Tuesday, September 28, 2010

Scenes from the Cancer Personalized Medicine Wilderness

I'm going to attempt to synthesize a number of thoughts which I've long pondered along with a bunch of news items I came across today. With luck, the result will be coherent and I'll not make a fool of myself.

There was a very interesting article last week in the New York Times on a serious ethical dilemma in melanoma and how different specialists in the field are voicing opinions on both sides of the divide. Even better, today I came across an excellent blog post reviewing that article which also added a lot of expert background. I'll summarize the two very quickly.

Metastatic melanoma is an awful diagnosis; the disease is very aggressive. Furthermore, the standard-of-care chemotherapy drug is a very ugly cytotoxic, with nasty side effects and very poor efficacy (more on that later). Sequencing studies have revealed that well over half of metastatic melanomas have a mutant form of the kinase B-RAF (gene: BRAF), most commonly the mutation V600E (which, alas, due to some sequencing error was for a while known as V599E). That's the substitution of an acidic residue (glutamate) for a hydrophobic one (valine), and it is right in the kinase active site.

Now, a biotech called Plexxikon, in conjunction with Roche, has developed an inhibitor of B-RAF called PLX4032. In Phase I trial results reported this summer in the New England Journal of Medicine, very promising tumor regressions were seen. Now remember, this was a single-arm Phase I trial for safety, meaning we don't have an objective comparison to make.

And there begins the rub. To some doctors (and many patients), the combination of great preclinical results, the theoretical and experimental underpinnings for targeting B-RAF in melanoma and the observed regression means we have a winner on our hands and it is now unethical to have a randomized trial comparing the new compound against the standard-of-care.

At the other pole are doctors who worry that we have been fooled before.
My standard example to trot out for such cases is a famous CAST cardiovascular trial to which a placebo arm was grudgingly added -- a sound theory had been advanced that
suppressing arrythmias in certain patients would prevent death. CAST was stopped early when it was clear the placebo arm fared far better; the toxicities of the drugs overwhelmed any benefits. Even closer to our current story is the drug sorafenib, which was originally developed as a B-RAF antagonist. Now, there are many in the field who argued that it really wasn't, but Bayer and Onyx got it to market (probably based on its inhibition of numerous other kinases) and the "raf" syllable in the generic name points to their belief in the B-RAF theory. Unfortunately, in randomized clinical trials it failed to work in V600E melanomas.

One idea that was apparently floated by at least one oncologist working in the trials, but rejected by the corporate sponsors, was to try to win approval based on nearly miraculous recoveries seen in some patients on death's door. What the NYT article failed to discuss is whether the FDA would buy that argument; there are many reasons to think they wouldn't -- they really do not like single arm trials, because all too often spurious results occur do to random chance (or rarely, to manipulation of the trial).

An important idea discussed in all this is the concept that once we have established a therapy as efficacious, it is generally unethical to withhold that therapy from patients. But, we are often not on such solid ground even in this area. Clinical trials represent a horrible case of multiple testing; more than a few drugs that squeaked through their trial would not if you ran the trial again; they just got lucky. Don't believe me? Think back to Iressa, which received accelerated approval for lung cancer and then had it withdrawn (only to later be reintroduced). We now know a key piece of that particular puzzle: Iressa works in patients whose tumors have mutant forms of the EGFR. The first trial, by chance, was enriched for such patients and the second trial (also by chance) was not as enriched. Given that the EGFR hypothesis wasn't known, neither trial could have been manipulated.

But another recent item, covered in a different post on the same blog, reminds us that even well-established clinical approaches may not hold true over time. Screening mammography is a hot potato issue in cancer: can you save lives by screening healthy women for breast cancer. Various studies have tried to ask this question not just for women overall, but by age groups since the incidence of breast cancer and the quality of mammograms changes with patient age. The newest fuel on this fire is a very clever Norwegian study, which I won't attempt to summarize, that suggests that much (but perhaps not all) of the benefit of screening mammography has been eroded by improvements in cancer care. In other words, the advantage of early detection has been blunted by better treatments. Now, I'm not qualified to really review that study, but certainly this is a concept we should keep in mind: the utility of medical strategies may change over time, and not always for the better.

In my mail tonight was a thick magazine-sized volume from Scientific American, which I confess I am not a subscriber of (it's a fine magazine; I just already subscribe to too many fine magazines). This special edition, titled "Pathways: The changing science, business & experience of health", focuses on healthcare with a mix of articles. Some appear to be written by professional writers, while others are thinly-veiled advertisements for various companies.

In scanning the table of contents, I was caught by "Pioneering Personalized Cancer Care", though unfortunately this turns out to be one of the puffier pieces. Written by two principles in the company, it mostly describes N-of-one, a company which has as its customers cancer patients. N-of-one tries to distill the available knowledge on a person's tumor and help them navigate to the most appropriate tests. It's a business model I've sometimes wondered about for myself, since playing an oncologic Sherlock Holmes could be both fascinating and rewarding. On the other hand, the regulatory environment is fraught with uncertainty and most likely this sort of organization will have to rely on wealthy customers willing to pay their own way.

Now, the article did set my teeth on edge early on with the statement "Recently, projects such as the Cancer Genome Atlas have documented thousands of mutations in cancer cells that can lead to unregulated cell growth and prevent apoptosis (cell death), the hallmarks of malignancy". Any regular reader of this space knows that I am a gung-ho proponent of sequencing tumors, but with that comes an obligation to be honest. And the honest truth is that sequencing has yielded thousands of candidates, but only a handful of those have actually been shown to have transforming ability -- there's just no high-throughput way to do that en masse.

But, what N-of-one and others are doing is where I strongly believe the future of oncology lies. But, it will be a complicated place. Getting back to B-RAF, I've heard noise that it has been found in a number of additional tumor types, albeit at low frequency. So, supposes it occurs at 1 in 1000 frequency in some awful tumor type. With routine whole-genome sequencing of tumors, we could detect that. Such sequencing is starting to be used to good effect, as reported recently in Nature. That leads to a conundrum for everyone. For a patient or clinician, do you go with PLX4032, given that we know it targets BRAF -- but knowing that we don't know whether BRAF is really driving your tumor (especially if the mutation is not V600E)? For those wanting to design clinical trials, could you really find enough patients to stock a trial -- or are you willing to have a trial with "any cancer, as long as it has a BRAF mutation"?

This is the challenge that personalized medicine presents us. With genome sequencing (and eventually also routine whole methylome profiling), we can find what makes cancers different -- but how will we ever actually sort through all those differences? Should we move away from randomized trials to going where the science seems to lead us, even knowing that more than a few times there have been dead ends?

I can find only one easy answer to all this: don't trust anyone who offers an easy answer to all this.


bioseoinformatics said...


Quit interesting topic you chose to work upon and appreciate information you provide..thanx.

Melchizedek 2012 said...

Every time I hear about a new anticancer compound that achieves tumor regression, I'm reminded of someone who convinced me that people die from metastases and mostly not from tumor growth. Furthermore, it is not all clear that tumor size and metastasis are closely linked (I think?). So are we applying the wrong endpoint?