The search for the Holy Grail

One of the holy grails in carcinoid/NETs research is a reliable diagnostic test that will consistently find the presence of the disease. Many forms of imaging, blood tests and urine tests fail to see tumors that a surgeon’s knife discovers. But opening up a patient absent a good reason to do so is not a practice any reputable surgeon would consider.

…it could be a game changer…

As a result, many patients are excited by a new test, called NETest, marketed by Wren Laboratories that promises to detect carcinoid/NETs tumors with a single blood test. The test is based on three papers by researchers from Yale and uses 51 different genetic markers that, taken together, indicate the presence of carcinoid NETs in a person’s body according to the researchers.

Claims for the test

According to the company website, the NETest can reliably tell if a patient has carcinoid/NETs. It says it can be used after an operation to determine whether or not surgeons got all the tumors there were to get or not. It says it can measure the efficacy of treatment. It says it can be used after a “cure” to determine whether or not the disease is really entirely gone.  Finally, it says it can, if you have symptoms, determine whether or not those symptoms are caused by carcinoid/NETs.

…many patients are excited by a new test…

The test uses two five ml blood samples and does a polymerase chain reaction test on them to unveil those 51 genetic markers that may be hiding in the sample. The lab then reports those results on a 0-8 scale with 1-4 representing low levels of NETs activity, 5-6 representing medium activity, and 7-8 high activity. Both the site and the papers the test is based on say the test has a high sensitivity level for carcinoid/NETs: 85-98 percent compared to the 64 percent recorded for the Chromogranin A test that is currently in use. CgA tests for a single peptide many–but not all–carcinoid NETs tumors produce. The company says the better  results come from the fact it is looking for 51 markers that are all associated with the disease.

The cost of the test

While the samples themselves do require some special handling, there are no real restrictions on what foods patients can have beforehand–nor much of anything else. The cost of the test is $750. If you want a consultation with one of their physicians before or after the test, it’s another $1000–but that consultation is not required.

The test uses two five ml blood samples…

However, the test is not yet covered by insurance. The company says they have applied to the AMA for a billing number and their decision is due this month (April 2014). Meanwhile, they are offering three free tests per patient. So what’s not to like?

Where is the FDA testing?

The papers the test is based on were written last fall. The test became available very quickly after those papers were published. That struck me as peculiar because most tests don’t become available until they have gone through a series of FDA trials. Even a Phase I trial for an orphan disease like carcinoid/NETs takes more than six months to complete. I first heard about a possible blood test to replace the 5-HIAA urine test not long after Jane’s death–and it may have been around well before that. It is only becoming available broadly now.

…the test is not yet covered by insurance.

I can find no record of an FDA trial for NETest. The website says the test has been validated with over 600 NET cancer patients–and another 1000 either cancer free or with other cancers. But if that took place under an FDA regimen, I would expect that to be mentioned. It isn’t. The only trials specifically mentioned are going on overseas.

What the numbers say–Part I

In the company’s defense, they do say the test is being used at “the Mount Sinai Hospital (New York), the Mayo Clinic (Rochester), and Yale University (New Haven) and is being implemented at Cedars-Sinai Medical Center (Los Angeles), the University of Iowa (Iowa City) and Columbia University (New York),” all of which are respected cancer centers in the US. But the tests were also available at a number of patient conferences as well–bypassing traditional ways of gaining access to patients.

I can find no record of an FDA trial for this test.

There are also some problems involving the way in which one of the papers lays out the basics of carcinoid/NETs incidence and prevalence. Using the same statistics every other paper uses to declare this a rare disease–an incidence of 3.6/100,000 and a prevalence of 35/100,000–the authors declare the disease common. I am not quite sure how that works.

What the numbers say–Part II

Do not misunderstand me: I think the disease is significantly more frequent than those numbers show. But I can muster no evidence beyond the anecdotal for that belief. Until we have other, concrete and replicable, evidence to dispute the prevalent view, we don’t get to argue the disease is common on the scientific stage. Nor do we get to cite the same numbers that declare the disease rare to declare it common.

…the authors declare the disease common.

That use of the interpretation of numbers makes me nervous about the rest of the paper: is this a work of science or is it the prospectus for a business venture? The two don’t mix very well for me.

Financial Connections

Another problem is the connection between Wren Laboratories and two of the authors of the papers who have a financial connection to the company. Irvin Modlin, the Medical Director of Wren Laboratories, is the primary author on two papers the test is based on, and the second author of a third paper cited on the website. Mark Kidd is the company’s Scientific Adviser–and the third author on two papers.

 Nor do we get to cite the same numbers that declare the disease rare to declare it common.

The authors do acknowledge in the studies that the research was funded by Clifton Life Sciences, but make no mention of Wren in their disclosures. Perhaps that is because Wren was only formed after the pieces went to press, but some acknowledgement on their website of that connection for papers posted there would be the ethical thing to do–or so it would seem to me.

The scientific method

That connection may not mean much to some people, but it evidences a significant problem: there is no independent acknowledgement that what they are saying is true. No one has independently reproduced their results–and that is one of the hallmarks of modern science: can someone else replicate your results independently of your lab and supervision?

 …two of the authors…have a financial connection to the company.

I am not saying they are lying or that they fudged their results. But I grew up in a household where the scientific method was sacred–and part of that method is independent verification. That seems to be missing here. I’d be much more comfortable if it were present. FDA trials would provide that.

Where do we go from here?

For now, at least, we need to treat these results as preliminary, for all that they are interesting–even promising. I can fully understand the excitement patients feel about them. I feel that same excitement myself. And for those who have been trying–sometimes for years–to get a straight answer about what they have, the test may offer that knowledge.

No one has independently reproduced their results…

But from a medical point of view, there are other questions that need to be answered before doctors can be entirely comfortable with it. In addition to those I’ve raised above, these include how–or if–this test should influence patient treatment; who should be tested and when; and finally, what ethical questions will doctors have to deal with? Assuming the test does work as advertised, these pieces of the puzzle still need to be addressed.

Trust, but verify

I really hope that this  turns out to be the armor-piercing bullet we are all looking for. It would be nice to have an ironclad diagnostic tool for carcinoid/NETs. It would be more than nice: for many, many patients it could be a game-changer. It could be a game-changer for researchers as well because it potentially provides a fuller genetic map to the disease’s weaknesses.

I feel that same excitement myself.

But until these red flags are lowered, I am not entirely willing to place even a small wager on what is on offer here. After the three free tests, each additional test is $750. Whether insurance companies will agree to pick up that tab absent FDA approval or other replication of the results remains to be seen.