. 2 The E6 protein associates with the tumor suppressor protein p53 and promotes proteolytic destruction of the protein. This leads to malignant transformation and loss of regulated cell growth. The E7 protein associates with the pRB, which inactivates the cell cycle restriction function of this protein. 2 References 1. Gallo G, Bibbo M, Bagella L, et al. Study of viral integration of HPV-16 in young patients with LSIL. J Clin Pathol . 2003;56:532 – 53 6. 2. Syrj ä nen KJ, Syrj ä nen SM. Molecular biology of papillomaviruses. In: Papillomavirus Infections in Human Pathology . Chichester, United Kingdom: John Wiley & Sons, Inc.; 2000: 11 – 51. 3. Doorbar J. The papillomavirus life cycle. J Clin Virol . 2005;32(suppl):S7 – S15.
  • Key Point Vaccines generate a broad spectrum of antibodies, only a small proportion of which are demonstrated to neutralize viruses. Background There appears to be at least 2 distinct mechanisms in regards to antibody-mediated neutralization of HPV. By one mechanism, antibodies block the binding of HPV to cellular receptors. 1 By a second mechanism, neutralizing antibodies prevent uncoating of the virus. 2 Neutralizing antibodies against HPV are predominantly type specific. 3 Conversely, vaccination with L1 VLPs also elicits antibodies against nonneutralizing epitopes and, potentially, against other vaccine components. 4 Therefore, when quantifying the immune response to an L1 VLP vaccine, it is advantageous to measure only neutralizing antibodies. 4 Antibody color legend: Blue = Neutralizing antibodies Yellow = Nonneutralizing antibodies References Chen XS, Garcea RL, Goldberg I, Casini G, Harrison SC. Structure of small virus-like particles assembled from the L1 protein of human papillomavirus 16. Mol Cell. 2000;5:557–567. Booy FP, Roden RBS, Greenstone HL, Schiller JT, Trus BL. Two antibodies that neutralize papillomavirus by different mechanisms show distinct binding patterns at 13 Å resolution. J Mol Biol. 1998;281:95–106. Roden RBS, Hubbert NL, Kirnbauer R, Christensen ND, Lowy DR, Schiller JT. Assessment of the serological relatedness of genital human papillomaviruses by hemagglutination inhibition. J Virol . 1996;70:3298–3301. Opalka D, Lachman CE, MacMullen SA, et al. Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed Luminex assay. Clin Diagn Lab Immunol. 2003;10:108–115.

Transcript

  • 1. Cervical Cancer The disease and its burden in India
  • 2. Cervical cancer Epidemiology: India
  • 3. Population prospects for women >15 years 1. FX Bosch, X Castellsague´. S de Sanjose´. British Journal of Cancer (2008) 98(1), 15 – 21
  • 4. Population Pyramid of India 2. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18 th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
  • 5. Incidence (Women: all ages) - Cervical Cancer 1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV and Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre
  • 6. 1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV and Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre Mortality (Women: all ages) - Cervical Cancer
  • 7. Age Specific Incidence vs Mortality 2. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18 th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
  • 8. HPV Type Distribution - Invasive cervical cancer 1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV and Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre HPV 16+18=76.7%
  • 9. Years of Life Lost to Cervical Cancer* *In women in the United States (2003), 1. Ries LAG, Harkins D, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2003 , National Cancer Institute. Bethesda, MD; 2006. 26 19 18 Largest single cause of years of life lost to cancer in the developing world
  • 10. Cervical Cancer - Disease Burden New cervical cancer cases diagnosed annually India : 1,32,082, World : 4,93,243 India accounts for ~27% of new Cervical Cancer cases in world Deaths due to cervical cancer annually India : 74,118, World : 2,73,505 India - 27% Rest of World - 73% India accounts for 27% of deaths due to Cervical Cancer in world Rest of World - 73% India - 27% India - 27% 1. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV and Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre
  • 11. > 200 women die every day Every 7 minutes a women dies 8 women die every hour Cervical Cancer : India This ‘Cause’ need to be taken up by multiple stake holders. Cervical Cancer in India
