Current Status and Future Trends in Cervical Cancer Screening

How has testing for cervical cancer changed since the discovery that persisting cervical infection with human papillomavirus causes the disease?

The discovery that persistent cervical infection of high-risk human papillomavirus (HR-HPV) genotypes causes virtually all cervical cancer and its immediate precursors has led to the development of clinical DNA and RNA tests for HR-HPV. There are currently four US FDA-approved HR-HPV tests (cobas® 4800, Roche Molecular Systems [IN, USA]; APTIMA, Gen-Probe, Hologic [MA, USA]; Hybrid Capture® 2, QIAGEN [Hilden, Germany]; and Cervista®, Hologic [MA, USA]) and several other tests being commercialized and validated. Many countries are switching to, or evaluating the switch to HR-HPV testing. There is overwhelming evidence that HR-HPV testing is more sensitive, but less specific, than cervical cytology (e.g., Pap smears or liquid-based cytology) for the detection of cervical precancer and cancer. Over the last few years we have started to see countries switch from cervical cytology to HPV testing. Even those countries that have very good cervical cytology programs are examining when and how to switch; we will see much more of that in the future. In low- and middle-income countries where there is currently no cervical cytology testing (80% of the world), those that are now considering any secondary cervical cancer prevention are just going straight to, or considering, HR-HPV testing rather than cytology.

What is the current status of cervical cancer screening? What are some of the innovative practices that countries are testing?

The main innovation is the switch from cervical cytology to HR-HPV testing as a preliminary screen (as a rule out test). An important attribute of HR-HPV is that because it is more sensitive than cervical cytology for cervical precancer and cancer, it permits a safe extension of screening intervals among the negatives, which then results in less harm due to screening and potentially lower costs. Essentially, by using HR-HPV testing to first screen the population; it permits a shift from performing frequent cervical cytology testing on all women, to performing cervical cytology testing on just those who have the necessary cause of cervical cancer, HR-HPV. The innovation is the extending of intervals, so rather than screen every 1, 2 or 3 years by cervical cytology you can extend to 5, 6 or 7 years with HR-HPV, and what has started to happen, and will happen over the next year, is that there will be guidelines from various national and international organizations recommending HR-HPV testing. The EU is going to recommend HR testing, some other international bodies will also recommend HR testing, the USA has already recommended HPV and cytology ‘cotesting’ every 5 years, but I believe that may eventually change to HPV testing alone every 3–5 years. So that is the real innovation, that we are shifting the screening from doing routine cervical cytology on everybody at a high frequency, to doing cervical cytology among HPV-positive women who have the necessary cause for cervical cancer. Through doing so, one can potentially save money, clinical visits (which is also money) and manpower. Ideally women who are low risk and don't have the causal factor will be screened infrequently, which is common sense; the focus and effort will be on those who have the causal factor. It may seem obvious, but until we had the tools and until they were clinically validated, this was just a theoretical discussion. Now, with these assays becoming readily available, we can shift priorities and resources to HPV-positive women.

In which environments or circumstances would HPV-based screening be appropriate? Where are screening programs headed in terms of adoption of HPV-based testing?

HR-HPV testing is suitable for all environments where cervical cytology testing currently occurs and, in addition, in many where cervical cytology testing is not possible – that is, in all environments that provide basic laboratory services, except perhaps in populations with high HR-HPV prevalence, such as HIV-infected populations. Many countries are already either implementing or evaluating HR-HPV (some are still performing randomized clinical trials to decide if and how to use it), but over the next 5–10 years we will see a big shift away from cervical cytology as a screening test, instead using cervical cytology as a diagnostic in HPV-positive women to determine who needs care today and who can wait. In low-resource settings that have never been able to establish a cervical cytology-based program (Pap testing has been around for over 50 years), simplified molecular testing will offer a much more robust solution than the traditional conventional Pap test smear or other cervical cytology methods.

Another point is that many of the new laboratory platforms will be multi-analyte platforms, so they will run multiple clinical tests. Therefore, these can be very easily integrated in the laboratory, as opposed to cervical cytology, which requires a standalone skill set. I believe that it is fairly straightforward to train a laboratory technician to run the tests so it is not a specialized skill, it doesn't use specialized tools and can provide a suite of assays that many platforms have or will have that will meet the clinical laboratory needs, for example, a gonorrhea and chlamydia test. Thus, one person will be running 10, 15 or 20 laboratory tests from a single platform. This simplified laboratory testing is good for everyone and is certainly good for patient care and quality assurance.

What are some of the reasons behind why women do not participate in screening programs?

I think it is important to differentiate between high-income and low- and middle-income countries.

