This piece in Science says something that needs to be said louder and more publicly. If you live in the US, you’ve surely seen various cancer treatment centers talking about their personalized therapy plans, and especially how they’ll tailor things to your DNA sequence and so on. You would get the impression that we have an arsenal of specifically targeted cancer therapies, waiting for patients to get their tumors sequenced so they can be paired with the optimal treatment.
That’s not true. I wish it were, but it just isn’t. And I fear that a lot of patients and their families actually believe that it is, which can make for some bad decisions (both medically and financially). I can hardly blame them much, though, because for years now there’s been a ceaseless flow of stories in the press about targeted therapies, genomic sequencing of patients, breakthroughs, advances, new DNA this and advanced sequence that and on and on. I think it’s safe to say that the average patient does not have the time nor the expertise to keep up with the actual biomedical literature, and thus relies on headlines and advertisements for an impression of the field, and that impression is pretty far off of reality.
The Science article, which covers a debate at the recent AACR meeting between David Hyman and Vinay Prasad, estimates that only about 15% of patients total are currently even eligible (under FDA guidelines) to have their tumors sequenced in hope of matching with a targeted therapy. About one third-of those may actually benefit from the process in the end. This is not exactly what you’d expect if all you knew about this stuff was what you heard on TV. The thing is, that’s actually a great advance, because the number used to be zero, in both categories. We really are making progress, and the people who can benefit really can benefit. It’s just that there aren’t nearly as many of them as we’d like, not yet.
But I can’t pin this just on clueless news readers – even back in 2003, the head of the NCI (later head of the FDA, Andy Eschenbach) was talking about “eliminating death and suffering” due to cancer by. . .2015. We have missed that deadline. In 2006 (as that link shows), he was going on in a similar way about how we’d moved to a whole new level, everything had changed, etc. In general, whenever someone starts talking about “the next level” or something like that, I check to make sure my wallet is still in my pocket. This isn’t a game we’re working through – it doesn’t have “levels”, and in fact, not many large complicated real-world things do. Quantized jumps happen on the microscale. Up here, we’re grinding it out, and that’s how cancer therapy is advancing.
Another reason for the confusion is that people have different ideas about what “precision targeting” in oncology really is. The term got applied early on to the wave of kinase inhibitors and so on that targeted particular cellular mechanisms (rather than just being wrecking balls like some of the earlier chemotherapy drugs), and that muddied things a bit. Some of the earlier successes in this area came about because some (relatively rare) tumor types really do seem to be pretty genetically homogeneous: they occur in pretty much the same way for the same reasons. So if you target that mechanism, you’re likely to see an effect; it’s like the situation in many human genetic disorders, and it doesn’t happen that way in cancer too often. But the high-profile successes against things like GIST confused some parts the public, I think, into thinking that the different bodily locations of cancer were all like that – genetically distinct from cancer in other organs, but very similar to each other.
Would that it were so. The second level of confusion comes to the DNA-sequencing aspect, which is at least closer to reality in terms of how cancer works, if not its treatment. “OK’, this story goes, “this patient has (something)oma, so let’s take some cells and see what variety of it they have so we can give them the drug that works against that subtype”. That’s what too many people think we have now, and what in a few cases we actually do (as above). But most of the time we don’t really understand what’s going on at a cellular level, as gets proven every time another promising oncology mechanism wipes out in the clinic.
And even with those successes, there’s room to wonder how far this idea can be pushed. Here’s a piece on that from 2016 (more Vinay Prasad), wondering just how precise it’s possible to get. One big problem is that many solid tumors are a terrible mixture of cell types. They generally got that way by being genomically unstable, and that unstability just goes on and on. That’s where all this fine targeting really runs into trouble: what if a given patient’s tumor is a mixture of eight or nine different cellular forms of cancer? Well, eight or nine that you know about so far?
That’s one reason that immuno-oncology is such a hot field, because (to a first approximation) it’s saying “OK, we don’t know how all you cells became cancerous and we don’t care. We can set it up so that (for example) you all get recognized by killer T cells, and they will take you out no matter what your pedigree”. Problem is, we’re not quite to this stage for all but a very few forms of cancer. By far the most successful are blood-based cancers like leukemia, where the cells really are quite similar to each other by oncology standards, giving you a chance to wipe them out en masse. Getting that to happen for solid tumors is. . .not so easy. The more successful immuno-oncology for solid tumors, so far, is using antibodies to go after potential common mechanisms like PD-L1 that are fending off such T-cell attack, but (a) we don’t have such markers for most solid tumors, and (b) in many cases, the most we can do now, usually, is to wipe out most of of a patient’s tumors (best case) leaving behind an untouched residue of mutated cells that eventually comes back in untreatable fashion.
I’m not putting that down at all – this can buy people substantial more life, although not always. In every case, you have to see (with real-world clinical data) how much actual survival you’ve been able to achieve. That’s another big reason that we missed that absurd 2015 date, because it takes years to figure out just how well these therapies actually work in practice. It’s a slog, and I don’t see any way for it not to be a slog, and it’s too bad that that doesn’t make for a very compelling slogan.