By: Patricia S. Braly, MD
Following more than a year of review and discussion, experts representing the Society of Gynecologic Oncology, the American Society for Colposcopy and Cervical Pathology and representatives from five other professional associations published interim clinical guidance (“interim guidance”) on the use of primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening.1 The panel supports primary hrHPV screening in women 25 years and older as an alternative to current U.S. cytology-based cervical cancer screening methods and states that “a negative hrHPV test provides greater assurance of low CIN3+ risk than a negative cytology result.”
To clinicians, this is only the beginning as we go through the process of understanding the guidance, reviewing the underlying evidence and rationale, assessing the practical considerations for implementation, evaluating its impact on patient care and putting the guidance into practice.
Results from the ATHENA trial,2 along with 11 publications since November 2011, informed the panel’s decision. Results from several studies, including European trials and a study of more than 300,000 women at Kaiser Permanente Northern California, showed significantly lower three-year risk of developing CIN3 or worse in hrHPV-negative women compared to cytology-negative women.2-5 In the ATHENA trial, there was a substantially lower three-year cumulative incidence rate of high-grade cervical intraepithelial neoplasia (CIN3) and cancer (CIN3+) in women 25 years and older who were hrHPV-negative at enrollment compared to women who were cytology-negative at enrollment. “Because of equivalent or superior effectiveness, primary hrHPV screening can be considered as an alternative to current U.S. cytology-based cervical screening methods,” the panel notes.
In determining the appropriate strategy for cervical cancer screening, a key consideration for the practitioner is the level of assurance that a negative test result can provide to the patient. From this perspective, the ATHENA data clearly demonstrates that the cobas® HPV Test, approved by the FDA for primary screening, has better negative predictive value than the Pap test and increased sensitivity for the detection of pre-cancer, particularly in women aged 25 to 29.2 In particular, the likelihood of a woman with a negative Pap test progressing to CIN3 in three years is 0.8%. By contrast, the likelihood of progression to CIN3 for a woman who tests negative on the cobas HPV Test is 0.3%. The likelihood of progression to CIN3 for a woman who tests negative on both cytology and HPV is also 0.3%. This means a negative cobas HPV Test provides twice the safety reassurance of a negative Pap test.6
What about patients who test positive in primary HPV screening? What approach should the clinician take to provide patients with information they need to understand the results? The primary HPV screening algorithm recommended by the panel offers clear directions.
More than 100 types of HPV have been identified to date, one third of which infect the genital tract.7 Two HPV types, HPV 16 and HPV 18, account for about 70% of cervical cancer. The ATHENA study demonstrated that one in four women who are HPV 16 positive will progress to CIN3 or greater within three years. Twelve other genotypes (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) have also been identified as high risk. For women who are positive for HPV 18, risk for CIN3 or greater within three years is intermediate between HPV 16 and the 12 other high-risk genotypes.
Thus, HPV genotyping can provide additional information for risk stratification to guide appropriate management. The interim guidance recommends colposcopy for women who test positive on HPV 16 or 18. For women who test positive for HPV on the other 12 genotypes, but not 16 or 18, a Pap test is recommended. If the Pap test is positive (i.e., ASCUS or greater), then colposcopy is indicated. If the Pap test is negative, the interim guidance suggests a follow-up in 12 months.
In this way, appropriate management, and use of healthcare resources, is stratified by level of risk based on genotyping. An added benefit is being able to provide patients with information they need to better understand their test results.
While the evidence is compelling, widespread adoption of the interim guidance will depend on several factors. First and foremost is awareness by the clinical community of the guidance and the availability of an FDA-approved HPV test for primary screening. Second, despite long-standing guidelines on co-testing, the value of HPV testing is not universally recognized. As a gynecologic oncologist, I see many patients referred with abnormal Pap results. And it is not unusual for the patient presenting with invasive cervical cancer to have a history of normal Pap results. This experience suggests that negative Pap results alone are not sufficient to classify a patient as low risk. In fact, I believe that HPV testing over time can be used to predict ongoing risk assessment. Equally important is educating staff and patients about the value of HPV testing. In particular, education to help remove the stigma associated with HPV as a sexually transmitted agent will go a long way in convincing patients that testing positive for HPV does not equate to having a sexually transmitted disease.
A 60-year-old woman with a history of normal Pap test results presented with heavy bleeding. Upon referral by her gynecologist, biopsy showed that she had invasive squamous carcinoma extended to the left parametrial tissue as well as enlarged pelvic lymph nodes. The patient responded well to primary external beam radiation and chemotherapy. HPV testing would have identified the patient as high risk for cervical cancer, and pre-invasive lesions could have been treated before cancer progression.
A 26-year-old nulligravid woman presented with a history of post-coital bleeding for 1 to 2 months. She had no history of abnormal Pap smears, with her last normal Pap being done 15 months before her presentation. Her Pap done at presentation was HSIL, suspicious for invasion, and she was positive for hrHPV. An exam showed an exophytic mass on her exocervix, and biopsies confirmed invasive squamous cancer of the cervix. Her workup confirmed a Stage 1B1 cancer, and she underwent a radical hysterectomy with pelvic lymph node dissection. Her final pathology showed a 2.3-cm invasive cancer with negative margins and lymph nodes. She developed a local recurrence eight months later and was treated with chemotherapy and radiation therapy but eventually died of her disease.
In the published interim guidance, the panel includes several cautionary notes. The panel points out that test results can vary based on factors such as specimen adequacy and laboratory procedures. The panel emphasizes the importance of using FDA-approved tests, and that the interim guidance restricts primary hrHPV screening to only one assay with an approved primary screening indication. Accordingly, the panel recommends that clinicians “inquire with their respective testing laboratories as to which hrHPV test is currently used and whether it is FDA-approved for primary screening.”
To an extent, the more than 50% decrease in the incidence of cervical cancer over the past 30 years, largely due to the use of cervical cancer screening with the Pap test, may be a reason for complacency. However, cervical cancer remains a key concern for clinicians and patients. According to the National Cancer Institute, there are more than 12,000 new cases of cervical cancer in the United States annually and 4,210 deaths due to the disease, with the incidence and death rate failing to improve over the last 20 years. In the face of compelling data demonstrating the value of HPV testing, the clinical community needs to work toward integrating HPV testing into their strategy for preventing cervical cancer. Long-term outcome data on the impact of HPV testing as a primary screening modality on reducing cervical cancer and the associated health and cost benefits will help drive change.
Patricia S. Braly, MD, is a board-certified gynecologic oncologist with a practice at Women’s Cancer Care, Covington, Louisiana, and former Chief, Section of Gynecologic Oncology of the Louisiana State University Medical Center in New Orleans. Dr. Braly has published more than 100 papers, abstracts and book chapters and is an invited speaker at numerous professional conferences here in the U.S. and abroad.
1. 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.
2. 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.
3. Gage J, Schiffman M, Katki HA, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst 2014;106:1-4.
4. Ronco G, Giorgi-Rossi P, Carozzi F, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 2010;11:249-257.
5. Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ 2008;337:a1754.
6. cobas® HPV Test [package insert]. Indianapolis, IN: Roche Diagnostics, 2014.
7. ACOG Practice Bulletin no. 109: Cervical cytology screening. Obstet Gynecol 2009;114:1409-1420.