Biography

Dr. Dr. Castle received his Ph.D. in Biophysics from the Johns Hopkins University in 1995. Dr. Castle then did a post-doctoral fellowship in Laboratory of Cellular and Developmental Biology, NIDDK, NIH on the molecular biology of the zona pellucida. In 1999, he joined the Cancer Prevention Fellowship at NCI and received his MPH from the Johns Hopkins Bloomberg School of Public Health in 2000. He did his Cancer Prevention Fellowship training with NCI's Hormonal and Reproductive Epidemiology Branch (2000-2003) and joined the branch as a principle investigator in 2003.

Research Interests

• Natural history of HPV infection and cervical cancer; using HPV natural history to guide cervical cancer
• Evaluation of screening and diagnostic technologies for HPV infection, cervical precancer, and cervical cancer; development and validation of low-cost strategies for resource-limited countries
• The science of cancer prevention

Natural History of HPV and Cervical Cancer

Cervical infections by approximately 15 cancer-associated (carcinogenic) HPV genotypes cause virtually all cervical cancer and its immediate precursors worldwide. While HPV infection is the most common sexually transmitted infection, with the vast majority sexually-active women being exposed in their lifetime, most infections resolve or become undetectable within 2 years. Most HPV infections cause nothing more than mild pathologic abnormalities. Less commonly, carcinogenic HPV infections persist and then can progress to cervical precancer, which if undetected and treated in a timely manner, can become invasive cancer.

The necessary role of carcinogenic HPV in cervical cancer has led to a new paradigm of cervical carcinogenesis based on the natural history of HPV infection. The 4 stages are 1) HPV acquisition; 2) HPV persistence (vs. clearance); 3) progression of a persisting infection to cervical precancer; and 4) invasion. Each stage has a forward transition probability, and acquisition and persistence have reverse transition probability to normal; cervical precancer, as defined as cervical intraepithelial grade 3 (CIN3) or carcinoma in situ (CIS), probably has a very low reverse transition probability and cancer has none. This model replaces the lock-step model of progression from normal to CIN1 to CIN2 to CIN3 to cancer, with cytologic changes and histologic diagnoses representing surrogate measurements of these underlying stages of HPV-induced carcinogenesis.

Despite the fact that we have a better epidemiological and molecular understanding of cervical cancer than any other cancers, important etiologic questions remain. CIN3/CIS is our most scientifically rigorous definition of cervical precancer. However, only a fraction of all CIN3/CIS will develop the potential to invade. My colleagues and I want to evaluate the molecular heterogeneity of CIN3/CIS related to size and “age of the lesion”, including evaluating the physical and biological states of HPV and the epigenetic changes of both the virus.

Also, there are two main histopathologic types of cervical cancer, squamous cell carcinoma and adenocarcinoma, both caused by carcinogenic HPV. Squamous cell carcinoma is much more common than adenocarcinoma although the rates of adenocarcinoma are on the rise in many Western countries and now compose about 1/5th of all cases. While squamous cell carcinoma of the cervix has been extensively studied, less is known about adenocarcinoma histology. The biological basis of adenocarcinoma is a complete mystery, since viral expression and virion production is tied to epithelial differentiation but glandular cells, the cell type of adenocarcinoma, do not undergo epithelial differentiation. We wish to study the physical and biological states of HPV in adenocarcinoma of the cervix and compare it to squamous cell carcinoma to explore the difference in the etiology of these two main, HPV-dependent histopathologic types of cervical cancer.

Novel Strategies for Cervical Cancer Prevention: U.S.

Based on this nearly absolute etiologic link between carcinogenic HPV and cervical cancer, two new approaches for the prevention of cervical cancer have emerged: 1) HPV vaccination for primary HPV prevention in younger women and 2) carcinogenic HPV detection for secondary prevention via identifying and treating cervical precancer and early cancers. Both have demonstrated high degrees of efficacy with maximum effectiveness guided by an understanding of the causal model and application of these technologies in an age-appropriate manner. Prophylactic HPV vaccines targeting HPV16 and HPV18 have shown better than 90% efficacy for preventing persistent infections and cervical precancer caused by these genotypes in uninfected women for up to 5 years. However, these vaccines will only prevent ~70% of cancer and do not treat preexisting carcinogenic HPV infections, cervical precancer, and cancer. Therefore, screening will play an important role in cervical cancer prevention programs in the U.S. for years to come.

