Two experts discuss whether a DNA test can replace the Pap.
Sarah Feldman, MD, MPH
Dr. Feldman is Associate Professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School, Director of Ambulatory Gynecologic Oncology, and Director of the Center for Pre-Invasive Disease of the Lower Genital Tract, Brigham and Women’s Hospital/Dana Farber Cancer Institute, Boston, Massachusetts.
She has no conflicts of interest to report with respect to the content of this article.
On April 24, the United States Food and Drug Administration (FDA) approved the cobas human papillomavirus (HPV) DNA test for use as primary cervical cancer screening among women aged 25 years and older. This is the first time that an HPV test has been approved in the United States for use independent of a Pap test, although there are 4 FDA-approved tests for use as a reflex (ie, after an abnormal Pap test) or as a cotest (at the same time as a Pap test).1
The FDA approval is limited to the cobas test within the screening framework presented to them, and the agency stated that it is the only test that is safe and effective as an alternative to cytology testing. This means that the FDA does not recommend the cobas test but has indicated that it is safe and no worse than the standard of care, ie, cytology/Pap screening or cotesting after age 30. National guideline committees so far have not issued recommendations about how to use the test, and we do not yet know whether the data presented to the FDA concerning the cobas test can be extrapolated to other HPV tests (which may not have been as rigorously studied), nor do we know the costs and benefits of different screening alternatives in different settings.
So what is known about primary HPV screening? Several prospective European studies have shown the improved sensitivity of HPV as compared to Pap in detecting high-grade dysplasia earlier, with improved long-term detection of cancer, although increased rates of colposcopy were noted, as compared to the use of cytology alone for primary screening.2
The recent FDA approval is based on a well-designed prospective study set in multiple US clinics (known as the ATHENA trial, funded by ROCHE and studying the cobas HPV test and ThinPrep cytology) and comparison of 4 screening strategies in women 25 and older who were managed under a specific study protocol.3 Only 3 years of data are available to date, and they have not yet been published (although they were presented to the FDA). Of note, current guidelines in women older than age 30 recommend cotesting at 5-year intervals; thus the comparison to standard of care is not yet available.
So far, the data presented show a notably improved rate of detection of high-grade dysplasia among women aged 25–30, especially those who test positive for HPV 16/18.4 Cytology is a particularly poor test in this age group, although HPV is particularly common, and the best balance of testing and increasing rates of colposcopy with actual cancer prevention is not yet clear. More data need to be accrued to understand the relative costs and benefits. The relative benefits for women age 30 and older are less clear, given that dysplasia is less common and cytology or cotesting at currently recommended intervals are reliable approaches in this age group.
Promising data from a well-designed study in US women, with limited long-term data, a very specific set of comparison algorithms, and using only one type of HPV test suggest that use of primary HPV testing for some women (especially in the 25–30 age group) may enable us to detect high-grade dysplasia earlier and more effectively than Pap testing. This might allow us to identify and treat precancers sooner, and thus perhaps focus our resources on greater surveillance of higher-risk women or screening of women who were previously unscreened.
It is important to note, however, that improved detection of precancerous changes of the cervix may not automatically translate into fewer cancers, as the ability to prevent cancer is related not just to the screening test used, but also to the management and resources used to intervene to prevent cancer. As greater numbers of young women receive HPV vaccination before the onset of sexual activity, a test that could better differentiate women at higher risk of developing cervical cancer may enable us to better focus our resources for cervical cancer prevention on those at higher risk. So, although we need longer-term data, as well as data about other tests in both vaccinated and unvaccinated women, HPV testing is promising and likely to have a role in the future in cervical cancer screening in the United States.
1. U.S. Food and Drug Administration. FDA News Release: FDA approves first human papillomavirus test for primary cervical cancer screening. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm394773.htm. Accessed October 23, 2014.
2. Ronco G, Dillner J, Elfstrom 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.
3. Wright TC, Stoler MH, Behrens CM et al. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46,e1-46.e11.
4. Roche Molecular Systems, Inc. Cobas HPV Test Medical Devices Advisory Committee Microbiology Panel Meeting: Sponsor Executive Summary. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/medicaldevices/medicaldevicesadvisorycommittee/microbiologydevicespanel/ucm388565.pdf. Accessed July 1, 2014.
