Myriads of Indecency: Ruling Against Patenting Cancer Genes Makes Scientific, Legal and Ethical Sense

The decision of a US federal judge to rule against the patenting of the BRCA-1 and BRCA-2 genes this Monday came as a pleasant surprise after a period of several years when the ability to patent human genome segments within the US legal context has been taken for granted. The ruling - a result of the efforts of the American Civil Liberties Union in conjunction with the Association for Molecular Pathology, individual women and others - was, of course, not welcomed by the commercial company Myriad Genetics, which during the period when it thought it had its patent rights secured has been pestering genetic health service providers in the US and around the world with their absurd claims (by implied threats of massive compensation suits) to world monopoly on predictive genetic testing for breast and ovarian cancer, alternatively the cashing in of handsome licensing fees.

Just a quick browsing of the Myriad Genetics website tells you that this company embodies just about everything bioethics researchers have been warning for in connection to the commercialisation of genetic testing since the late 1980's. The University of Utah Research Foundation that held the claimed patent together with Myriad - and that may be assumed to have been cashing in handsomely as a passive partner - should be held equally, if not more, accountable for this attempt to undercut sound business law, decent health care ethical standards, scientific progress and, not least, the health of those people belonging to families burdened by hereditary cancer, whose access to the preventive opportunities offered through genetic testing, and forthcoming advances of medical research, has been undercut. But back to the poverty of Myriad Genetics.

To take just one example of this moral morass, Myriad offers predictive genetic testing for hereditary melanoma - a disease for which the actual risk figure is never given at the Myriad website. Clicking this product, you are immediately told that "Changes in the p16 gene increase cancer risk, making a melanoma diagnosis up to 50 times more likely by age 50", which of course tells you absolutely nothing about what risk of melanoma you actually run before the age of 50 if you have the indicated genetic mutation, but for most people convey the impression that a mutation makes your risk of contracting melanoma before 50 an even game. Clicking further on to the page supposed to give you an in-depth background to hereditary melanoma, you're exposed to the following explanation. Take a minute or so to read it!

Having that horrible mutation must make for a helluva risk, doesn't it? Actually: no! Even considering that the people involved in Myriad are presumably not proper clinical doctors (if they were, AMA would have revoked their licenses by now, right? - I'm being charitable to the US medical profession here), but a bunch of lab rats and business executives, this is as close to actual fraud you can get without actually committing it in the strict legal sense. Remember that nice graph you just saw? Its Y-axis measures not the actual risk of contracting melanoma, but - again! - the change in risk compared to what risk of contracting melanoma you would run were you a random member of the general population. But the impression of the picture is not that - the impression is - once again - that if you carry the mutation you run a 50/50 risk. This message is cleverly conveyed by the sinister manner in which the general population risk figure is illustrated in the graph. That green staple to the right of the tall blue one seems to reach up to the 1 of the Y-axis, right? It's 1% - right? Or something close to 1%? Actually, no! Have a closer look at the graph:



It is <1% - i.e. "less than 1%", i.e. the risk is not given. It could be 0.99%, it could be 0.0000000000000000000001% For all we know based on the information provided, the 50% increased risk may thus equal a 0.0000000000000000000002% risk. Who knows? Obviously not Myriad Genetics - or can they really be consciously hiding highly relevant facts from potential customers??

Just to get some perspective, hereditary melanoma is what geneticists refer to as a multi-factorial disease, i.e. it occurs as a result of the interaction between several genetic mutations and the environment. The p16 test offered by Myriad targets just one among many different genes where a mutation may increase the risk for melanoma. This is actually conveyed by this admirably pedagogic (right!) explanation of what a test result mean. Scroll down and read the message about the "uncertain variant", there you have it! But just above, Myriad boosts about the "comprehensive" (and presumably ridiculously expensive) variant of the test, described thus: "Think of a comprehensive analysis as reading an entire encyclopedia, line by line, to look for a single misspelled word" (italics added by me). Again, as close to fraud as you might dare to wander. The "entire encyclopedia" must be read the entire human genome, including all the other genes that may increase the risk of melanoma - right?? Actually, no! It's the same p16 gene, i.e. it's more or less the same test, just properly done so that all known melanoma predisposing mutations of this particular gene are included. So, suppose you test negative in a "comprehensive" test - this is compatible with you carrying any of the other known genetic mutations of other genes that increase the risk of melanoma - what Myriad so handsomely describe as "no increased cancer risk" when explaining what a test result means. Did anyone mention fraud or deceitful behaviour? - I certainly did not, but it would be interesting indeed to have melanoma or cancer patient organisations trying out that concept in US civil courts (in which case, the University of Utah Research Foundation must, of course, be included in the lawsuit)!