Since its introduction in the middle of the last century, cervical cytologic screening using Papanicolaou (Pap) smears has significantly reduced the incidence of cervical cancer in populations where programs have been successfully implemented. For example, in the U.S., these rates have been reduced by over 70%. It is now recognized that Pap smears detect human papillomavirus (HPV)-induced cytomorphologic changes (e.g., low-grade squamous intraepithelial lesions [LSIL] and high-grade squamous intraepithelial lesions [HSIL]) that typically precede the development of invasive cervical cancer by many years. Although Pap smear screening has reduce the incidence of cervical cancer to 10,000 cases and 4,000 related mortalities per year in the U.S., Pap smears are an insensitive method of detection for HPV infection and HPV-induced changes, and the success of the Pap smear programs can be attributed to annual screening resulting in repeated screening tests in timeframe of disease progression. The current cervical cancer prevention program costs billions of dollars annual in healthcare dollars before considering the costs of adding HPV vaccination at $500-1,000 per person.

Thus, current screening programs could improve on efficiency and cost-effectiveness and in the future must evolve to address the need for screening in HPV-vaccinated populations. A number of epidemiologic and early clinical trials have demonstrated the superior sensitivity of carcinogenic HPV testing compared to cervical cytology for detecting cervical precancer, and the tremendous reassurance provided by a negative carcinogenic HPV test. Recent randomized trials have emphatically confirmed these findings. In the U.S., carcinogenic HPV testing in conjunction with cervical cytology has been accepted for cervical cancer screening in women 30 and older, with those who test negative for both not to be screened again for an interval of three years. In the future, it seems likely that carcinogenic HPV testing will be accepted and adopted as an option for primary cervical cancer screening.

However, key questions remain. First, given the lower specificity and positive predictive value of HPV tests, what is the best secondary triage test to predict who has cervical precancer and cancer? Is it cytology, HPV genotyping, other biomarkers, or some combination of tests? Do we need to find a new biomarker for triage? Second, how will HPV vaccination influence the performance of current screening tests and how should we modify their use in HPV-vaccinated populations? That is, how do we integrate screening and HPV vaccination in the most cost-effective manner? Third, are new technologies such as computer-assisted liquid-based cytology a significant improvement over old cytology methods and how do they compare to HPV testing. Finally, how do promote compliance with evidence-based recommendations for screening and HPV vaccination to avoid waste and over-treatment? These are all questions that my colleagues and I are trying to tackle.

We also have an active program of validation and evaluations of new technologies for HPV and biomarker detection for use in epidemiologic research as well as for cervical cancer screening. In particular, we have extensively evaluated the clinical performance of each generation of Hybrid Capture tests for HPV DNA detection made by Qiagen (formerly Digene Corporation). The Hybrid Capture 2 test is now FDA-approved for use in screening and clinical management of equivocal Pap smears. However, new tests are now becoming available and we continue to actively evaluate these products for their use for detecting clinically-relevant cervical disease.

We are conducting a number of collaborative projects with colleagues at Kaiser Permanente Northern California to evaluate the use of new screening tools for secondary prevention. We have initiated a large cohort of HPV-positive women, called the HPV Persistence and Progression Cohort (The PaP Cohort), to study the risk of cervical precancer and cancer for each carcinogenic HPV genotype, the utility of HPV genotyping, and to evaluate other biomarkers of cervical cancer risk. We are also undertaking a large database mining project to examine the impact of introducing HPV testing into routine practice. Finally, also with colleagues at the University of California San Francisco, we will be launching a study in HIV-positive men to look at predictors of anal precancer and cancer.

Novel Strategies for Cervical Cancer Prevention: Underserved Populations

However, current methods of cervical cancer screening are not useful in developing countries because either the method is difficult to maintain at a high performance level, as is the case of cytology, or the test is unaffordable, as is the case with the current HPV DNA test. Likewise, current HPV vaccines will not be widely available because of cost and the need for a cold-chain for vaccine delivery. Both current screening and vaccination strategies require multiple visits and use the limited infrastructure and personnel for mostly healthy people. Thus, we are now working with public health organizations to encourage the development and validation of new, affordable tests (e.g., CareHPV) or testing modalities (e.g. self-collection) suitable for resource-limited regions of the world. Complementary to this effort, we are now working with the states and academic institutions in those states to reach underserved U.S. populations with these new screening methods to test efficacy and validate their use globally.

In collaboration with the Program for Appropriate Technology in Health (PATH; Seattle, WA) and the Chinese Academy of Medical Sciences, we are planning a study to evaluate the best low-cost triage strategies to colposcopy for women who test HPV-positive by CareHPV. I am also developing a low-cost, rationally-designed self-collection device for screening in underserved populations.

