Dr. Nayar, professor of pathology at Northwestern University Feinberg School of Medicine in Chicago, is co-chair of the Cytopathology Education and Technology Consortium, president of the American Society of Cytopathology, and a member of the CAP Cytopathology Committee. She spoke with CAP TODAY recently about the FDA advisory committee’s recommendation on cervical cancer screening.
CAP TODAY: What is your reaction to the FDA Microbiology Devices Advisory Committee’s recommendation that Roche’s Cobas HPV test be approved by the FDA as a primary screen for cervical cancer?
Dr. Nayar: This is an exciting, albeit sometimes difficult, transition period for cervical cancer prevention. Primary screening with HPV is a natural progression to a more sensitive first-line screen, especially important in the vaccine era.
The American Society of Cytopathology (ASC) has been preparing judiciously and consistently to meet the challenges related to changing practice patterns in pathology, while simultaneously identifying the opportunities these challenges pose. Specifically in cytopathology, the decrease in gynecologic test volume and increase in nongynecologic samples and associated ancillary testing have been predicted for more than a decade, even before the FDA approved cotesting with Pap and HPV. This advisory panel recommendation was not an unexpected or sudden turn of events.
This is the time for cytologists and laboratorians to continue to evolve, acquire emerging skills through changes in training and continuing education, and adapt to new roles. We must simultaneously work with our clinical colleagues to ensure that implementation of any new laboratory testing is appropriately validated, justified, and clinically relevant, and meets all quality and proficiency requirements.
CAP TODAY: Assuming the FDA accepts the recommendation, how do you believe the American Cancer Society and other professional societies along with the U.S. Preventive Services Task Force will respond in the formulation of cervical cancer screening guidelines?
Dr. Nayar: A task force was appointed in fall 2013 by the Society of Gynecologic Oncology (SGO) and the American Society for Colposcopy and Cervical Pathology (ASCCP) to proactively prepare a document for interim clinical guidance on HPV primary screening in the United States. Three joint representatives from the ASC, the ASCP, and the CAP were appointed to this group to provide input.
The guidance from this multidisciplinary group is expected to be published in the next few months. It will provide interim guidelines for the use of primary HPV screening, indicate when testing is inappropriate, and acknowledge the areas of caution due to limited data, including the laboratory-related issues raised by our pathology representatives on the task force.
At this time it is not known when the professional societies, the American Cancer Society, and the U.S. Preventive Services Task Force will issue updated guidelines for screening and managing cervical cancer and its precursors.
Clinicians in the United States will now have three different first-line screening options that have varying testing intervals and downstream triage algorithms. We know from prior guidelines it takes substantial time and effort to develop evidence-based algorithms and provide education for providers and patients. Despite concerted efforts to disseminate the 2012 consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, there is still significant variation in compliance. Cytology-only testing as well as cotesting are being used variably in different age groups. Thus, as with any new testing strategy, the adoption of primary HPV testing will most certainly require time and ongoing monitoring of clinician acceptance and patient compliance, as well as a cost-benefit and outcomes analysis.
CAP TODAY: The letter of the Cytotechnology Education and Technology Consortium to the FDA states: “There is a risk of false negative HPV results without the added morphologic control offered by co-testing because the platform lacks a control mechanism that specifically identifies the DNA of epithelial cells as opposed to other contaminating cells.” Please explain this concern in more detail. Did this problem show up in the ATHENA trial, or do you believe it is something that will only manifest itself in the real world outside the trial setting?
Dr. Nayar: The CETC is an independent consortium of professional organizations involved in diagnostic cytopathology. The member organizations are the American Society of Cytopathology, American Society for Clinical Pathology, American Society for Cytotechnology, College of American Pathologists, International Academy of Cytology, and Papanicolaou Society of Cytopathology.
As laboratorians, we are concerned about appropriate test quality 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 beta-globin gene internal control 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.
Although lack of the morphologic control (Pap test) did not appear to affect the candidate test’s clinical performance, this issue was not specifically addressed in the ATHENA trial data.
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.
Another current point of uncertainty regarding the data is that no follow-up protocol was provided for women who test HPV negative.
Laboratories should be cautioned that even when using FDA-approved HPV tests for primary screening and/or in conjunction with cervical cytology, they need to perform verification and continue to monitor quality assurance.
