The ASC leadership and its membership are committed to supporting women’s health and working collaboratively with other pathology and clinical professionals to effectively prevent cervical cancer in the United States.
Primary screening with HPV is now one of three currently available test options for cervical cancer screening. We can best serve our patients by:
a) Understanding the value, as well as the limitations of various testing options available for cervical cancer screening.
b) Offering clinically validated testing with adequate quality control in our laboratories.
c) Keep abreast of the current published scientific data so that we are able to effectively communicate with our clinical colleagues and other professional organizations.
With the FDA approval of the first HPV test for primary cervical cancer screening on April 25th 2014, clinicians in the United States will now have 3 different first line screening options that they may offer to patients: the Pap test, co-testing with Pap and HPV tests, and HPV testing as a stand-alone test. Specifically, the Roche Cobas® HPV Test was approved for primary screening for cervical cancer as a stand-alone test. To date, none of the other FDA-approved HPV tests (Qiagen’s Digene Hybrid capture® 2, Hologic’s Cervista® HPV and Hologic-Genprobe’s APTIMA® HPV Assay) have been approved for this indication. Note that there is no role for low-risk HPV testing in cervical cancer screening and management.
As cytopathologists and cytotechnologists what should we be aware of with respect to discussing this testing option with our clinical colleagues and among ourselves when considering offering this test in our laboratory? Some key considerations are included below.
Which Test has been recently approved for primary cervical cancer screening by the US FDA?
The first, and currently only FDA approved test for Primary HPV screening for cervical cancer in women 25 and older in the United States is the cobas® HPV Test, which is manufactured by Roche Molecular Systems, Incorporated, Pleasanton, California.
The cobas® HPV Test is a qualitative in vitro test for the detection of Human Papillomavirus (HPV) in patient specimens. The test utilizes amplification of target DNA by the Polymerase Chain Reaction (PCR) and nucleic acid hybridization for the detection of 14 high-risk (HR) HPV types in a single analysis. The test specifically identifies types HPV 16 and HPV 18 while concurrently detecting an additional 12 high- risk types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68).
The cobas® HPV Test was first approved by the FDA in 2011 for use in conjunction with or as a follow-up to a Pap test. The additional approval expands the use of the test as a first-line primary cervical cancer screening test.
Cervical specimens that may be tested with the cobas® HPV Test include the following liquid based collection media and collection device:
• ThinPrep® Pap TestTM PreservCyt® Solution
• Endocervical Brush/Spatula
Details of the test and approval can be found in the cobas® HPV Test package insert and at www.hpv16and18.com. (Ref 1).
What was FDA’s basis for approving the Roche HPV test for primary screening?
The FDA requested the appointed advisory committee to assess whether the cobas® HPV Test is safe and effective for the proposed new intended use as a primary screening test for cervical cancer.
Data supporting the use of the cobas® HPV Test as a primary screening test for cervical cancer included the U.S. based, multicenter, prospective ATHENA study of approximately 40,000 women, ages 25 years and older undergoing routine cervical cancer screening. Women who had a positive Pap test or who screened positive for HPV, as well as a subset of women whose Pap and HPV tests were both negative, underwent a colposcopy and cervical biopsy. All biopsy results were compared to the Pap and cobas® HPV test results. Data from this study, which included three years of follow-up on women who went to colposcopy, suggested that the cobas® HPV Test is safe and effective for this expanded indication for use as a primary screening test (Ref 2-4).
Details of the FDA advisory meeting, including a complete transcript of the proceedings and supporting data are available on the FDA website (Ref 5-6). Additional data from Roche’s ATHENA trial, as well as data pertaining to comparison of HPV only testing at 3 years to Pap/HPV co-testing at 5 year intervals is due to be published later this year.
What should laboratorians be aware of when considering if they should offer HPV primary screening?