Hopefully, the ruling against patenting actual genes or naturally occurring genetic mutations will undercut the sour-tasting business of Myriad Genetics and other similar companies. For one thing, as a legal precedent, it has the potential of putting a stop to attempts of making ethically well-motivated and responsibly handled predictive genetic testing offered by national health services - for instance for colon-, breast- and ovarian cancer - unnecessary expensive and thus accessible for more people at risk. From a moral point of view, it is thus most welcome. From a legal point of view as well, since what judge Robert Sweet argues in the ruling, "...the claimed isolated DNA is not markedly different from native DNA as it exists in nature, it constitutes unpatentable subject matter" has been obvious to anyone from the outset interested in applying actual patent law, rather than laying the foundation for a new branch of business. If Myriad has a unique procedure to detect DNA, they may patent that, of course, but do they? It remains to be seen, but my guess is that they use the same state of the art science and technology as does any molecular genetic research lab, and that they knew very well that their only chance to make a buck was attempting the patenting of DNA trick.

The only defense offered by Myriad's and the UURF's lawyer was that patenting genes promotes "innovation" and therefore promotes health. False. In fact, the patent claims on BRCA-1 and BRCA-2 has made medical research based on these genes that may lead to deeper understanding of the mechanisms of these forms of cancer, and thus to newer and better treatments, slower and/or more expensive. Patents have the potential of furthering innovation only when all of the basic scientific work has been done (until then, the scientific principle of openness, free sharing, access and use of information is far superior), and in the case of human genetics, identifying genes connected to disease-groups is just the first letter of the first name of that long process. When Myriad says "innovation" they mean business and so does - shame on them - the UURF.

[Cross-posted from Christian Munthe's Philosophical Comment blog.  Christian and research fellow Daniela Cutas have agreed to guest blog in the coming months]

"Cancer-free" baby born in UK: what's wrong with this picture?

So: today's news reports that the first "cancer-free" baby has been born.

"What's this?" you ask. "Isn't it awfully rare for babies to have cancer?" Yep. Especially breast cancer, which is more common in older women. But the genetic test to identify known breast-cancer-causing mutations has been around for some time. Now, for the first time, it has been used as a prenatal test--technically, in this case, through preimplantation genetic diagnosis (PGD), which is testing embryos conceived through IVF prior to their being implanted in the uterus.

Certain rare BRCA mutations greatly increase a woman's risk of breast cancer and ovarian cancer--so much so that some women with these mutations decide on prophylactic surgery to remove their breasts and ovaries. However, because these really bad mutations are rare, experts recommend that only women with a strong family history of breast cancer pursue testing. The news story doesn't say whether the couple had such concerns, though presumably this is the case.

Stories like this one don't help the general public understand what genetic testing can and can't do. Even BRCA results are probabilistic: not everyone who has a positive result will go on to develop breast cancer. And there are prophylactic and curative treatments available for breast cancer (though they are, obviously, pretty awful). And who knows what the state of medicine and oncology will be by the time the BRCA mutation carrier born today is old enough to worry about breast cancer?

The opposite set of concerns plays in here too; the fact that this fetus happens not to have any of the mutations that have been shown to increase breast cancer risk does not guarantee that she won't get breast cancer anyway -- presumably there are causal factors we don't know anything about yet, since the vast majority of breast cancer is not due to one of these familial syndromes -- or any of the other zillions of cancers that afflict humankind. "Cancer-free" may be a misnomer in this case.