In high-income countries, the small percentage of women (>20%) who do not participate in screening programs tend to be impoverished and cannot pay, or do not have health insurance to pay for screening. Lack of participation can also be linked to geographical barriers and lack of education on the importance of screening. All of these factors are inter-related. In these countries, while there is good screening coverage of most of the population (>80%), through surveillance one can identify ‘hotspots’ where the coverage is poor. This is true in the USA, in places such as in the Mississippi Delta, along the US–Mexico Border, in Appalachia and the US-Associated Pacific Islands. These are small segments of the population that are either disenfranchised or underserved and are not receiving routine care. Importantly, the high cervical cancer incidence observed in these regions is a flag for other health disparities.

In the low- and middle-income countries, there have been no effective, high-coverage cervical cancer prevention programs, so having robust, easy to use tests makes it at least theoretically possible to establish regional or national programs, provided that a country is willing to invest in the healthcare infrastructure to deliver both the screening and the care.

Which methods for self-collection have been previously tried for cervical cancer screening? What are the advantages of paper/card-based collection methodologies?

Taking a step back, self-collection has two components. One is how you actually collect the sample and the second is how you get it to the laboratory. There are a lot of different methods for self-collection, for example, different brushes. There are a couple of decent strategies now that, from a clinical performance standpoint, work basically equivalently, so fancy methods do not really work any better than the simple soft bristle brush that is easily inserted in the lower genital tract, turned three times and pulled out. The results suggest that this method is successful and probably more sensitive than very good cervical cytology testing, although it is a little less specific [1,2]. Again, the fact that the patient doesn't have to travel to the clinic is a real benefit, particularly in third-world countries where there are not enough clinics. If you wanted to screen the entire population even once, you would shut down the few clinics there are for all of the other care, which they need to provide to their population. The clinics would cease to operate because there would be lines out the door for screening. We must, therefore, consider the possibility that at least the primary screen should be moved out of the clinic. Now we come to the transport part, which is really where the paper-card collection methods, such as GE Healthcare's indicating FTA™ elute card, could help. The potential advantages of this method, once validated clinically (i.e., demonstrated to have good clinical performance characteristics), when coupled with HR-HPV testing, is that there could be potential lower cost, better specimen stabilization, easier laboratory processing, reduced spillage in transport (as there is no liquid medium) and increased safety (nonflammable and lower toxicity) in transport. Some other collection methods may provide for dry transport, which may have some advantages too.

How do self-collection methods compare with traditional screening methods in terms of analytical performance?

In terms of analytical performance, there is solid evidence that there is good agreement between a set of patients who self-collected sample and a clinician collected sample. The analytic perimeters, such as agreement, tend to be approximately 90% and κ-values tend to be approximately 0.7 or 0.8.

In terms of clinical performance, as I mentioned previously, the clinical performance of HPV testing using self-collected specimens is less sensitive and less specific than using clinician-collected specimens, but more sensitive than cervical cytology.

As many places in the world do not currently have high-coverage, effective cervical cytology programs, the use of self-collected samples and HR-HPV testing could potentially take screening from virtually 0 to 70–90% sensitivity, which could have a major impact on the population risk of cervical cancer, if implemented widely.

In terms of the card specifically, there has been a series of pilot studies demonstrating that the card, like any self-collection medium, has very good agreement with the clinician-collected sample [3–10]. In a recently published study, we demonstrated that there was good 90% total agreement, 68% positive agreement and κ-value of 0.75 between a standard specimen medium and paper/card-based medium for HR-HPV detection [11]. The next step will be to demonstrate that the card, used with self-collection in a large population, can achieve the clinical performance that is needed for effective screening, for example, a range of 70–90% sensitivity and 80–90% specificity.

What is the current level of interest & willingness to accept self-collection among women? What opportunities exist to drive adoption of this methodology?

Again, I would split the issue up into the high-income and low- and middle-income countries.

In the high-income countries, typically 50% of cervical cancer occurs in small pockets of the population not being served by the current healthcare programs, either because the programs do not reach them or there are social, political, economic, geographic and/or racial/ethnic barriers preventing them from participating in these programs. A few studies have started to target these medically underserved women to see whether they will self-collect. The results are variable and depend on the population and what technique was tried. Several studies have tried to simply mail self-collection kits to women who were identified through a data registry as not having undergone screening in recommended intervals. Approximately 25% of women sent back their self-collection kit [11].