Since cervical cancer screening using HPV alone is a new option, with limited long term follow up data, it is important for laboratories who offer HPV primary screening to use methodology that has been FDA-approved for this specific indication and verified in the testing laboratory. Laboratories should be enrolled in adequate proficiency testing and perform regular quality control and statistical analysis of HPV tests that are used for screening (co-testing/ primary screening) and triage.
Laboratorians should communicate with their clinical colleagues to clarify the various testing modalities that the laboratory is able to offer for cervical cancer screening and provide adequate and clear test options in order to enable appropriate test utilization.
Did the ASC and CETC give any input to the FDA before its approval of the Roche HPV test for Primary Screening?
The Cytopathology Education and Technology Consortium (CETC) member organizations include the American Society of Cytopathology (ASC), the American Society for Clinical Pathology (ASCP), the American Society for Cytotechnology (ASCT), the College of American Pathologists (CAP), the International Academy of Cytology (IAC) and the Papanicolaou Society of Cytopathology (PSC).
The CETC submitted a written statement to the FDA advisory panel for its March 12, 2014 hearing on the Roche PMA, and a summary of the CETC concerns was presented to the panel by CAP CETC liaison and ASC Executive Board member, Dr. Patricia Wasserman.
The CETC stated that
“The Pap test and the dedication of professionals like cytotechnologists and pathologists have significantly benefited women’s health by reducing the incidence of, and mortality from, cervical cancer. However, cervical cancer screening in the United States remains opportunistic, with far from uniform test accessibility and patient compliance. It is not an organized national program with patient reminders as in the United Kingdom and other European countries that are considering adoption of primary HPV screening. To avoid an increase in cervical cancer, regular screening is required, with methodologies that provide an optimal balance between sensitivity and specificity and remain readily accessible and affordable for all women.”
The CETC asked the FDA advisory panel to consider the following concerns that may potentially impact safety and efficacy for cervical cancer screening in the United States, if HPV primary screening is approved by the FDA:
(1)Test internal control.
In the Roche package insert for the cobas® HPV test, information regarding specimen adequacy, the internal control for epithelial cellular components and potential interfering substances is limited. The Roche HPV test uses a beta-globin gene internal control as a measure of specimen adequacy; this is not specific for cervical epithelial cells. For example, Roche did not show that beta-globin from inflammatory cells could not cause a false assessment of a specimen as adequate if it contained only inflammatory cells and no epithelial cells. In the ATHENA trial, several morphologically unsatisfactory cytology samples did appear to have valid HPV testing results; however, more problems may arise when this testing is used outside of clinical trials.
(2) HPV Negative Cervical Cancer
As with any laboratory test, the sensitivity of HPV testing is not 100%. A subset of carcinomas, both squamous and glandular, and other tumor types may not be detected by HPV testing. A recent United States cancer registry study found that 9.4% of cervical cancers were HPV negative and an additional 3.2% contained rare HPV subtypes (Ref 7).
(3) HPV Testing Methodology
As laboratorians, CETC cautioned that primary screening should be performed using HPV tests that are FDA-approved for the specific indication of primary cervical cancer screening. The testing laboratory should be CLIA-approved and participate in regular proficiency testing and perform verification and continually monitor quality assurance.
(4) Follow up of Primary HPV screen results
Before primary HPV screening for cervical cancer is adopted in clinical practice, there should be clear evidence-based guidelines for the follow-up of positive and negative tests to prevent loss of women to appropriate follow up and potential increases in cervical cancer incidence. The prevalence of HR-HPV types varies with demographic populations and the current US population is very diverse, in contrast to the patient populations in the prior European trials. Due to the documentation of HPV-negative squamous cell carcinoma and adenocarcinoma, women should have a morphological examination (Pap test) in their screening history and should not be screened solely with HPV tests. Screening younger women with HPV tests may increase overall patient harm from overtreatment of positive results that detect low grade squamous lesions and women under 30 may be better served using a less expensive, more specific test – the Pap test.
When will clinical management guidelines for HPV Primary Screening be available?
