Abstract PL01-02: Human papillomavirus in the etiology and prevention of genital cancers
Authors: Muñoz Nubia 
Published: August 2012

Abstract
Infectious agents and tobacco are today the leading causes of cancer worldwide. It is estimated that each accounts for about 18% of all cancers. Among the infectious agents causing cancer, human papillomavirus (HPV) account for 5% of all cancers. Although already 170 years ago Rigoni Stern thought that a sexually transmitted agent could be linked to cervical cancer, only during the last three decades HPV has been identified as main cause of this cancer. I have had the privilege of being one of the scientists who participated in the demonstration of HPV as the central and necessary cause of cervical cancer and on the application of this discovery to the prevention of this malignancy. I will summarize the molecular epidemiological evidence linking HPV to cervical cancer and other genital cancers and the implications for prevention. Cervical cancer and HPV During my former job as chief of one of the Epidemiology Units at the International Agency for Research on Cancer (IARC) in Lyon, France I conducted a series of Case-control studies. In 12 countries around the world we studied about 2,500 women with cervical cancer and about 2,500 control women without cancer. These women were interviewed using a standardized questionnaire and cervical cells from the tumors and normal cervices were collected for the detection of HPV DNA of 30 HPV types that infect the genital tract. The prevalence of HPV DNA was over 95% in the tumors cells of women with cervical cancer and it ranged from 5 to 20% in normal cervical cells of control women. These prevalences correspond to Odds Ratios (ORs) of over 100 indicating a very strong association between HPV and cervical cancer. The magnitude of the ORs allowed an epidemiological classification of 15 HPV types as carcinogenic or high-risk types, 12 as low-risk types and 3 types as probably carcinogenic (Muñoz et al 1992, Int. J. Cancer, 52, 743-49. Muñoz et al, 2003 N. Eng. J. Med, 348(6): 518-27.). This classification was recently reviewed by the IARC Monographs program. Our case-control studies also allowed the identification of the following cofactors that acting together with HPV increase the risk of progression from HPV persistent infection to cervical cancer: tobacco, high parity, long term use of oral contraceptives and past infections with herpes simplex type 2 and Chlamydia trachomatis. In addition, they contributed to establish the important role of male sexual behavior in the risk of developing cervical cancer (Muñoz et al 2006 Vaccine, 24(3), 1-10. In an international survey of HPV types in invasive cervical cancers over 1,000 women with invasive cervical cancer from 22 countries around the world were included in this study. HPV DNA detection in frozen tissue specimens with PCR-based assays revealed that 99.7% of the cases were HPV-positive. This finding led us to propose for the first time that HPV was not only the main cause of cervical cancer, but also a necessary cause (Walboomers et al. 1999J. Pathol., 189, 12-19.). No other cancer has been shown to have a necessary cause. In an extension of this survey, HPV DNA was detected in paraffin blocks from over 10,000 histologically confirmed cases of cervical cancers from 38 countries around the world. This is the largest survey ever conducted using a standard protocol and centralized HPV DNA testing with a very sensitive PCR-based assay. It confirmed that HPV 16 and 18 account for 70% of all cervical cancers and that the worldwide relative contribution of HPV 16, 18, 45, 33, 31, 52, 58 and 35 is 91% (de Sanjose et al 2010 Lancet 11(11): 1048-1056.) Other genital cancers and HPV In an ongoing international survey of HPV genotypes in other cancers of the genital tract and head and neck tumors, paraffin blocks from over 5,000 cancers from 43 countries worldwide have been analyzed for HPV DNA. HPV DNA was detected in 29% of over 1,500 cases of cancer of the vulva, in 33% of about 900 cases of cancer the penis, in over 80% of cancers of the vagina (400 cases) and the anus (450 cases) and 20% of cancers of the oropharynx and oral cavity (∼2,000 cases). HPV 16 and 18 accounted for over 90% of the HPV-positive cancers of the vulva, penis, vagina, anus and oropharynx. Implications The demonstration that infection with certain types of HPV is not only the main cause but also a necessary cause of cervical cancer has led to great advances in the prevention of this disease and other HPV associated diseases on two fronts: (i) In primary prevention by the use of prophylactic HPV vaccines; (ii) In secondary prevention by increasing the accuracy of cervical cancer screening. In relation to primary prevention, two prophylactic HPV vaccines have been developed, the bivalent vaccine against HPV 16 and 18 (Cervarix) and the quadrivalent against HPV 16, 18, 6 and 11 (Gardasil). Both protect against infection with the two HPV types, HPV 16 and 18 responsible for about 70% of cervical cancer, and the quadrivalent vaccine in addition protect against infection with HPV 6 and 11 that cause 90% of genital warts and of recurrent respiratory papillomatosis. Both vaccines have been shown to be safe and highly efficacious for the prevention of high grade precancerous lesions of the cervix. In addition, a high efficacy of the quadrivalent vaccine has been shown for the prevention of precancerous lesions of the vulva, vagina and of the anus (Munoz et al JNCI 2010, Palefsky et al N Engl J Med 2011;365:1576 85., Lehtinen et al 2011 Lancet Oncology Nov 9). The bivalent vaccine has been shown to be efficacious for the prevention of HPV anal HPV infection and of VIN1+/VaIN1+ lesions. They have been approved in over 100 countries and HPV vaccination is now offered through government programs in 33 developed countries, and in a few middle-income countries. In developed countries screening programs have reduced the incidence of cervical cancer, but this highly effective vaccine was still considered an important public health investment. Concerning secondary prevention, although well-organized screening programs have been successful in reducing cervical cancer incidence and mortality in developed nations, they have been unsuccessful in the majority of developing countries. Several randomized trials have shown that HPV testing has a higher sensitivity but a slightly lower specificity than cytology for the detection of high grade precancerous lesions of the cervix and indicate that the use of the HPV assay as a primary screening test is the way to go (Munoz et al Vaccine 2008;26 Suppl 11:L96-L107). A comprehensive cervical cancer control program with immunization of adolescent girls and an HPV-based screening program for older women is the ideal strategy to eradicate cervical cancer in the developing world where 86% of the cases occur. High price of the HPV vaccine and of the HPV assay is one of the main barriers to reach the high coverage of vaccination and of the screening program needed to accomplish this goal, but efforts are being done to overcome this barrier. The GAVI alliance has recently added the HPV vaccine to its roster of vaccines subsidized for the poorest country worldwide, and a new low-cost HPV DNA test, careHPV has been shown to have a performance comparable to the currently commercially available Hybrid Capture 2 test, and is in the process of being commercialized.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr PL01-02. doi:1538-7445.AM2012-PL01-02