The shifting landscape in cervical cancer screening

By several measures, however, cervical cancer screening is bucking that trend. In little more than five years, screening protocols, society guidelines, and even clinical practice have evolved dramatically to acknowledge the critical role of human papillomavirus (HPV) DNA testing in identifying women at risk—both in the United States and around the globe.

Evolution of screening guidelines

The American Cancer Society, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP)¹ issued joint guidelines for cervical cancer screening in March 2012, and very similar guidelines were issued by the U.S. Preventive Services Task Force² at about the same time. Although clinical studies highlighting the value of HPV DNA testing in detecting cervical disease had been proliferating for several years, the publication of the 2012 guidelines represented an authoritative validation of the growing realization that screening for certain high-risk genotypes of HPV DNA, coupled with appropriate triage strategies, had equivalent, if not better, positive and negative predictive value compared to cytology. Later that year, the influential American College of Obstetricians and Gynecologists (ACOG) issued updated screening guidelines³ also endorsing the use of HPV testing. All of these guidelines supported the use of HPV testing in a cotesting paradigm with the Pap test, for women 30 to 65 years of age.

Fast forward just two years to another landmark event in April 2014, when the FDA approved the first HPV test for primary cervical cancer screening in women 25 and older, along with an associated primary HPV testing algorithm. The decision was based on compelling data from recent landmark studies by Ronco,⁴ Wright,⁵ and others. Medical societies moved at uncharacteristically high speed to provide guidance to clinicians regarding this new option in screening protocols. Just nine months later, ASCCP and the Society of Gynecologic Oncology, with input from several other medical societies, issued an Interim Guidance Report supporting the option of primary HPV testing for women 25 and older. The following year, ACOG issued Practice Bulletin 157, updating its recommendations for cervical cancer screening to also support the option of using the FDA-approved test and algorithm for primary HPV testing.

More recently, in October 2016, the American Society of Clinical Oncology issued an evidence-based guideline⁶ for screening women around the globe for secondary prevention of cervical cancer. The guideline stratifies countries into low-, medium-, and high-resource settings (the U.S. being a high-resource setting). While specific screening and treatment protocol recommendations depend on the resource setting, the clear takeaway from the guidelines is that HPV testing is the optimal screening method, and that it should play a primary role in every resource setting.

Changes in global screening protocols

This trend of advancing the role of HPV DNA testing in screening protocols is not unique to the United States. If anything, the U.S. lags behind its more nimble global neighbors.

In the last three years, a notable list of developed countries has implemented guidelines that move HPV DNA testing into a prominent role for cervical cancer screening, often as a stand-alone test, while other nations are considering changes.

Several countries—the Netherlands, Sweden, Denmark, and Italy in particular—have already started to implement federally sponsored screening programs based on a primary HPV DNA testing model, either for the entire population or for specific subpopulations based on geography or age. Australia is moving in that direction as well. Some countries, such as Denmark, have opted to begin trial implementation of primary HPV DNA testing in older populations and gather outcome-based evidence while they assess the benefits of expanding the scope to include younger age groups. One of the critical age groups to consider for HPV testing is women 25 to 29 years old, a group that has shown a surprisingly high incidence of cervical disease and low sensitivity for the Pap test. (Currently in the U.S., guidelines only support HPV testing for this age group in the setting of primary HPV testing or ASC-US [atypical squamous cells of undetermined significance] reflex testing, in which HPV testing is done as a follow-up to inconclusive Pap results.) In the Wright et al. 2015 study, for example, there were more cases of CIN3+ in the 6,647 women ages 25 to 29 than in the 22,006 women ages 40 and older (119 cases vs. 88). And primary HPV testing had a slightly higher positive predictive value and equal negative predictive value for CIN3+ when applied to women 25 and older compared to women 30 and older.5

In the Asia-Pacific region, Taiwan and the Republic of Korea have taken the lead recently in updating screening guidelines to incorporate HPV testing, and currently follow a cotesting model. Turkey has a nationally sponsored program, and South Africa has recently updated guidelines to incorporate HPV primary screening.

Reinforcement from clinical data

The primary reason for the relatively fast evolution in guidelines and national protocol adoption across the globe is the continuing aggregation of consistent data underscoring the clinical value of HPV DNA testing, whether in a primary screening or cotesting model.

For example, ten-year data was recently reported from the Canadian Cervical Cancer Screening Trial,7 a randomized controlled study designed to compare the effectiveness of HPV DNA testing and Pap testing in a primary screening role for detecting antecedents of cervical cancer. The results indicated that a negative HPV DNA test at a three-year interval was associated with significantly less risk of  cervical disease versus a negative Pap. The authors also concluded that primary HPV DNA testing may allow for extended time between screenings and that genotype-specific testing for HPV 16 and HPV 18 may enhance the positive predictive value of the screening protocol.

