Put to the Test

In 2008, about 11,070 cases of invasive cervical cancer will be diagnosed in the United States. Screening has made an enormous difference to the mortality rate, which now decline by nearly 4% every year. Douglas P. Malinowski provides his insight.

EHM. Please describe the current screening methods to detect cervical disease. What are the strengths and weaknesses of these methods?
DPM. Current screening for cervical cancer and the malignant precursors has historically been accomplished through the annual Pap test, where cervical cells are collected and then examined for morphologic abnormalities as detected using a microscope. We now understand that oncogenic forms of Human Papillomavirus (HPV) are the etiologic agents responsible for greater than 99 percent of all cervical cancers and the malignant precursors. Hence HPV testing has become an integral part of the screen for cervical disease. These two testing methods complement each other well. HPV testing is associated with a high sensitivity but a limited specificity. Conversely, the Pap test is associated with a lower sensitivity, but much higher specificity than HPV testing alone. Hence both methods are used together to improve the overall accuracy of cervical disease.

Epidemiologic data collected by the NCI over the past 40 years has indicated a significant decrease in the rate of cervical cancer detected in the US. This is a direct result of the use of an annual screen in the US healthcare system. Of the approximately 14,000 new cases of cervical cancer detected in the US on a yearly basis, most of these cases are found in women who do not participate in an annual Pap screen. Although the use of annual Pap tests and HPV testing has resulted in the detection of malignant precursors before the clinical development of cervical cancer, these methods refer too many women to the subsequent clinical management procedures of colposcopy examination and biopsy.

EHM. How important is HPV testing?
DPM. HPV testing is used in two clinical applications. The first application is triage testing for the ASCUS (Atypical Squamous Cells of Undeterminded Significance) cytology category. This is a cytologic classification, which identifies suspicious appearing abnormal cells, although the morphology interpretation is inconclusive. The use of HPV testing in these cases has been shown to improve the detection of biopsy confirmed disease in these patients relative to cytology alone. In the US, the use of HPV triage testing for the ASCUS patient population has now become a standard of care for the management of ASCUS patients to refer these patients to colposcopy versus repeat testing in six months.

The second application is the direct use of DNA testing in conjunction with cytology for the primary screen of cervical disease. This application is approved for women over the age of 30 years old. The value of HPV plus cytology screening is in the negative predictive value of the test. Numerous clinical studies have demonstrated that patients who are double negative, for example, they are negative for HPV and have a normal cytology status have a significant reduction in the likelihood of harboring cervical disease or in the development of cervical disease within a three-year period. The use of HPV plus cytology has been recommended to extend the screening intervals of women who test negative to both HPV and the Pap test.

EHM. What do you see as future changes in cervical cancer diagnostics?
DPM. Due to the fact that HPV is the etiologic agent responsible for the development of cervical neoplasia, it has become an important biomarker for use in cervical screening paradigms. The interest in HPV testing and the trend toward adopting HPV as the primary screen is tempered with the issue that HPV assays which detect DNA have a low specificity for CIN2+ disease. Currently, the value of HPV testing is achieved in conjunction with cytology where the high sensitivity of HPV testing is coupled to the high specificity of cytology. The adoption of HPV as a primary screen will require a more specific reflex test. Biomarkers are often cited as the obvious choice for this specific reflex test. Initial work on biomarkers such as the MCM proteins, TOP2A and p16 INK4a indicate the promise that biomarkers hold for the development of more effective and specific tests for the improved detection of cervical disease.

Dr. Douglas P. Malinowski is the VP of Research and Scientific Affairs and the Chief Scientific Officer for BD Diagnostics– TriPath. His responsibilities include technology strategy for cancer biomarker identification and characterization, scientific affairs and publications, and chairmanship of BD-TriPath’s Scientific and Clinical Advisory Board and Expert Advisory Panels.