The Roche PMA sought the expanded indication for using HPV as a first-line screening test for the cobas® HPV Test – Roche specifically proposed that women who are 25 years and above can be tested first with the cobas® HPV Test in order to triage them into the appropriate risk groups as follows:
a) Women who test negative for high-risk HPV tests by the cobas® HPV Test should be followed up in accordance with physician’s assessment of screening and medical history, other risk factors, and professional guidelines.
b) Women who test positive for HPV genotype 16 and/or 18 by the cobas® HPV Test should be referred to colposcopy.
c) Women who test high-risk HPV positive for any of the 12 other high-risk HPV types, but are 16 and 18 negative, should be followed up with cytology to assess the need for colposcopy.
The FDA approval of primary HPV screening does not change current medical practice guidelines for cervical cancer screening. Primary screening with HPV alone is currently not included in the consensus guidelines for cervical cancer screening in the U.S. and it will be up to our professional societies to discuss inclusion of such a screening option in future medical practice guidelines. Cervical cancer screening guidelines allow professional societies to distinguish preferred screening algorithms from acceptable screening algorithms. They are also able to provide detailed recommendations for how to follow-up on specific cytology results and/or specific combinations of cytology and HPV test results over time, even for women who do not have immediate colposcopy. A woman who is not sent immediately to colposcopy may be followed up in different ways depending upon her test results, history and clinical findings.
A task force appointed by the Society of Gynecologic Oncology (SGO) and the American Society of Colposcopy and Cervical Pathology (ASCCP) is preparing an interim clinical guidance document for HPV primary screening in the United States. This is expected to be published in the next few months. Drs Diane Davey, Robert Goulart and Ann Moriarty were the joint ASC-ASCP-CAP representatives to this task force. At this time it is not known when other professional societies, including the ACS and USPSTF, will issue updated guidelines for cervical cancer screening.
We know from experience with prior guidelines that it takes substantial time and effort to develop evidence-based algorithms and provide education for providers and patients. In spite of concerted efforts to disseminate the 2012 ASCCP Consensus Guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, there is still significant variation with compliance. Currently, cytology only testing, as well as, co-testing are being used variably in different age groups for cervical cancer screening. It is estimated that co-testing is being utilized in less than 50% of patients in the United States. Thus as with any new testing strategy, the adoption of primary HPV testing will most certainly require time and ongoing monitoring of clinician acceptance, patient compliance, as well as, cost-benefit and outcomes analysis.
As we consider the current and future scientific data and literature, our overriding goal should remain the same – to provide the highest level of quality care to the patients we serve. However, we must remember and reiterate that no screening test is perfect. We cannot eliminate all risk with screening, no matter what is the test or target. The very basis of screening requires that it be done periodically and repeatedly be it a Pap test, mammogram or primary HPV screening.
The choice of cervical screening method may vary for a variety of reasons. Patient and provider preference, geographic, demographic, and socio-economic considerations may all affect the choice of screening modality in a specific country, region, or practice setting. As is well proven, any screening is better than no screening, and we must keep availability and cost to our patients for all of these screening options in the forefront of our discussions.
- Cobas® HPV Test [package insert, US]. Branchburg, NJ: Roche Molecular Systems, Inc; 2011
- Stoler MH, Wright TC, 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.
- Wright TC Jr, Stoler MH, Sharma A, Zhang G, Behrens CM, Wright TL. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol. 2011; 136: 578-586.
- Castle PE, Stoler MH, Wright TC Jr., Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a sub analysis of the ATHENA study. Lancet Oncol. 2011; 12(9):880–890.
- US FDA Primary HPV Screening Approval- Press Release
- US FDA Advisory Meeting materials
- Hopenhayn C, Christian A, Christian WJ, et al. Prevalence of Human Papillomavirus Types in Invasive Cervical Cancers From 7 US Cancer Registries Before Vaccine Introduction. Journal of Lower Genital Tract Disease 2014; 18(3). DOI:10.1097/LGT.0b013e3182a577c7