NEXT: No. More data are needed before the HPV test can stand alone >>
Aparna Kamat, MD
Dr. Kamat is the Director of Gynecologic Oncology in the Department of Obstetrics and Gynecology at the Methodist Hospital, Houston, Texas.
She reports receiving service fees from Myriad Genetics.
The United States Food and Drug Administration (FDA) recently approved a DNA-based human papillomavirus (HPV) test as a primary screening option for cervical cancer in women 25 years and older. The cobas HPV test provides high-risk pooled HPV DNA results and individual detection of HPV 16 and HPV 18, both responsible for about 70% of invasive cervical cancer. While the cobas test is currently recommended for use alongside the traditional Pap smear, the FDA’s new approval permits the HPV test to be used on its own as a screening tool.
Current guidelines based on recommendations by the American Cancer Society and the US Preventive Services Task Force recommend that doctors screen women ages 21 to 65 every 3 years using a Pap smear.1 Alternatively, the groups recommend a screening procedure called “cotesting,” which combines the Pap smear and HPV testing for screening of women ages 30 to 65 for cervical cancer every 5 years. With the newly approved algorithm, women would be screened using the cobas HPV test. Those who test positive for HPV 16 and HPV 18 would be triaged directly to colposcopy and directed biopsies and only those who were positive for the other 14 HPV types would undergo cytology. Patients who are HPV-negative would undergo routine screening with further DNA testing, thus eliminating the Pap smear in the majority of cases.
While current screening guidelines remain unchanged, patients and physicians will now have the ability to choose the cobas HPV test over current screening methods. I believe that this will add confusion to an already complicated screening process, may result in unnecessary procedures in women between ages 25 and 30, and may miss detection of non-HPV cervical cancers.
These recommendations were largely based on the results of the ATHENA trial that tested 47,000 women and compared HPV testing to cytology as a screening option.2 The trial has several weaknesses. First, CIN2/3 was used as a surrogate for invasive cervical cancer in the trial. Based on different studies, the rate of spontaneous regression of these lesions varies from 6% to 50%. Thus, using CIN2/3 as a surrogate for invasive cervical cancer is likely overestimating the rate of detection. In addition, the quality of the cytology used in the trial varied widely with below-average abnormal cytology rates reported among the patients tested. Sensitivity for >CIN3 was only 58% in the trial,3 whereas the reported rate in our laboratory and others for significant cervical neoplastic disease approaches 93%; this is a quality control issue that was not addressed in the trial. More importantly, about 4% of cervical cancer cases are not HPV-related at all and about 10% of patients with invasive cervical cancer will test negative for HPV.3 These data underscore the importance of using HPV typing as an adjunct and not as a replacement for screening cytology.
In fact, data from Kaiser Permanente show that 5-year cumulative cervical cancer incidence is lowest with conventional Pap and HPV cotesting as compared to either method used alone.4 Using data from the largest laboratory pathology database in the United States, Quest Diagnostics issued a statement to the FDA that primary screening with HPV testing alone could miss 13.5% of cervical cancers that would normally be identified with cotesting. Finally, the FDA approval allows HPV testing in women ages 25 to 30, a group not covered under current screening guidelines. There are currently no data to support routine HPV testing in women in this age group, given their high rate of spontaneous clearance of the virus.
In addition, more women, especially in this age group, are likely to be referred to colposcopy and for unnecessary biopsies. The recent FDA approval will allow direct marketing of the cobas HPV test to patients and physicians as a screening test, a move that may be premature given the limited data concerning its efficacy as a primary screening tool for cervical cancer.
In summary, while HPV typing plays a key role in screening women for invasive cervical cancer, I believe longer follow-up and more data are needed before replacing the current screening guidelines with the cobas HPV test as a stand-alone screening tool for cervical cancer.
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. Am J Clin Pathol. 2012;137(4):516-542.
2. Stoler MH, Wright TC Jr, Sharma A, et al. High-risk human papillomavirus testing in women with ASC-US cytology.: results from the ATHENA HPV study. Am J Clin Pathol. 2011;135(3):468–475.
3. Park Y, Lee E, Choi J, Jeong S, Kim HS. Comparison of the Abbott RealTime high-risk human papillomavirus (HPV), Roche Cobas HPV, and Hybrid Capture 2 assays to direct sequencing and genotyping of HPV DNA. J Clin Microbiol. 2012;50(7):2359–2365.
4. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12(7):663–672.