And finally, isn't there a morally relevant difference between choosing to terminate a pregnancy because of a positive diagnostic result (eg, Tay-Sachs, Down syndrome) and choosing to do so based on a measure of susceptibility? And no hate mail please: I don't mean to imply that the former sort of case is necessarily the right thing to do...only that some such choices might be more easily justified than others.

Gene testing for Breast Cancer: Hype or Hope?

WBP supporter and personable pundit Art Caplan explains in his most recent MSNBC column that biotechnology firms hope to cash in on women’s fear of the disease:

Fear of breast cancer has created a tempting market for companies to sell genetic testing directly to consumers. The disease kills 40,000 people a year in the U.S., with an estimated 212,920 new cases diagnosed in 2007, according to the Mayo Clinic.

It’s no wonder women would want a reliable gauge of their risk. However, American women should be aware that genetic tests for breast cancer are more hype than real hope.

On Wednesday the biotech research company Decode Genetics of Reykjavik, Iceland, announced it will sell a new test for $1,625 that it claims will allow women “to assess their personal risk for the common forms of breast cancer.”

Genetic testing for all sorts of conditions is all the rage these days. Everywhere you turn, some company is urging you to spit in a cup, take some blood or swab your cheek so your DNA can reveal your health risks, know who your long-dead ancestors are, pick the right mate or help you design a diet that is perfect for your genetic makeup. But, “spitomics” has gotten way ahead of genomics.

Sadly, the tests Decode and other companies are offering are more likely to empty family pocketbooks and leave women with a false sense of security than they are to prevent breast cancer. There is simply not enough federal and international regulation in place to determine which tests are accurate or how heredity interacts with lifestyle to create individual risks.

If the Food and Drug Administration and Congress do not rein in the corporate greed that is currently driving the sale of genetic tests for breast cancer and other diseases and conditions, we could soon have an industry that bears an uncanny resemblance to the home mortgage business.

Marketing for genetic tests is already ubiquitous. The television commercials and magazine ads, which ran in Denver, Atlanta and various cities in the Northeast, promise women that cancer does not have to be “inevitable." They also claim that the average woman can reduce her risk of developing cancer through genetic testing.

Myriad Genetics, the Salt Lake City biotechnology company behind the heavy ad push, charges about $3,000 for a complete risk-disposition test. Myriad, which holds a patent on the first breast cancer test, has been taking full advantage of the genetic testing monopoly it enjoyed until Wednesday when Decode entered the market with its new, more generalized test. To date, Myriad has been very tough about enforcing the patent, even though medical centers in the United States and other countries say they could do the same testing for a much lower cost.

Only small fraction would benefit
In reality, the numbers about detectable risk don’t really back up Myriad’s ad claims.

Of the more than 200,000 new breast cancer cases, only about 20,000 seem to be connected to the BRCA1 and BRCA2 genes — the genes most closely linked to the inherited form of the disease that Myriad’s test can detect. For women without a family history of the disease, perhaps 1 percent would benefit from the test.

On one hand, it would seem to make sense to seek out genetic testing to avoid becoming a breast cancer statistic. Or does it?

Contrary to the marketing messages, only women who have a strong family history of breast cancer — two or more parents, grandparents or siblings who have developed the disease — need to talk to their doctor or a genetic counselor about the value of any form of genetic testing.

Decode’s newer test is not really accurate enough or based on a large enough sample of women to accurately predict much about an individual woman’s chance of getting breast cancer.

If you are worried about your risk of getting the disease, or are thinking about getting a genetic test done for any other reason, talk with your doctor or a genetic counselor who can determine whether your family history justifies the expense. You may be surprised to find that you can make changes in lifestyle and monitoring your own health that can reduce your risk without testing.

The genetic revolution holds much promise for improving our health. Currently, profit and market advantage are playing the key roles in shaping how genetic testing is evolving. These are not the right navigation tools to help women at risk of breast cancer — or the rest of us — capture that promise.

Arthur Caplan, Ph.D., is director of the Center for Bioethics at the University of Pennsylvania.

Original article can be found here.

Testing positive for BRCA: then what?

Studies (here's one) have shown that women tend to overestimate the risk of breast cancer and underestimate the risk of other things that are more likely to kill them--such as heart disease.