CAP TODAY: The CETC letter cites the 9.4 percent of HPV-negative cervical cancers and 3.2 percent of rare HPV subtype cervical cancers seen in the U.S. cancer registry study, cases that the Cobas HPV test would miss. But what about the 40 percent higher rate of false-negatives seen in Pap testing compared with the Cobas HPV test according to Roche’s prospective trial? How do you weigh the potential cancers missed by HPV testing against those potentially missed with Pap testing?
Dr. Nayar: The Pap is a specific but not very sensitive test. HPV testing, on the other hand, is more sensitive—though not 100 percent sensitive—but is less specific. Current management guidelines suggest cotesting in women age 30 or older. Cytology alone is suggested for younger women. This strategy significantly reduces the risk of false-negatives by cytology alone. In the Roche submission to the FDA, the candidate (HPV primary screening) was compared with cytology alone (comparator), not with cotesting. So the scientific question to be considered here is: How much protection does cytology cotesting add to HPV testing alone?
As we consider the scientific data and literature that have been gathered and presented and the data that will subsequently follow, our overriding goal should remain the same: to provide the highest level of quality care to the patients we serve.
We must, however, remember and reiterate that no screening test is perfect, and we cannot eliminate all risk with screening, no matter what 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.
A wide range of negative detection rates of high-risk HPV have been reported in cervical cancers, in the United States and internationally, using different HPV detection methods. HPV-negative cervical cancers are more frequently adenocarcinomas, which are on the rise compared with squamous carcinomas.
The Roche trial had relatively few women who were diagnosed with invasive cancer, and there was no significant difference in Pap versus HPV performance in these women. Most other HPV screening studies have also had relatively few women with invasive cancer, and many studies have been retrospective and used a variety of HPV analytic techniques.
Screening with HPV testing first, to be followed when positive by more specific testing (HPV 16/18 genotyping or Pap test), does follow general scientific principles and is supported by the ATHENA trial data. However as real-world testing offers challenges not seen in controlled clinical studies, the application of this testing algorithm to the general U.S. population will be far more complex.
To this point, the CETC letter to the FDA also stated: “To avoid an increase in cervical cancer cases, regular screening is required, with methodologies that provide an optimal balance between sensitivity and specificity and remain readily accessible and affordable for all women.”
CAP TODAY: What else should practicing pathologists be considering as they await the FDA’s decision on this matter?
Dr. Nayar: Practice patterns don’t change overnight. It takes time—sometimes several years—before new tests and guidelines receive acceptance and significant penetration in everyday practice. For example, cotesting (Pap with HPV testing) was approved by the FDA in 2003 and endorsed by management guidelines in 2006. Yet even today, a number of physicians perform cervical cancer screening in all women with Pap testing alone, with use of HPV limited to reflex testing for ASC-US (atypical squamous cells-undetermined significance).
We recommend that pathologists become knowledgeable about the relevant scientific data, the FDA’s final decision, and the subsequent clinical guidance document, or documents, so they are able to talk about HPV primary screening with clinicians who use their laboratory.
Calm, patience, and continued collaborative efforts among all pathology and medical specialties involved in cervical cancer screening will serve our patients best at this time.
CAP TODAY: Can you say a few words about the importance of HPV testing methodology?
Dr. Nayar: If FDA approval is granted for the Roche test, clinicians will very likely equate all HPV tests. However, individual laboratories use different HPV testing platforms, including laboratory developed tests (LDT). In this era of evidence-based medicine, we urge caution and stress that the use of the various available HPV tests should be restricted to indications supported by clinical evidence. In general, this means testing should be performed only with HPV tests that are FDA-approved for the specific indication—be it primary cervical cancer screening, cotesting, or triage of the minimally abnormal Pap.
The testing laboratory should be CLIA-approved and participate in regular proficiency testing. Clinicians should be advised to ask their respective testing laboratories which HPV test is used and whether it is FDA-approved for primary cervical cancer screening.
Note that Roche is seeking approval for primary HPV testing as an alternative method to cervical cytology alone and cotesting. The choice of cervical screening method may vary for a variety of reasons. Patient and provider preference, geographic, demographic, and socioeconomic considerations may all affect the choice of screening modality in a specific country, area, 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.