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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: Twitter: Dereklowe

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February 26, 2010

HER2 Confusion

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Posted by Derek

For years now, drug companies and journalists have been touted the new era of personalized medicine. This is one of those things that always seems to be arriving, but is taking its time getting here. The industry has sunk a huge pile of money into biomarker research, and it's safe to say that it hasn't paid off yet - although, at the same time, one still has to think that it should, eventually.

Nature Biotechnology has a good article that shows how tricky the whole business can be. HER2 is one of the more validated cancer biomarkers, and there's a drug (Herceptin) that's targeted specifically for breast cancer patients that express it. So how's that going? Not so well:

A recent study from the University of California, San Francisco, reveals that one in five HER2 tests gives the wrong answer1. Furthermore, the article, which reviews the medical literature, reports that as many as two-thirds of breast cancer patients who should be tested for HER2 are not, and consequently a significant fraction of women treated with Genentech's Herceptin (trastuzumab) have never been tested for HER2 overexpression.

The health benefit provider Wellpoint, of Indianapolis, might dispute that finding. According to Genentech staff scientist Mark Sliwkowski, the insurer has data showing that 98% of its breast cancer patients are tested. However, doctors differ in their views on testing before prescribing Herceptin. “Some doctors don't know how to interpret test results, they prefer just to prescribe it and assess the patient's progress,” says Michael Liebman of the patient stratification company Strategic Medicine of Kennett Square, Pennsylvania.

More than a decade after the drug received US Food and Drug Administration (FDA) approval, the personalized medicine paradigm clearly has holes. . .

That it does. As the article goes on to explain, there are doubts about how good many of the existing HER2 tests are, worries about how they don't always agree, questions about whether some HER2-negative patients might be benefiting from Herceptin anyway, and more questions about those results due to uncertainties about the tests. That's the state of the art right there, folks, and it's clear that we have a long way to go. I don't see any reason why biomarkers (of various kinds, not just genetic) won't help us figure out which patients should be getting which drugs, but don't let anyone tell you that we're there yet.

Comments (15) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs


1. Keith Robison on February 26, 2010 9:54 AM writes...

It certainly isn't impossible that Herceptin is benefiting patients without HER2 amplification, though I think that would come as quite a surprise to a lot of people.

But, if you aren't documenting who is getting it when they are not positive in a HER2 test, then this is practicing random medicine and won't help anyone figure out if there is an effect and if so what is driving it.

An interesting approach if it could be done would be to do a retrospective study looking for patients who were put on Herceptin after a positive HER2 test, but retesting shows that the initial test was wrong. Hard to impossible to do in practice (getting the samples retested will be brutal -- in many cases insufficient clinical material will be in the archives), plus folks may be worried about lawsuits. But, it's hard to imagine with the current state of knowledge that anyone would approve a prospective trial of Herceptin in HER2- patients.

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2. PharmaHeretic on February 26, 2010 9:57 AM writes...

Reality does not conform to human perception.. as usual.

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3. bbot on February 26, 2010 10:08 AM writes...

Whenever you quote something, only the first paragraph ends up being indented on the RSS feed.


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4. EFPIA Blogger on February 26, 2010 11:45 AM writes...

At a meeting I attend recently, a wise man from Novartis who is heavily involved in biomarker development, pointed out that the inevitable consequence of personalised medicine is that by the very process of refining and refining, eventually every disease becomes a rare disease and every treatment an orphan drug...

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5. Steve on February 26, 2010 12:36 PM writes...

Huh. Thanks for this reference, too! I'm helping another grad student in my department organize a lecture series on human genomics and the future of personalized medicine; I'll make sure she gives this a read!

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6. partial agonist on February 26, 2010 12:50 PM writes...

It certainly is distressing if the tests themselves are not any good. If the tests are decent though, the oncologists need the mindset of the infectologist- embrace the data. If you show up with a bad sore throat the doc will figure out whether it is bacterial or viral and treat you accordingly, because picking the wrong treatment makes you suffer needlessly for a few more days. It shouldn't be too much to ask for the oncologist to embrace that same mindset.

It can't hurt the job market for pathologists, biomarker researchers, diagnostics companies, etc. either. Saying you have "cancer" is every bit as vague as saying you have "an infection" and not knowing if it is bacterial, viral, or fungal (or prion too, I guess).

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7. Henok on February 26, 2010 1:54 PM writes...

Interesting post as always Derek. In light of these latest insights, does Pharmas strategy of buying diagnostic companies make sense? Or are we still not at the stage, biologically speaking, where any test is not very useful?

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8. David Young MD on February 26, 2010 2:37 PM writes...

I am an oncologist and my partners and I see a fair number of women with breast cancer. HER2 testing is done on a routine basis, at least 98 percent (seems like 100 percent). And, in fact, we are sufficiently critical of the testing to know that some need to have FISH confirmation of the IHC test results (and some don't require FISH testing). This is the standard of care. There is no move to recommend FISH testing of every patient although I suppose a very rare patient may be over expressing and have a low IHC stain score. There have been one or two companies that offer services of a more enhance testing proceedure (a quantitative look at the number of receptor sites rather than gene amplification) but only at a much higher cost and none of us want to further break the health care bank by doing expensive tests on everyone.

In other words, I don't think that we often miss patients who would benefit from anti-HER2 therapy and we certainly don't treatment negative patients with adjuvant Hercetin.

So, do 1 in 5 HER2 tests give the wrong answer? I don't think so. I don't think it is anywhere near that high.

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9. Anon on February 26, 2010 3:40 PM writes...

Equating the managable problems of assay heterogeneity (and associated output) to a broader problem with the concept of personalized medicine, is weak thinking.

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10. Jose on February 26, 2010 9:10 PM writes...

Actually, anon, it is not. Real-world clinical medicine and decision making rarely match what is found in trials or other highly organized settings. If one of the key tenants of personalized medicine is the requirement that everyone is screened (at a reasonable cost/efficacy ratio), it is important to ask if the health systems and assays can truly do that.

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11. Esteban on February 26, 2010 10:06 PM writes...

I rarely think that Derek has mischaracterized an issue, but I'd agree with #9 on this -- there is nothing in this tale that indicts the inherent utility of HER2. It's really all about poor execution in real world clinical practice, not poor science. Interestingly, Roche (owner of Herceptin) has a diagnostics division, though I don't know whether they manufacture the test or HER2.

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13. RKN on March 1, 2010 11:43 AM writes...

Read the paper. Good to see some people advocating that HER2 be measured at the level of protein, even homodimers, as opposed to gene copies. Too much can occur between transcription and translation to rely on FISH, tho I accept that it may often be a good indicator.

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14. anon on March 1, 2010 12:48 PM writes...

We validated HER2 status with PCR for some evaluation of taxanes we were doing. Only about 70% of physician calls (don't know what tests they were using) were correct. 30% is a huge error.

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15. Anonymous on March 29, 2013 11:54 PM writes...

Actually, there are multiple laboratories reporting false positives by other "validated" technologies not sufficiently supported by any scientific data. Such patients may be unnecessarily treated with herceptin and chemo therapeutic agents.

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