Shifting clinician attitudes and practice

Even with an abundance of persuasive scientific data, clinical adoption of newer screening methods like HPV testing often lags behind guidelines, sometimes for reasons apart from science. (Some clinicians, for example, continue to perform annual Pap tests, a practice that is contrary to guidelines and out-of-sync with scientific evidence.) However, anecdotal evidence suggests a shift in attitudes and clinical practice among OB-GYNs in the U.S.

At the very least, there is clearly a migration from using cytology alone toward cotesting for women ages 30 to 65, which has been recommended in most U.S. guidelines for more than five years. A conservative estimate would place the proportion of OB-GYNS practicing cotesting above 50 percent.

At this point, few U.S. clinicians are performing stand-alone primary HPV testing rather than cotesting, despite support in updated guidelines and the availability of an FDA-approved IVD test. However, this may be driven by factors unrelated to scientific evidence or personal practice preferences. Many clinicians are constrained by HEDIS (Healthcare Effectiveness Data and Information Set) measures—which are used by most U.S. health insurance payers to measure performance on key service parameters. A low score may have a negative impact on a provider’s income. Current HEDIS requirements include a recent cytology (Pap) screening, so a clinician who opts for primary HPV testing will have a failing grade for this parameter on a HEDIS report card—unless he or she cotests, and can thus check off the Pap test box.

Current guidelines in the U.S also recommend a five-year testing interval in a cotesting model and a three-year interval for primary HPV testing or cytology alone, but evidence suggests that many clinicians are resistant to the five-year interval and some are even resistant to the three-year interval (as noted above). This is probably driven by a combination of factors, most notably the challenge of motivating patients to return for regular well-woman check-ups and a lack of confidence in the safety of waiting three to five years to rescreen patients.

Simplifying patient management algorithms

While clinicians assess the appropriate way to incorporate HPV testing into their screening practices, another trend is underway that may affect the way they manage patients—and potentially even the way labs report test results—for cervical cancer screening and prevention.

A concept currently in discussion in some clinical circles is the idea of streamlining and simplifying the multiple complex management algorithms and linking them to overall risk scores. While current U.S. guidelines are already risk-based, the alternative being discussed is that instead of having numerous algorithms to direct management for various combinations of testing in various groups of women, there would be a small number of management options depending on the patient’s risk level (e.g., dismiss from current round of screening, rescreen sooner than routine, colposcopy, direct to treatment without colposcopy).

The management option would be selected on the basis of the risk predicted by any combination of testing being above a certain amount. Guidelines would spell out the risk threshold and the appropriate management according to the level of risk. Thus, the tests could be used in combinations to determine the risk level, and the risk level would determine the treatment.

Another trend that may impact both HPV testing and patient management in the U.S. is the broader implementation of HPV vaccinations. Data from some studies in Australia show that vaccination is having an impact there, but HPV-based screening is still effective.⁸ However, it could take decades before vaccination in the U.S. population impacts HPV testing protocols.

REFERENCES

1. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American
   Society for Colposcopy and Cervical Pathology, and American Society for Clinical
   Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62(3):147-172.
2. Final Update Summary: Cervical Cancer: Screening. U.S. Preventive Services Task Force. September 2016. https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cervical-cancer-screening.
3. Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin Number 131: Screening for cervical cancer. Obstet Gynecol. 2012;120(5):1222-1238.
4. Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for
   prevention of invasive cervical cancer: follow-up of four European randomised
   controlled trials. Lancet. 2014;383(9916):524-532.
5. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. 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(2):189-197.
6. Jeronimo J, Castle PE, Temin S, et al. Secondary prevention of cervical cancer resource-stratified guideline. J Glob Oncol. 2016;Oct. 7.
7. Isidean SD, Mayrand M-H, Ramanakumar AV, et al. Human papillomavirus testing versus cytology in primary cervical cancer screening: end-of-study and extended follow-up results from the Canadian cervical cancer screening trial. Int J Cancer. 2016;139(11):2456-2466.
8. Brotherton JM, Gertig DM, May C, Chappell G, Saville M. HPV vaccine impact in Australian women: ready for an HPV-based screening program. Med J Aust. 2016;204(5):184.

A board-certified OB-GYN, Ed Baker, MD, FACOG, serves as Senior Director, Medical Affairs, for Roche Molecular Diagnostics, a business area of Roche Diagnostics that offers a broad range of PCR-based diagnostic and blood screening assays. He also serves on the faculty of the University of California-Davis Medical School.