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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Antipsychotic Drugs Against Cancer? | Main | Cancer Drugs: Value for the Money? »

July 30, 2012

Bert Vogelstein on Cancer Drugs and Cancer Screening

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Posted by Derek

Here's an interesting profile of Bert Vogelstein, who has had a major impact on oncology over the years, especially in the area of cancer-associated genetic mutations. Some of his recent work bears on the question of how useful some of the newer drugs are:

Vogelstein seems to enjoy pricking balloons. Recently, he has focused on a new target: exuberance over targeted cancer drugs. He says he got interested after seeing a paper last year on melanoma therapy. It included photos of the torso of a man with melanoma who had received a new drug aimed at a mutated gene called BRAF. Before treatment, the patient's skin was riddled with metastatic tumors; soon after treatment, the tumors vanished, and the man looked perfectly healthy. Five months later, the tumors reappeared in exactly the same locations. The photos “blew my mind,” Vogelstein says. “Why do the tumors all return at roughly the same time? It's almost as miraculous as when they disappear.”

Targeted drugs for other cancers usually stop working after about the same number of months, presumably because rare resistant cells in the tumors continue to grow and ultimately proliferate. To investigate, Luis Diaz and others in the Vogelstein-Kinzler lab drew on a sensitive technique they had developed for detecting mutations in the very small amount of tumor DNA present in a cancer patient's blood. They collected a series of these “liquid biopsy” measurements from patients with advanced colorectal cancer whose tumors had become resistant to a targeted cancer drug. With Harvard University computational biologist Martin Nowak, they devised a model showing that even before the patient begins treatment, some tumor cells always carry genes with random mutations that can support resistance to targeted drugs. This form of resistance, they wrote last month in Nature, is therefore “a fait accompli.”

But the modeling study also suggested that this resistance can be delayed by combining two drugs that target different pathways. Indeed, Vogelstein and colleagues suggest that once a targeted drug has passed initial safety trials, it's so clear that single-drug therapy will fail that they consider it unethical to give patients just one such drug. “Why shouldn't you design a large, very expensive trial to incorporate more than one agent?” Vogelstein asks.

There are a lot of labs working on this "liquid biopsy" idea, and it's the sort of thing that you could only imagine doing with modern DNA sequencing technology (and modern DNA sequencing costs). A big worry, as with any screening technology, is the false positive rate. As you make finer and finer distinctions among different tumor types, the incidence of any given one in the population gets lower and lower, and thus your test has to be more and more reliable in order to avoid overdiagnosing hordes of panicked patients.

Interestingly, when I talk to people outside of the medical research field, they seem less worried about overdiagnosis than underdiagnosis (false positives versus false negatives). Psychologically, I can see how that happens - they don't want to the test to miss anyone. But being told that you do have cancer, when you really don't, is not a good outcome, considering what the therapy will put you through. And this is what makes things like the PSA test recommendation (and mammograms in younger patients) so controversial. In the push to make sure that you find every patient, you can end up harming more people than you help. "But if you just save one life. . ." goes the phrase, at least goes the phrase from people who don't realize that they might be ending the sentence with ". . .it's worth killing off a few more".

I hope that the blood test idea works out; it would be a great advance. But a less-than-optimal one could be worse than having none at all. Look for plenty of arguments about this in the coming years - I'll fill in some of the talking points in advance: "The FDA is holding back medical progress by not approving this new test". "The FDA has given in to commercial pressures by approving this faulty new test". "This test will end up hurting more people than it helps". "How can you be against cancer screening? Isn't it always worth looking?". "This is all just a disguised cost-cutting effort; they're approving this test because it's cheaper than doing better screening". "This is all just a disguised cost-cutting effort; they're not approving this test because they're afraid that too many people will be diagnosed with cancer". And so on.

Comments (11) + TrackBacks (0) | Category: Cancer | Regulatory Affairs


COMMENTS

1. SP on July 30, 2012 9:03 AM writes...

I find that explaining things like statistics to non-scientists is easier if you present the extreme cases. We could do no cancer testing at all; or I could market my new UltraSensitive test, which comes back positive for every singe person. It's 100% guaranteed to never miss a case of cancer, so shouldn't everyone get tested?

