CHAPEL HILL, N.C. - University of North Carolina at Chapel Hill researchers are studying the value of a new biomarker for improving cervical cancer screening.
The clinical trial will examine cervical smears for telomerase, a protein released into cells when chromosomes shorten, stick together and become genetically unstable. The protein helps rebuild eroded telomeres, the caps at the ends of chromosomes. Its presence in cervical cells removed during Pap smear testing may help predict those women who are at greatest risk for developing cancer.
"Pap smear screening has been very effective at decreasing the number of deaths from cervical cancer. But many of the abnormal results it produces do not lead to an increased risk of cancer," says Dr. John Boggess, assistant professor of obstetrics and gynecology at UNC-CH School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center. "A lot of women undergo expensive testing and painful procedures only to find out they've got something that doesn't need treatment or is unlikely to become cancer."
According to the UNC gynecologic oncologist, Pap smear sensitivity is only 70% and can be as low as 50% in women with ulceration and inflammation of the cervix, conditions commonly found in women with cancer. Over 2.5 million abnormal Pap smears are reported in the U.S. per year.
"Of these the majority represent minimally abnormal cytology, or ASCUS, atypical squamous cells of undetermined significance or LGSIL, low-grade squamous intraepithelial lesions, and less than one percent represent invasive lesions."
The current standard of medical care, notes Boggess, calls for assessment of two consecutive minimally abnormal Pap smears by colposcopy - a technique where the cervix is examined with a magnifying instrument and biopsies of suspicious lesions are taken to rule-out cancer. He notes that most biopsy diangoses from women with minimally abnormal Pap smears do not require treatment.
"Colposcopy is both expensive -- $200 to $500 per patient -- and invasive, requiring examination and painful biopsy," he says. "Given that only a small percent of minimally abnormal Pap smears result in clinically significant lesions, most of this expense is unnecessary. In addition, depending on the site of biopsy, results may be misleading and miss a clinically important lesion."
Boggess adds: "Identifying an alternative screening method other than colposcopy that could better predict which minimally abnormal Pap smears are more likely to progress to pre-invasive or invasive cancer, would significantly decrease the expense and increase the efficacy of cervical cancer screening."
Some tantalizing earlier research findings are leading Boggess and his UNC colleagues to view telomerase testing as a possible solution.
The major cause of cervical cancer and its pre-invasive lesions is HPV - human papillomavirus. It is found in cervical cancers worldwide. But the usefulness of HPV testing for the HPV types that are associated with cervical cancer has proved only of limited clinical value.
Boggess's collaborator, Dr. William Kauffmann, professor of pathology and laboratory medicine, has infected human cells with DNA from highly oncogenic HPV strains. "Over time, you see increased amounts of genetic instability that occurs as chromosomes shorten, as telomeres shorten," Boggess says. "Depending on what chromosomal material is lost, some cells will acquire telomerase, which stabilizes chromosomes and produces immortal cell lines."
Thus, instead of an unstable cell that eventually dies, what results is a cell line that can divide indefinitely. And depending on its genetics can become cancer.
Two years ago, the UNC researchers decided to determine if the test-tube findings would apply in people. They took extra Pap smears from 120 women who had been referred for colposcopy because of abnormal Pap results. Demographic information was obtained, including smoking history. The data analysis is not yet complete, but very preliminary results indicate that significant abnormal colposcopy results do correlate with telomerase activity," Boggess says.
"The finding that telomerase can be detected in a Pap smear is not new, but its use as a biomarker for cervical cancer development is new," the researcher notes.
"We need to establish the prevalence of this enzyme and validate the assay for detecting it," Boggess adds. "We also want to find out if we can correlate the genetics of abnormal biopsy with the expression of telomerase in pap smears. So, ultimately, if you're expressing telomerase in your Pap smear, we can say you have genetically altered cells in your cervix, which can be treated. But if you're not expressing telomerase, we can say with greater certainty that a colposcopy and other treatments might not be necessary."
To answer these issues, Boggess and his colleagues plan to recruit women for a larger study to begin in October. "We hope to include women who do and don't have abnormal Pap smears. We'll screen everybody."
Note to media: John F. Boggess, MD can be reached at 919-966-5996; email: jboggess@med.unc.edu