Cervical Cancer Early Endpoints and Determinants

For the past twenty years, large epidemiologic natural history studies have played a crucial
role in achieving our current understanding of cervical neoplasia. We now know that human
papillomavirus (HPV) infection is necessary but not sufficient cause of cervical cancer.
Cervical pathogenesis evolves as follows: normal 'yields' oncogenic HPV infection 'yields'
precancer 'yields' invasive cancer. The majority of women with oncogenic HPV infections will
not develop cancer, and most HPV infections, even those with associated cellular changes,
regress in 1-2 years, probably eradicated or controlled by cellular immune response.
Morevoer, while invasive cancer and precancer are histologically welldefined, the
histological classification of low-grade lesions, now better defined as HPV infection, is
very heterogeneous and poorly reproducible. Identifying women at highest risk for cancer
prior to neoplastic progression is therefore a challenge. At present, we are unable to
predict with any accuracy which HPV infections will progress and which are among the majority
that regress. Currently, cytologic, histologic, and to some extent, HPV DNA assays are the
basis for triage, treatment, and follow-up. While this approach has permitted successful
cervical cancer prevention efforts, millions of women are diagnosed each year with HPV
infections, and because of the inability to distinguish those who will progress from those
who will regress, many women are over-treated as a result. It is therefore of etiologic
interest and of public health benefit to develop a method for identifying the HPV-infected
women at risk for progressing to precancer and invasion. To develop an accurate and
reproducible division of precursor lesions (HPV infection and precancer) will require gaining
knowledge about the molecular distinctions at each progressive disease state. Our goal is to
therefore comprehensively assess biomarkers of risk for progressive cervical neoplasia, and
thus develop a new set of biomarkers that can distinguish those at highest risk of cervical
cancer from those with benign infection. Specifically, we will initially implement a
cross-sectional study to develop a comprehensive list of potential risk biomarkers by
examining cervical tissues of women with normal, HPV infection, precancer, and cancer. They
will measure gene expression profiles to gain an accurate and comprehensive in vivo picture
of cervical neoplasia carcinogenesis. We propose to then validate the most promising
identified candidate biomarkers in a prospective design by assessing their predictive values
for key outcomes related to progression (HPV persistence, diagnosis of precancer) or
non-progression (HPV clearance).

- INCLUSION CRITERIA:

All women who are referred for cervical colposcopy to the University of Oklahoma will be
considered eligible for the study. These women will be categorized into four groups: (i)
cancer, (ii) precancer, (iii) HPV-infected, and (iv) normal. Cancers will be limited to
women diagnosed with early cancer (Stage 1-2) to minimize potential disease effects.
Precancers will be defined as women diagnosed histologically with cervical intraepithelial
neoplasia 3 (CIN3). This is a highly specific and well-reproduced diagnosis which
effectively represents carcinoma in situ. All women testing DNA positive for any of the 13
known oncogenic HPV types (HPV-infected), but not diagnosed with CIN3 or cancer (all
stages) will be placed in the HPV-positive group. This group will therefore encompass all
HPV-infected women diagnosed with either cervical intraepithelial neoplasia 1 (CIN1), CIN2,
low grade squamous intraepithelial lesion (LSIL), atypical squamous cells of undetermined
significance (ASCUS), atypical glandular cells of underdetermined significance (AGUS), or
found cytologically normal. Women referred to the colposcopy clinic but found to be
negative for oncogenic HPV and normal upon histological diagnoses will be eligible as
normal controls; this approach will be an ethical method for collecting biopsies from
essentially "normal" women as there are many benign "look alike" conditions that are ruled
out in colposcopy clinics. While this group may not be a random sample of the general
population, the use of specimens from these women as controls will ensure a group of women
who are truly confirmed as having no neoplasia.

EXCLUSION CRITERIA:

Women attending the clinic solely for vaginal colposcopies will be excluded from the study.
Women who are under 18 years of age or pregnant at the visit will also be excluded from the
study. In addition, women who have had prior treatment (women coming to the clinic for a
follow-up visit subsequent to treatment (women coming to the clinic for a follow-up visit
subsequent to treatment or women coming for their initial clinic visit following
pretreatment with chemotherapy or radiation) will be excluded. All women with known HIV or
AIDS will be excluded from the study. This information will not be readily available unless
the woman has previously been seen at the University of Oklahoma clinic. This event is
considered rare; recent studies of HIV and AIDS by the University of Oklahoma from the same
population have been terminated due to the lack of HIV/AIDS detected in the population.