A study published in the online edition of the July 30, 2012 issue of the Journal of Clinical Oncology (JCO) explores the long-term benefits of human papillomavirus (HPV) DNA testing alone, cytology (Pap testing), and combinations of the two, to predict cervical precancerous disease and invasive cervical cancer risk. Based on the outcome, the researchers concluded that primary screening with HPV testing is a viable, efficient strategy.

The results from this prospective study indicate that HPV testing can predict which women will develop cervical precancers for 10 to 18 years after the test is conducted. The study found that, while both a positive HPV test and an abnormal Pap test predicted which women would develop precancers within two years of testing, the positive HPV test continued to predict which women were at risk for the entire 18-year follow-up of the study.

Reassurance
An initial negative HPV test, on the other hand, provided greater reassurance against cervical precancer and cancer over 18 years than a one-time normal Pap test. “While we knew that testing for high-risk HPV can predict cervical cancer risk for a few years, it’s remarkable that this predictive effect lasts for almost two decades,” said senior study author Philip E. Castle, PhD, MPH, of the American Society for Clinical Pathology (ASCP). “Our findings strongly reinforce the value of HPV testing as a routine part of care, in line with recent guidelines.”

Screening guideline
The findings support cervical cancer screening guidelines, issued by the American Cancer Society, American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology in 2012, which call for combining high-risk HPV testing with Pap testing every five years for women 30 to 65 years old. Their conclusion also supports an alternative strategy to HPV/Pap co-testing for women in this age group: HPV testing first to rule out cervical disease, followed by Pap testing only in HPV positive women to identify those who are at immediate risk of cervical precancer or cancer.

A major component of cervical cancer testing
HPV testing was introduced as a component of cervical cancer screening about a decade ago, when research identified persistent infection (lasting more than one or two years) with high-risk HPV types as the cause of all cervical cancers. “It takes on average five to 10 years for an HPV infection to persist and progress to cervical precancer, and 20 to 25 years to go from an HPV infection to invasive cancer,” Castle said. “This means that women who test HPV-negative are very unlikely to develop cervical precancer or cancer before their next screening appointment.”

The new study enrolled 20,000 women receiving routine Pap screening at Kaiser Permanente in Portland, Oregon. The women underwent baseline Pap as part of routine care and high-risk HPV testing for research purposes and were then followed up by conventional Pap testing for up to 18 years. Researchers calculated cumulative incidence rates (CIR; rates of new cases) for two different outcomes, grade 2 Cervical Intraepithelial Neoplasia (CIN2)or the more severe grade 2+ (CIN2+), and CIN3 or more severe diagnoses (CIN3+). Grade 2 and grade 3 cervical intraepithelial neoplasia (CIN2 and CIN 3), also known as cervical dysplasia and cervical interstitial neoplasia, are potentially premalignant transformation in which abnormal epithelial cells have replaced normal epithelial cells in the cervix. Those abnormal cells are not malignant but may eventually lead to cancer.

Molecular test
A U.S. Food and Drug Administration-approved molecular test, which screens for a pool of 13 high-risk HPV types, was used for baseline HPV testing. Those women who tested positive on the pooled test were also tested for HPV16 and HPV18 separately, using a prototype clinical assay. These two high-risk types are known to account for approximately 55% and 15% of all cervical cancers, respectively.

Among study participants older than 30 years, 8.7% tested HPV-positive and 4.3 had an abnormal Pap test result at initial testing. More cases of CIN3 and cervical cancer occurred after a baseline HPV-positive result versus abnormal Pap over the 18-year period (112 versus 65). Furthermore, HPV-positive women were more likely to have precancer at 10 to 18 years than HPV-negative women, regardless of the result of their initial Pap test. Thus, positive HPV test results were better at forecasting long-term cervical cancer risk than abnormal Pap results.

A stronger predictor
Over the 18-year follow-up, the incidence of CIN3 and cervical cancer was lower after a one-time negative HPV test than after one normal Pap test (0.9% vs. 1.27%), suggesting that HPV testing is a stronger predictor of not developing cervical precancer years later. And finally, the study showed that, among women older than 30 years who had negative HPV and normal Pap tests, increasing the screening interval from 3 years to 5 years did not substantially increase the CIN3 and cervical cancer risk (0.08% vs. 0.16%).

The researchers also found that, over an 18-year period, HPV16- and HPV-18 positive women with normal Pap results were at elevated risk of developing CIN2, CIN3, and cervical cancer compared with other HPV-positive women with normal Pap.This study’s findings support the current screening guidelines for women 30 to 65 years old:

• HPV testing followed by Pap testing every five years or Pap alone every three years.
• Women who test positive for high-risk HPV types ought to be followed up annually, even if they have a normal Pap test result.
• Separate testing for HPV16 and HPV18 may be conducted among HPV-positive, Pap-negative women to identify women at immediate risk for CIN3.

HPV16 or HPV18
Women who test positive for HPV16 or HPV and/or HPV18 test are referred to colposcopy. “Adding HPV testing to cervical cancer screening has two benefits for patients – it increases cervical precancer and cancer detection, and it can also extend the length of time between screenings safely,” Castle explaind, noting that less frequent and more reliable screening can help reduce the harms associated with unnecessary diagnostic tests and treatments, which can range from anxiety and discomfort to risk of preterm delivery due to treatment. “Overtesting is a big concern for patients, because it leads to more harm than cancer prevention,” Castle said.

Potential benefits of any screening test should be balanced with its potential harms. “It may take years to get doctors to comply with the new screening guidelines, but we need to educate and encourage appropriate test utilization,” he added. “This includes education of health insurers, who have an important role in encouraging appropriate use of tests through reimbursement.”

Castle also emphasized that the biggest obstacle to reducing cervical cancer deaths in the U.S. remains limited access to screening for some women. “Half of all cervical cancers in the U.S. are diagnosed in medically underserved women. They have incidence and mortality rates that are consistent with second and third world countries. We have to find ways to reach those women with any screening modality,” he said.

Maurie Markman, MD, Associate Editor of Cancer.Net and ASCO an Gynecologic Cancers Expert noted: “This is an excellent and important study. While we will need more research than this study alone to change the standard-of-care for cervix cancer screening, the data provide very solid support for a strategy of baseline HPV testing to help define an individual woman’s subsequent screening strategy.”

Reference:
Castle PE, Glass AG, Rush BB, Scott DR, Wentzensen N, et al. Clinical Human Papillomavirus Detection Forecasts Cervical Cancer Risk in Women Over 18 Years of Follow-Up. J Clin Oncol. 2012 Jul 30. [Epub ahead of print]

For more information (healthcare professionals):
Clinical HPV Detection Forecasts Cervical Cancer Risk [PDF]

For morte information (for patients):

• American Cancer Society - Learn more about cervical cancer [PDF]
• CDC - Cervical Cancer Screening Guidelines chart [PDF]
• ASCO Facts: What is Cervical Cancer [PDF]
• CDC - Making Sense of Tour Pap and HVP-test Results

Illustration courtesy of the American Society of Clinical Oncology (ASCO)

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