The greater challenge is to increase this coverage to approximately 70–80%. This will require more interactive outreach than just sending it by mail. We carried out a study in the Mississippi Delta region in the USA, which is one of our hotspots, where we offered women who had not undergone screening in 3 years or more, self-collection versus Pap and free cervical cytology screening at the local clinic, through a door-to-door recruitment. More women selected self-collection and HPV testing, even though that was the first time they had ever heard of it; and more women returned their self-collected specimen compared with those who went for their free Pap test. As result, almost four times the number of women participated in self-collection and HPV testing as underwent their free Pap test. Outcomes can vary greatly depending on how these programs are rolled out, but this is a potential tool to increase coverage [11].

In low- and middle-income countries, it is a different scenario. There is tremendous international interest in utilizing self-collection and HR-HPV testing for screening, especially in low- and middle-income countries, where there is a severe lack of clinics to permit the collection of specimens by providers. At the individual level, the acceptability is quite variable, and probably depends on a number of factors, such as education and knowledge or ease of use.

There is often a knee-jerk reaction when you talk to people from third-world countries, when they state “our women won't self-collect”. However, most women have never had a pelvic examination either. I would argue that these women may not like the idea of a pelvic examination in front of a complete stranger either and perhaps like it less than self-collection in privacy.

I think that it will be easier to encourage the general population to self-collect in the privacy of their own home, at a clinic or at some other acceptable location (e.g., in bathroom at a pharmacy); have the specimen returned to a healthcare worker, delivered to collection site or mailed; and have it tested for HR-HPV than clinic-based screening. The program can then focus its outreach efforts on the 10 or 15% who test positive for HR-HPV and let them know that they have to come in for a pelvic examination to see what is going on with their cervix. That is more feasible than trying to get 100% of the population to undergo a pelvic examination.

How could the adoption of new methodologies for screening be fostered?

It always starts with data, so you have to develop the evidence. You have to demonstrate how the whole thing works as a package, that women will be willing to do it, that they will successfully do it, that you will achieve good clinical performance, and ultimately you will demonstrate that not only are you finding precancerous disease, but that doing so also leads to future reductions in cancer incidence and mortality. This is the goal. I think that demonstrating good clinical performance in an objective, unbiased trial has tremendous importance in terms of acceptance, because then that can serve as the basis for creating evidence-based guidelines for best practices. Education of providers and patients is critical. Providers need to know what best practices are. If women aren't aware of the importance of cervical cancer screening then they don't understand and they will probably not take part in the screening program. So the importance of educating patients can't be underestimated. The upside is, of course, that self-collection has the potential for empowering women to start taking care of their own health. It is a small thing to go into the bathroom and collect a sample, put it on a card, seal it in a container and mail it back or have your community healthcare worker pick it up. This would allow women to contribute greatly to their own health and that empowerment is a great secondary benefit of extending screening programs through self-collection.

Are self-collection-based screening methods appropriate for both the developed and low-resource regions of the world?

In developed regions, self-collection could be used to reach underserved populations and populations unwilling to come to the clinic or undergo a routine pelvic examination. Even though cervical cancer incidence rates are low in these countries, half the cancers that do occur are in those small pockets of the population who are underserved by the current programs. As discussed above, in low-resource settings, self-collection can permit the primary step of screening to occur outside the clinics, which are in short supply, and overcome potential barriers to pelvic examination.

What other diseases could self-collection be used for? How can you see this technology impacting on women's health in the future?

First, we don't need to limit this technology to women; any specimen that is easily obtained or that can be taken at home could be amenable to self-collection and put on some sort of transport medium. Related to HPV, men identified as at high risk of anal cancer could self-collect anal specimens at home, as has been demonstrated to work. For women and men, self-collected anogenital specimens could be collected to screen for other sexually transmitted infections, such as chlamydia and gonorrhea, as has been carried out widely in the USA, or for other infections. Another example would be that self-collected oral specimens could be used for genetic testing, provided that the genetic marker for particular diseases is useful for clinical decision-making. Any specimen that is safe and amenable to self-collection could be collected onto a card and sent in as a primary screen and the advantage, even in developed countries, is that the cost of the clinic visit may be averted. We all know that rising healthcare costs are presenting a significant burden on the global economy, so the more that we can reduce unnecessary clinical visits, the better for everybody.

Disclaimer

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd.

Financial & competing interests disclosure

P Castle has served as a paid consultant for BD, Roche, Cepheid, GE Healthcare and Gen-Probe/Hologic. P Castle has received HPV tests and reagents for research at a reduced or no cost from QIAGEN, Roche, Norchip and mtm. P Castle is a paid member of a data and safety monitoring board for clinical trials of HPV vaccines for Merck. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Future Medicine Ltd conducted this interview, support for which was provided by GE Healthcare. GE Healthcare had no editorial control over the content. The opinions expressed in this article are the author's own and do not necessarily reflect the views of Future Medicine Ltd or GE Healthcare.