In an effort to increase the accuracy of cervical cancer diagnoses, a team of researchers is developing a urine test that looks for methylation (a mechanism used by cells to control gene expression) in four genes and, at this early stage, shows evidence of both dramatically improving detection of cancer and enhancing physicians’ ability to determine that a woman does not have cancer. Their work was recently published in the Cancer Prevention Research journal. This news release on the test is something of an explanatory tour de force that explores the path taken to develop the test, but it may require a great deal of effort to follow that path. The release doesn’t give enough attention to the potential downside of the test — a real risk of under-diagnosis — and fails to clearly signal that this diagnostic effort is still at an early stage, making the validity and eventual availability of the test uncertain.
Most cases of cervical cancer occur in developing countries, where Pap tests may be less available for cultural or cost reasons. A urine test that costs less than current diagnostic procedures and that provides increased diagnostic accuracy would offer significant public health advantages in these countries.
This study seeks to address whether a simpler tests could be used to screen initially positive Pap/HPV results in a way that eliminates the falsely positive ones while keeping all of the ones that really need definitive treatment. The investigators used several DNA tests that show promise, but still aren’t perfect. Here the key parameter of interest is sensitivity. You want this to be as close to 100% as possible. Every miss could mean serious consequences for the affected woman. Specificity is less important — it means that the test wasn’t any better than the initial Pap/HPV, and a woman (living in the developed world) might be referred on to a colposcopy test. Whether further studies will show the advantage of this new test or a similar one remains to be seen. But what is really needed is a simple urine screening test that could replace the internal exam that is needed for the current Pap/HPV. Such a test would be useful in both the developed and developing world. That would be a game-changer.
The release suggests that a urine test would be less costly than a Pap test, but it makes no effort to indicate what the cost is of either the proposed test or a Pap test.
We rate this a borderline satisfactory. On the one hand, the release offers numerical summaries of the test’s abilities to both correctly detect cancer (sensitivity) and correctly identify someone who does not have the disease (specificity). But the text does a relatively dense job of explaining how the investigators reached the urine-test stage, creating a narrative that will require a determined reader and could thwart someone giving the text a more cursory view.
The release does make it clear that this small urine test study correctly identified those without cancer 83% of the time, a considerable improvement over the false positive rate of the more traditional Pap test.
But the real risk of this new test is that it may indicate a false negative — suggesting all is well — when it isn’t. Under the best of scenarios, the new test gets it wrong 10 in 100 times. When applied to a more usual practice setting, it gets it wrong 15 to 25 in 100 times. Here getting it wrong may mean missing an advanced pre-cancerous lesion or even a cancerous one. One can argue that even 1 in a 100 times is too much, but in developing countries this may be better than current practice. However, we don’t believe the risk of false negatives has been clearly or addressed.
The release offers a good bit of detail about the researchers’ path to the urine test, a process that involved isolating relevant genes and testing blood samples before turning to urine sample tests. This description gets specific about the size of the various samples used and, if read carefully, yields a reasonable understanding of the studies conducted. Left unsaid is that a “proof-of-concept” study is an early stage in the process of developing a diagnostic test.
Disease-mongering is not a feature of this release. The focus of the release is on a new, presumably cheaper test for cervical cancer, a major killer in less developed countries. The release also puts the problem of cervical cancer screening in global context.
Although the release offers no information about possible conflicts of interest (the article on which the release was based indicates the absence of such conflicts), it does provide information about funding. And it does disclose the start of a collaboration between the team and a company that intends to design and market a urine test product.
The text does a good job of comparing this potential urine test to the traditional Pap smear and to two relatively new commercial tests based on a search for methylation in DNA.
From the data provided, this new test offers no advantages in developed countries where Pap/HPV rates are high and follow-up with colposcopy is available. The issues in developing countries are two-fold. One is whether a urine test could be used as an alternative to the Pap smear/HPV test as the first screen. A urine test would be a much easier screening test. But what they’re examining is when the Pap/HPV is abnormal, can you can eliminate the need for some colposcopies.
All depends on a reader’s understanding of the nature of a proof-of-concept study. This urine test is not yet available, but that will be murky to non-specialists unless the term is defined. Reading between the lines it is evident that further testing is needed before it can be used as part of routine care.
The writer does a good job of making the case for novelty here.
The text is explanatory and not dominated by florid language or predictions. However, if the trial’s results came from better tissue samples than would routinely be available (sophisticated lab sampling versus testing performed in a clinic) the release may paint a rosier picture of the test than is warranted.