  • 12. *Ray K et al, Indian J Med Res 2006; 124: 559-568 Genital Warts – Disease Burden: India* Increasing trend of Genital warts in India 18% 6% 11% 10.5% 0 2 4 6 8 10 12 14 16 18 20 1990-93 1994-97 1998-01 2002-04 Study Period Percentage
  • 13. HPV & Cervical cancer
  • 14. HPV 16 HPV 18 HPV 6 HPV 11 Cancer causing Types 1,2,4 Non-cancer causing types 1,2
    • >75% of Cervical Cancer 5,6
    • ~50% of Vaginal & Vulvar Cancer 5
    90% of Anogenital warts 5 HPV is a necessary cause of cervical cancer - 99.7% 4 HPV 1.Schiffman M, Castle PE. Arch Pathol Lab Med . 2003;127:930–934. 2. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis . 2002;35(suppl 2):S210–S224. 3. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer . 2004;111:278–285. Reprinted from J Virol. 1994;68:4503–4505 with permission from the American Society for Microbiology Journals Department. 4. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19. 5. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne,F. X. Bosch. HPV and Cervical Cancer in the World. 2007 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre6 . Bhatla N et al.Vaccine (2008;26; 2811-17 Human Papillomavirus (HPV) Human Papilloma Virus (HPV)
  • 15. Human Papilloma Virus (HPV)
    • Non enveloped double stranded DNA virus: over 100 types
      • 15–20 oncogenic
      • 30–40 anogenital
    • L1: major viral capsid protein – immunogenic
    • L2: minor viral capsid protein – immunogenic
    1. Baker TS, et al. Biophys J . 1991;60:1445–1456. 2. Chen XS, et al. Mol Cell . 2000;5:557–567. Capsid proteins: L1 L2 Viral DNA Viral exterior Viral interior
  • 16. Changes in Cervical Epithelium by HPV Infection *CIN = cervical intraepithelial neoplasia Adapted from Goodman A, Wilbur DC. N Engl J Med . 2003;349:1555–1564. Copyright © 2003 Massachusetts Medical Society. All rights reserved . Normal Cervix HPV Infection / CIN* 1 CIN 2 / CIN 3 / Cervical Cancer
  • 17. HPV Infection Low Grade Lesions High Grade Lesions Invasive Cancer 0–1 Year 0–5 Years 1–20 Years HPV Infection may clear Adapted from Pinto AP et al. Clin Obstet Gynecol . 2000;43:352–362 . Facts about HPV Infection Facts about HPV Infection
  • 18. Neutralizing Antibodies and HPV Infection Chen XS, et al. Molecular Cell . 2000;5:557–567. Antibody color legend: Blue = Neutralizing antibodies Yellow = Nonneutralizing antibodies Neutralizing antibodies prevent HPV infection Nonneutralizing antibodies do not prevent infection No antibodies— viral infection Cell surface receptors
  • 19. Antibodies
    • The minimum protective antibody level against HPV is not known.
    • USFDA and WHO: Reduction in incidence of CIN 2/3 or AIS caused by vaccine HPV types should be criteria for licensure.
    • No International standards for assays have been developed as yet.
    • Different assay use different units so their results can not be compared
    • The major basis of protection against infection is neutralizing antibody
  • 20. HPV Prevalence (%) Cancer Incidence Rate (×10 5 ) * Two different cohorts (cross-sectional study) followed during the same time span to measure the rate of high-risk HPV infection in one and the rate of cervical cancer in the other. 1. Adapted from Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV. J Clin Pathol . 2002;55:244–265, with permission from the BMJ Publishing Group. Age-Specific Rates of HPV Infection & Cancer* Age for vaccination: 9 – 26 yrs Age for Screening > 35yrs 0 5 10 15 20 25 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 Age Group (Years) HPV infection Cervical Cancer 25 20 15 10 5 0 (n=3752) Peak of HPV infection Peak of cervical cancer
  • 21. Summary
    • HPV is a necessary cause of cervical cancer – 99.7%
    • Induction of neutralising antibodies by vaccination is critical for protection
    • HPV 16 & 18 cause ~75% * of cervical cancer cases while HPV 6 & 11 cause ~90% genital warts
    • 27% of the world burden of Cervical Cancer is seen in India.
    • Every 7 minutes a woman dies in India due to cervical cancer
    • Cervical Cancer is usually diagnosed in late stages in India.
    • Cervical cancer screening is recommended in women >30yrs
    • Vaccination between 9-26yrs can be an effective strategy to help reduce this huge disease burden.
    * India