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2. Morten G on July 30, 2012 10:34 AM writes...

Please close the italics.

The latest numbers I heard for mammograms was that they caused one case of breast cancer for every two they detected. Is that right?

One thing that makes the liquid biopsy more robust is that cancer cells are genetically unstable and thus very many of them simply die. This causes increased levels of DNA in the blood in general and some people are trying to use that as a screening tool for cancer. If you find low copy numbers of common cancer mutations in the blood you can simply repeat the test a week or two later and for that matter you can expand the number of mutations you look for.

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3. Anonymous on July 30, 2012 11:44 AM writes...

The drug needs to stop the rampant proliferation, and its ability to do that will depend on the tumor's genetic makeup. Of course it will mutate over time... evolutionary biology 101... so anyone pinning hopes on a single stand-alone treatment's long-term effectiveness is naive.

One cocktail to halt it, another follow-up cocktail to keep it under control.

Trouble is, the regulatory environment & cost to try out varying combinations that vary over time isn't ideal.

BTW... modern DNA sequencing costs are going down rapidly, from not at any cost 10 years ago, to millions of dollars, to thousands of dollars, to a recent estimate I heard of, with a goal of $100 within 5 years. That's less than what the doc charges for reading an Xray. If costs do get that low, false positives can be checked for by a duplicate run.

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4. partial agonist on July 30, 2012 11:45 AM writes...

The drug needs to stop the rampant proliferation, and its ability to do that will depend on the tumor's genetic makeup. Of course it will mutate over time... evolutionary biology 101... so anyone pinning hopes on a single stand-alone treatment's long-term effectiveness is naive.

One cocktail to halt it, another follow-up cocktail to keep it under control.

Trouble is, the regulatory environment & cost to try out varying combinations that vary over time isn't ideal.

BTW... modern DNA sequencing costs are going down rapidly, from not at any cost 10 years ago, to millions of dollars, to thousands of dollars, to a recent estimate I heard of, with a goal of $100 within 5 years. That's less than what the doc charges for reading an Xray. If costs do get that low, false positives can be checked for by a duplicate run.

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5. MDACC Student on July 30, 2012 12:41 PM writes...

I've spoken with graduate students and postdocs about this for years. I guess we need to get out of the lab and go to a conference or something...because this is so well ingrained we just gloss over it when we talk to each other.

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6. lewis robinson on July 30, 2012 12:41 PM writes...

One of cruelest things that the paranoid inflict on the research community, is that they know how to cure cancer and are keeping it for themselves.

One of the saddest points in the article Derek refers to, concerns his collaborator Kenneth Kinzler. Their lab had a 7 member Rock band called Wild Type including Vogelstein and Kinzler. 10 years ago Kinzler's wife developed leukemia and died in 6 months. The band has never played since.

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7. MDACC Student on July 30, 2012 12:47 PM writes...

Edit: I was referencing the "a fait accompli."

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8. Jonathan on July 30, 2012 2:42 PM writes...

Vogelstein recently gave a lecture on campus and I was horrified when he talked about his idea for massive cancer screening via sequencing. You think healthcare costs are bad now, wait until you're dealing with the huge number of false positives that generates!

Permalink to Comment

9. Anonymous on July 30, 2012 8:57 PM writes...

Incidentally, a group that we share a floor with has been working on a blood test since forever; it seems pretty tough going because some of the events are so rare that you almost unavoidably get both false positives and false negatives. I've always wondered if it's possible to compute or model the abundance of circulating tumor genetic material and then the probability of getting one or a few copies in any random blood sample. I would tend to guess that not all cancers shed enough cells or DNA into circulation to be assured that every sample from a positive patient contains the potential to produce a positive result.

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10. Helical_Investor on July 31, 2012 7:14 AM writes...

Genetic testing aside, cocktails just make a lot of sense, and more testing needs to be done with them, especially partnering with on the market treatments.

Permalink to Comment

11. simpl on July 31, 2012 7:25 AM writes...

I always felt that the ideal drug would be, say, an antidepressant that only worked when you are depressed. It would be self-testing, as it would only work on depressed people, and when it stops working you would know you're back to normal.

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