Keywords

Molecular epidemiology, HPV, cervical cancer, cancer prevention, screening and diagnostics

Selected Publications

• Castle PE, Solomon D, Schiffman M, Wheeler CM.Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities. J Natl Cancer Inst 2005;97:1066-71.
• Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, Rush BB, Glass AG, Schiffman M. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97:1072-9.
• Schiffman M, Castle PE. The promise of global cervical cancer prevention. N Engl J Med 2005;353:2101-4.
• Schiffman M, Castle PE. When to test women for human papillomavirus. Brit Med J 2006;332:61-2.
• Castle PE, Jeronimo J, Schiffman M, Herrero R, Rodríguez AC, Bratti MC, Hildesheim A, Wacholder S, Long LR, Neve L, Pfeiffer R, Burk RD. Age-related changes of the cervix influence HPV type distribution. Cancer Res 2006;66:1218-24.
• Butsch-Kovacic M, Castle PE, Herrero R, Schiffman M, Hutchinson ML, Bratti MC, Hildesheim A, Morales J, Alfaro M, Sherman ME, Wacholder S, Rodríguez AC, Burk RD. Relationships of HPV type, qualitative HPV viral load, and age with cytologic abnormality. Cancer Res 2006;66:10112-9
• Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, Goldie SJ, Harper DM, Kinney W, Moscicki AB, Noller KL, Wheeler CM, Ades T, Doroshenk M, Kahn KG, Andrews KS, Schmidt C, Shafey O, Smith RA, Partridge EE, Garcia FR. American Cancer Society Guideline for HPV Vaccine use to prevent cervical neoplasia and cancer. CA Cancer J Clin 2007;57:7-28.
• Schiffman M, Castle PE, Jeronimo J, Rodríguez AC, Wacholder S. The natural history and prevention of HPV and cervical cancer. Lancet 2007;370:890-907.
• Castle PE, Sideri M, Jeronimo J, Solomon D, Schiffman M. Risk assessment to guide the prevention of cervical cancer.J Lower Genit Tract Dis 2008;12:1-7.
• Wheeler CM, Hunt WC, Joste NE, Quint WGV, Castle PE. HPV genotypes among U.S. Hispanic and Non-Hispanic women: implications for vaccination and cervical cancer screening. Accepted by J Natl Cancer Inst 2008

Collaborators

DCEG Collaborators

• William F. Anderson, MD, MPH; Hormuzd Katki, PhD; Julia Gage, PhD, MPH; Mark Greene, MD; Katherine McGlynn, PhD; Ruth Pfeiffer, PhD; Mark Schiffman, M.D., M.P.H.; Sholom Wacholder, Ph.D.; Nicolas Wentzensen, MD, PhD, MS

Other NCI Collaborators

• Alexis Bakos, PhD; Lori Dodd, PhD; Jane Daye, MS; Sanya Springfield, PhD; Diane Solomon, MD

Other Scientific Collaborators

• Jerome L. Belinson, MD, Cleveland Clinic Foundation
• Sylvia Borgonovo, RN, Kaiser Permanente Northern California
• Robert D. Burk, MD, Albert Einstein College of Medicine
• J. Thomas Cox, MD, University of California Santa Barbara
• Theresa Darraugh, MD, University of California San Francisco
• Maire Duggan, MD, University of Calgary
• Catterina Ferreccio, MD, MPH, Pontificia Universidad Católica de Chile
• Barbara Fetterman, SCT, Kaiser Permanente Northern California
• Stephen Follansbee, MD, Kaiser Permanente Northern California
• Francisco A. Garcia, MD, MPH, University of Arizona
• Andrew G. Glass, MD, Kaiser Permanente Northwest
• Sue Goldie, MD, Harvard University
• Patti Gravitt, PhD, MS, Johns Hopkins University
• Rolando Herrero, MD, PhD., Proyecto Epidemiologico Guanacaste
• Jane Kim, PhD, Harvard University
• Walter Kinney, MD, Kaiser Permanente Northern California
• Jose Jeronimo, MD, PATH
• Ramey Littell, MD, Kaiser Permanente Northern California
• Attila T. Lorincz, PhD, Barts and the London Wolfson Institute of Preventive Medicine
• Stewart Massad, MD. Washington University
• Edward Partridge, MD, University of Alabama Birmingham
• Joel Palefsky, MD, University of California San Francisco
• You Lin Qiao, MD, Chinese Academy of Medical Sciences/Peking Union Medical College
• Ana-Cecilia Rodríguez, MD, MPH, Proyecto Epidemiologico Guanacaste
• Brenda Rush, RN, Kaiser Permanente Northwest
• Isabel Scarinci, Ph.D., MPH, University of Alabama Birmingham
• Ruth Shaber, MD, Kaiser Permanente Northern California
• Mark Stoler, MD, University of Virginia
• Howard Strickler, MD, MPH, Albert Einstein College of Medicine
• Cosette Wheeler, PhD, University of New Mexico
• Jenny Winkler, MS, PATH