In January 2015, the Society of Gynecologic Oncology (SGO) and the American Society for Colposcopy and Cervical Pathology (ASCCP), with input from five other professional associations, published interim clinical guidance on the use of primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening.1 The action followed the decision by the FDA in April 2014 to grant the first approval of an HPV test for use as a first-line screening test (primary HPV testing).
The guidance document supports primary HPV screening, using an FDA-approved test, in women 25 and older as an alternative to current U.S. cytology-based cervical cancer screening methods. Importantly, the new age threshold of 25 for the use of HPV testing is lower than the age threshold set by guidelines issued in 2012 by the American Cancer Society (ACS), ASCCP, and the American Society for Clinical Pathology (ASCP), which recommend HPV testing in addition to a Pap test (also known as co-testing) for women ages 30 to 65.
In the guidance, the societies provided substantial documentation to explain the rationale for HPV testing in the 25-to-29 age group. The key factors included the scientific evidence, clinical considerations that weigh the benefit of earlier detection of disease against the potential risk of interventions, including over-testing, in women who test positive, and the value of genotyping, which ultimately tips the balance in favor of early detection by providing a viable approach to risk stratification and appropriate management.
Cervical cancer risk ages 25 to 29
In issuing the interim guidance, the SGO and ASCCP considered evidence from 12 studies published since November 2011. In particular, the ATHENA trial,3 a study of more than 47,000 women, showed that approximately 30 percent of all women with grade III cervical intraepithelial neoplasia (CIN3), the highest grade of cervical pre-cancer, were between 25 and 29 years of age; by comparison, 37 percent were between 30 and 39 years of age. This is consistent with data from the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) Tumor Registry that show a sharp rise in the incidence of invasive cervical cancer between the ages of 25 and 34 years (Figure 1).4
Figure 1. Invasive cervical cancer in the U.S.: SEER Tumor Registry, 1975-2010
Summary of Interim Guidance (2015)1
Published by Society of Gynecologic Oncology, the American Society for Colposcopy and Cervical Pathology, and five other professional associations:
- A negative hrHPV test provides greater reassurance of low CIN3+ risk than a negative cytology result.
- Based on limited data, triage of hrHPV-positive women using a combination of genotyping for HPV 16 and 18 and reflex cytology for women positive for the 12 other hrHPV genotypes appears to be a reasonable approach to managing hrHPV-positive women.
- Re-screening after a negative primary hrHPV screen should occur no sooner than every three years.
- Primary hrHPV screening should not be initiated prior to 25 years of age.
Clinicians who wish to offer primary hrHPV screening to their patients are advised to inquire with their respective testing laboratories as to which hrHPV test is currently used and whether it is FDA-approved for primary screening.
The ATHENA trial also demonstrated that Pap testing performed poorly in this age group: more than 50 percent of the CIN3+ disease detected by the hrHPV test in women 25 to 29 was not detected by a Pap test. Together, the disease burden in this age group and the relative sensitivity of HPV testing compared to Pap testing support employing HPV testing to identify cervical cancer precursors in women of 25 to 29 years as part of an effective strategy to prevent progression to invasive cervical cancer.
The role of HPV genotyping
Historically, concern about HPV testing in women under 30 has been based on the relatively high prevalence of HPV infection in younger women, the emotional and financial burden of additional testing, and the belief that most HPV infections in younger women clear without intervention. However, the ATHENA data and other studies indicated a significant burden of pre-cancer in the 25-to-29 age group. The guidance documents note that genotyping provides actionable information that clinicians can use to help effectively utilize HPV testing. While 14 genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) have been identified as high risk, HPV 16 and HPV 18 are associated with about 70 percent of cervical cancer.
The interim guidance incorporates HPV genotyping as a risk stratification tool in the HPV primary screening algorithm in this way:
• Women who are HPV 16/18 positive should be referred to immediate colposcopy.
• Women who are HPV 16/18 negative but positive for one of the 12 other hrHPV genotypes should be reflexed to cytology (Pap) for further triage.
- If the sample is abnormal (≥ ASC-US), women should be referred to colposcopy.
- If the sample is normal (NILM—Negative for Intraepithelial Lesion or Malignancy), women should be re-screened in 12 months.
• Women testing negative for HPV should be re-screened no sooner than at a three-year interval.
In the ATHENA study, the strategy of combining primary screening with genotyping for HPV 16 and 18, starting at age 25, increased CIN3+ detection by 54 percent compared to applying the same strategy starting at 30 years of age—yet another reason for including the 25-to-29 age group in HPV screening.
In this context, it should be noted that the interim guidance document uses the term hrHPV testing, which is specific to the 14 hrHPV genotypes.
HPV vs. Pap clinical utility
The clinical societies have clearly signaled in the guidance that one of the most critical needs in cervical cancer screening is detecting clinically relevant infections and identifying patients who are at risk. The ATHENA study shows that HPV primary screening, compared to Pap testing, provided a 28.3 percent increase in sensitivity for CIN3+ in women ≥25 years and a 24.3 percent increase in women ≥30 years.
Just as important is the negative predictive value: A negative HPV test provides greater assurance of low CIN3+ risk than a negative cytology result, according to the study. In the ATHENA trial, the three-year cumulative incidence rate of high-grade pre-cancer (CIN3) and cancer (CIN3+) in women ≥25 years who were HPV-negative at enrollment was approximately half the rate compared to that of women who were cytology-negative at enrollment.
Also noted in the interim guidance is that performance characteristics vary among FDA-approved HPV assays and thus results are not necessarily comparable. “Clinicians who wish to offer primary hrHPV screening to their patients are advised to inquire with their respective testing laboratories as to which hrHPV test is currently used and whether it is FDA-approved for primary screening.”1
Implications for the clinical lab
As the clinical community continues to incorporate HPV testing in patient care, as new evidence points to the value of hrHPV testing in women 25-to-29 years, and as professional associations weigh the evidence supporting the uses of HPV testing for cervical cancer screening, the demand for HPV testing and genotyping is expected to increase. The clinical laboratory has the dual role of keeping its clinician clients up to date about the latest evidence, guidance and testing algorithms, as well as meeting the demand for increased testing. Above all, the clinical laboratory has a pivotal role in reducing the incidence of cervical cancer and lowering mortality through early detection.
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Gynecol Oncol. 2015;Jan 6. pii: S0090-8258(14)01577-7.
- Saslow D, Solomon D, Lawson HL, 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. doi: 10.3322/caac.21139.
- 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 Jan 6. pii: S0090-8258(14)01549-2.