An Early Cancer Detection Test, Put To The Test

There’s been a lot of talk in recent years about “liquid biopsies” and especially about the promise of using blood samples to test for a wide variety of cancers at once. In most cases, this involves looking for fragments of tumor-associated DNA or RNA that are circulating in the blood, and on the face of it, that seems like a pretty good plan. But it has some challenges.

One is whether or not a given tumor sheds enough signal to be a reliable marker or not, and that depends both on the amount of DNA/RNA and also on its stability in the blood. The second is just deciding what signal you’re looking for, and especially making sure that it’s not something that can lead to false positives when derived from normal tissue. And of course you have the usual analytical concerns when you’re looking for very small amounts of something in a very large and very mixed sample: what’s the signal/noise of your assay technology, and how much does it vary from marker to marker to marker? Then there are larger questions, such as: does this detection - even if it’s reasonably successful - actually benefit the patients? That sounds like an odd thing to ask, but consider what happens if some tumor type only generates a solid readout once it’s too advanced to treat. The real endpoints are improvements in mortality and morbidity, and those can be difficult to prove.

A test in this area that’s had a lot of press is Galleri, from a company called Grail. They’ve been selling the test for several years now although it hasn’t yet been FDA-approved, and that means that people are almost entirely paying out of pocket (nearly $1000, and last year the company says that they had 185,000 customers).

So how does that work? This business goes on under the provisions of the Clinical Laboratory Improvement Act (CLIA). That is a framework that tries to standardize the complexity and scope of various diagnostic tests, and if you read that link you’ll see that this is just as wooly a prospect as it sounds like. There is a category under the CLIA called “laboratory-developed tests”, which are supposed to be developed and used within a single lab, and the FDA has stated that these can indeed be on the market without prior approval. The 23-and-Me people started by offering their direct-to-consumer sequencing test in just such a fashion, but the FDA (in a rare move) forced them to seek approval as a medical device. I believe that Galleri (and the competing CancerGuard test) are in the “ask your doctor” category rather than being DTC to avoid this sort of problem.

People watching this field - physicians, patients, and not least, insurance providers - have been waiting for a large prospective trial in the UK to read out on Galleri, one involving 142,000 patients aged 50 to 77. This is just the sort of thing these tests need, and I have to applaud the Grail folks for being willing to run it rather than just continuing the wink-and-nudge business model (which of course does have its limitations, compared to, say, getting on the Medicare formulary). Over the weekend those results appeared.

The readouts were how many people got a cancer diagnosis, compared to a control group that didn’t get the test, and how many of these were in the (far more actionable) stage 1 or stage 2 of the cancer. The hope was to show a 20% reduction in advanced-cancer diagnoses overall. Unfortunately, the total number of people diagnosed at stage 3 or stage 4 did not show any statistically significant reduction in the Galleri patients as compared to controls - a complete miss.

Perhaps that endpoint was a bit ambitious, although if you look at the advertising in this field, it’s really the sort of thing that the early-screening companies are implicitly promising. This really is about the worst result that Grail could have had, and it’s not going to help out the other people in this field, either. I would have to think that the pressure is on now for anyone promulgating a multiple-early-detection assay to run a real trial like this one and to show that they don’t get the same disappointing results. And even if they'd met their goals, questions would remain, as pointed out here at Stat: this is still too short a trial to get the sorts of mortality improvement readouts mentioned above.

It should be! What we’ve seen here is that what seems to be a sensible idea for early cancer detetion, implemented with the latest technology, can come up completely short. And that should make everyone stop and think for a minute. Lots of reasonable and/or exciting ideas in medicine collapse when you put some weight on them, sadly, and we should never forget it and never pretend that we’ve suddenly rewritten the rulebook and dodged the need for experimental proof.