By Molly A. Brewer, DVM, MD, MS

Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington

Dr. Brewer reports that she receives grant/research support from the National Cancer Institute.

Synopsis: This is a review of the ATHENA trial, which evaluated the prevalence of hrHPV in a large cohort of women and evaluated the most sensitive screening strategy.

Sources: Wright TC, et al. Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol 2015;136:189-197.
Monsonego J, et al. Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical precancerous lesions in a large U.S. screening population: Data from the ATHENA trial Gynecol Oncol 2015;137;47-54.

This recent study presents data from the ATHENA (Advancing the need for advanced HPV diagnostics) trial conducted in 23 states from 2008-2009.1,2 In this study, 40,901 women > 25 years of age were screened with liquid-based cytology and HPV using the cobas-HPV assay (Roche), a PCR-based assay that tests for 14 HPV genotypes that are considered to be high risk subtypes (hr). These hr genotypes include HPV 16 and HPV 18, as well as 12 pooled HPV genotypes 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Depending on the result of both cytology and HPV, women were triaged to different algorithms. Women with abnormal cytology and hrHPV positivity went on to colposcopy and biopsy. Those women with < CIN2 were eligible for the 3-year follow-up study with yearly Pap smears and HPV testing.

Out of the 40,901 women in the study, 9353 women were selected for colposcopy. Those with > CIN2 exited the study and those with CIN2 were eligible for the 3-year screening cohort. These patients had Pap smear and hrHPV testing each year. The authors used a post-hoc analysis to compare the performance of three screening strategies: 1) cytology with hrHPV testing performed only for ASCUS without colposcopy; 2) a hybrid strategy: women aged 25-29 years old with hrHPV positive and negative cytology only had repeat cytology in 1 year, while women > 30 years old only had repeat hrHPV testing performed; 3) HPV strategy in which HPV negative women were rescreened in 3 years, HPV 16 or 18 positive women underwent colposcopy, and those women positive for the other 12 hr genotypes had reflex cytology and colposcopy if the cytology was ASCUS or greater. If the cytology was negative, women were rescreened with HPV and cytology in 1 year.

At baseline, 10.5% were hrHPV positive and 6.4% had ASCUS or greater cytology. Of the 40,901 women, there were 274 CIN3 or higher and 157 CIN2 or higher. HPV 16 was predictive of CIN3: 17% of those HPV16 positive had CIN3 at baseline, and after 3 years the cumulative incidence rate (CIR) was 25.2%. In contrast, the women with hrHPV positive but HPV 16/18 negative had a CIR of 5.4%. More than 50% of the women with CIN2/3 were HPV16/18 positive up to the age of 40 and then it dropped to 43% and 45% in 40-49 and > 50, respectively. Those women who were cytology negative had a CIR of 0.78% compared to those who were hrHPV negative who had a CIR of 0.34%. The HPV primary in women 25 years had the highest adjusted sensitivity over 3 years.

Commentary

So is the Pap smear a thing of the past? In their clinical commentary, Huh et al discuss this issue of using HPV for screening for high-grade dysplasia and cancer. This commentary was in response to an FDA application for using HPV as a standalone screening test for cervical precancer and cancer. We now understand that for cervical cancer to occur, except for some rare subtypes, patients must have a hrHPV infection that is persistent. Infection with HPV is extremely common among young sexually active women, but many women have only transient infections, the majority of which will clear the HPV infection without any intervention.3 Thus, using HPV testing to screen women, particularly those ages 25-29, will have a high rate of positive tests, but a few women will have a persistent infection and even fewer will develop high-grade dysplasia or cancer. The current guidelines state that HPV should not be used alone and, in fact, women ages 25-29 years should have cytology without HPV testing because of the transient nature of the infection in this age group. Unfortunately for cytology to be predictive, we need multiple negative Pap smears to reach a reasonable specificity.

This group represented Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American College of Pathology, College of American Pathologists, and the American Society for Cytopathology. The conclusion was that there was currently enough data from both the ATHENA trial and European trials to consider HPV testing to be the most sensitive and specific screening test. Given that HPV 16/18 are responsible for the majority of the cancers in the United States, as well as the majority of CIN2/3, testing for HPV 16 and 18 and the pooled hrHPV makes the most sense. Women who are positive for either HPV16 and 18 have a much higher probability of having or developing CIN3 or ACIS, the precursor lesions for most cervical cancers. These women should be referred for colposcopy and biopsy. Women who are positive for the other 12 hrHPV types should be referred for cytology. A positive cytology (ASCUS or greater) should be referred for colposcopy and biopsy. Women who are negative for HPV should be retested in 3 years.

What would this mean for the gynecologist and what would this mean for society? The gynecologist would triage patients solely based on HPV status. There would be a tremendous saving because the cost of follow-up for abnormal Pap smears is enormous and estimated at more than $3 billion per year. What happens when a young women develops a cervical cancer in the 3 years between screening because she was exposed to a virulent HPV? We live in a society that accepts nothing less than perfect when it comes to medical care, and we would inevitably miss a few cancers. We have to ask ourselves if we are willing to miss some cancers to save money. In addition, some of the early data suggest that women are less likely to see their gynecologist when they are on a 3-year rather than a 1-year schedule. In response to these findings, we will need to educate patients about the limitations of screening and help the general public understand there is no perfect screening test. We either overscreen and use up our precious resources, as well as increase overtreatment (with the associated morbidity), or we reduce our screening to save money and make sure that the women we treat need to be treated. With the cost of medical care increasing and the ability to pay for care decreasing, we will need to accept that using HPV as our triage will save money and will probably not miss a substantial number of cancers as long as we screen separately for HPV 16 and 18.

References

  1. Wright TC, et al. Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol 2015;136:189-197.
  2. Monsonego J, et al. Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical precancerous lesions in a large U.S. screening population: Data from the ATHENA trial Gynecol Oncol 2015;137;47-54.
  3. Huh WK, et al. Use of primary high-risk papillomavirus testing for cervical cancer screening: Interim clinical guidance. Gynecol Oncol 2015;136:178-182.