Biography

Dr. Schiffman received an M.D. from the University of Pennsylvania and an M.P.H. in epidemiology from The Johns Hopkins School of Hygiene and Public Health. He joined the NCI as a Staff Fellow in 1983, and was appointed Chief of the Interdisciplinary Studies Section in the Environmental Epidemiology Branch in 1996. Dr. Schiffman received a Fulbright Scholarship in 1977 to carry out epidemiologic studies in Senegal. He received the PHS Citation, Achievement, Commendation, and Outstanding Service Medals for his work in molecular epidemiology.

Research Interests

Molecular Epidemiology of Genital Cancers

The Interdisciplinary Studies Section conducts molecular epidemiologic research on multi-stage carcinogenesis. A major objective is to clarify the natural history of human papillomavirus (HPV) infection in relation to risk of cervical cancer. Studies also focus on other DNA tumor viruses and non-viral molecular epidemiologic topics of scientific interest. Junior investigators participate in all aspects of the research under the mentorship of more senior members.

Human Papillomavirus Infection and Cervical Cancer: Natural History Studies

After molecular biologists suggested in the early 1980s that human papillomavirus (HPV) is a cause of cervical cancer, our group began studying methods for detecting the virus. We are continuing methodologic research aimed at optimizing the measurement of HPV infection and host response by viral DNA, serologic, and cellular immune assays. Using increasingly accurate HPV testing strategies, we initiated several large natural history studies of HPV infection and cervical cancer. The first, a 10-year study of 24,000 women enrolled in the Kaiser-Permanente health plan in Portland, Oregon, is focusing on the epidemiologic determinants of HPV infection, and on the transition from infection to precancer/cancer. The data thus far have shown a strong prospective association between HPV infection and cervical precancer/cancer, sexual transmission of HPV, and a decreasing prevalence of infection with age. The trend with age, which is related to viral disappearance, sheds light on why the virus only rarely causes cancer.

In a second effort, we are conducting a more intensive, population-based, cohort study of HPV and cervical neoplasia among 10,000 women in Guanacaste, Costa Rica, where the rates of cervical cancer are perennially high. State-of-the-art visual, microscopic, and molecular screening tests are being used to examine the origins of cervical precancer/cancer and to explore which factors make a geographic region "high risk". The sensitivity of previous screening and treatment efforts appear to be most important, as opposed to more complicated biological answers. The Guanacaste study, which is in the seventh and final year of follow-up, involves a variety of subprojects. We are examining several potentially important etiologic co-factors, such as chronic inflammation and endogenous hormone levels, that may contribute to cervical cancer risk. Most ambitiously, over 20,000 DNA and 20,000 plasma specimens are being tested for HPV DNA and antibodies, respectively, to determine whether type-specific HPV antibodies are protective against subsequent re-infection by the same variant. Based on results thus far, we have published in the scientific literature our findings supporting or questioning prominent hypotheses in the etiology of cervical cancer. In a new, U.S.-based study, we are now beginning a search for biomarkers of risk of progression of HPV infection. The focus will be on microdissection and RNA expression.

HPV Infection and Cervical Cancer: Immunology Studies

It is now accepted that HPV infections usually clear spontaneously. Our attempts to understand the phenomena underlying HPV immunology are linked to ongoing vaccine efforts. We are conducting studies to examine the serologic and cellular immune responses accompanying HPV disappearance and persistence, and progression to high-grade lesions as part of a U.S. multicenter, randomized, clinical trial (ALTS) designed to evaluate three alternative methods of managing low-grade (LSIL) and equivocal (ASCUS) cervical cytologic diagnoses In the Costa Rica cohort, women have been tested repeatedly by HPV VLP (virus-like particles) serology to examine whether seropositivity signals subsequent immunity to re-infection. A Phase III trial of two prophylatic HPV vaccines, which were developed by NCI and have undergone Phase I/II testing in the United States, is currently underway in Costa Rica.

HPV Infection and Cervical Cancer: Prevention Studies

Results from HPV natural history studies suggest several strategies that could be applied in cervical cancer prevention. For example, HPV testing could be used to clarify equivocal Pap smears, a diagnosis affecting about three million U.S. women yearly. In collaboration with NCI's Division of Cancer Prevention, ALTS is evaluating HPV DNA testing, along with two visual and two automated cytology techniques in determining the optimum strategy for managing low-grade cervical abnormalities. Over 5,000 women are enrolled, and have been followed for about two years. The results of this effort will guide cervical screening and management practice in this country and elsewhere. In Costa Rica, we are examining HPV DNA testing, thin-layer cytology, and cervicography for cervical cancer screening in the general population. Vaccination is the ultimate goal in preventing HPV-associated cervical disease.

Keywords

• Molecular epidemiology, human papillomaviruses (HPV), cervical cancer, multi-stage carcinogenesis, vaccination, prevention

Selected Publications

• Schiffman M, et al. "HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica." JAMA 2000; 283:87-93.
• Herrero R, et al. "Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica." J Natl Cancer Inst 2000; 92:464-474.
• Solomon D, et al. "Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial." J Natl Cancer Inst 2001; 93:293-299.
• Stoler M, et al. "Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL triage study." JAMA 2001; 285:1500-1505.

Collaborators

DCEG Collaborators

• Philip Castle, Ph.D, M.P.H.; Patti Gravitt, M.S.; Allan Hildesheim, Ph.D.; Mark Sherman, M.D.; Tammy Shields, M.P.H.; Sholom Wacholder, Ph.D.; Sophia Wang, Ph.D.

Other NCI Collaborators

• Douglas Lowy, M.D.; John Schiller, M.D.; Diane Solomon, M.D.

Other ScientificCollaborators

• Xavier Bosch, M.D., ICO, Barcelona, Spain
• Concepcion Bratti, M.D., Costa Rican Social Security, San José, Costa Rica
• Robert Burk, M.D., Albert Einstein College of Medicine, Bronx, NY
• Thomas Cox, MD, University of California at Santa Barbara, Santa Barbara, CA
• Andrew Glass, M.D.; David Scott, M.D., Portland Kaiser-Permanente, Portland, Oregon
• Rolando Herrero, M.D., Ministry of Health, San Jose, Costa Rica
• Sharon Hillier, Ph.D.; Kai-Li Liaw, Ph.D., University of Pittsburgh, Pittsburgh, PA
• Martha Hutchinson, M.D., Brown University, Providence, RI
• Attila Lorincz, Ph.D., Digene Corporation, Silver Spring, MD
• Ana Cecilia Rodriguez, M.D., Costa Rican Social Security Administration, San Jose, Costa Rica
• Diana Schneider, Dr.P.H., Health Resources and Services Administration, Washington, D.C.