But some women really are at substantially increased risk of breast cancer. Specifically, women who have certain identified mutations in the BRCA1 or BRCA2 genes are much more likely to develop breast and/or ovarian cancer. These mutations are rare in the general population, but one expert group recommends genetic testing for women with 2 0r more relatives with breast cancer before age 50, or 3 or more relatives with breast cancer at any age. (deBock et al, 1999).

If a woman has one of the mutations, she has a few options. One is to have more frequent, and more intensive, screening. Another is to have prophylactic surgery: removal of the breast tissue (mastectomy) and/or oophorectomy (removal of the ovaries). In a new book, Pretty Is What Changes, author Jessica Queller tells her story, which began with her mother's death from ovarian cancer and her own decision to have a radical mastectomy in her mid-30s. You can listen to an NPR interview with the author, and read an excerpt from the book, here.

Breast reconstruction and infection: you be the judge

The NYT has run a couple of articles this week on breast implants. I might eventually come back to blog about the first one, but today, it's the second that's got my goat.

The second one reports on a research study published in Archives of Surgery (abstract). The NYT article reports, accurately, that the study found that women whose post-mastectomy reconstruction used silicone implants instead of women's own tissue were twice as likely to acquire infections. But there are a couple of interesting things you might notice, if you go look at the abstract.

One is that the absolute risk of infection in these procedures is 12.4% for women with implants, and 6.2% in women whose reconstructions don't involve implants. Double, yes, fair enough. But the abstract also notes and that women who had mastectomies without reconstruction had a 4.4% risk. So...a fairly substantial increase in relative risk occurs between women who forego reconstruction and those who have it, with still higher risks for those who also choose implants. But if you look at the news reports, no-reconstruction, interestingly, is not even reported on as a possible choice. How come? (No hate mail, please: I don't in any way mean to imply that women should or shouldn't have reconstructive surgery, only that the way this particular study has been reported in the popular press is somewhat misleading.)

If you look at the abstract yourself, you might notice a few other things that might give you pause. The study included only 50 women in total--not a very substantial sample size. And the finding that was picked up by the media was incidental to the primary finding of the project, which focused on the economic costs associated with such infections. Also, the study sample was women on their initial hospital admission for the mastectomy/reconstruction procedure, and women who were readmitted...which could conceivably leave out women who *didn't* experience infections as a result of these surgical procedures.

Given how much of our health information comes to us through media filters, we need to be savvy consumers of that information. We need to understand how research works, so that we don't uncritically accept the media spin of research reports. Something happens to research results when they are morphed into news bites...and if we're basing health care decisions for ourselves and our families based on that information, we've got to know how to read critically. It's my hope that we can educate ourselves about how to be more critical consumers of media products. At the same time, I'd like to see women apply judicious pressure on the media to step up to the educational role, and not just pursue the latest bright shiny object.

A Smart Bra

A few years ago, researchers in Australia entered the "smart bra" market, trying to design a bra made of intelligent fabrics that would change the strength of its fabric, stiffen or relax cups or tighten and loosen straps as needed. This was primarily going to be for very large chested women who needed the support, especially while working out.

Well, now another researcher is working on a smart bra design, only this one is for detecting breast cancer. The UK researchers are using

a series of microwave antennae to detect temperature changes in the breast that point to early stage breast cancer.

This is known as thermography, and the hope is that the temperature change will spot tumours before they grow and spread to the surrounding tissue. The microwaves are passive - the same sort used in astronomy or in detecting submarines - not harmful to individuals (which I'd hope wouldn't have to be said, but sometimes...) - and the bra itself would chime a little alarm when wearers needed to see a doctor due to potentially dangerous changes.

Now granted, it's still in the design stage, and there are concerns over whether or not the alarm would be triggered by false positives (nonmalignant changes in breast tissue, for example), or if it would be truly effective in catching cancerous growths before they advanced far enough to be seen by a mammogram or felt during a breast exam. And beyond the practical functionality, there's a cost issue.

While this isn't addressed in the articles I've read on the subject, I would be concerned about the exclusivity something like this would naturally have. I can't imagine it would be an inexpensive device to wear, so it would lock out a large segment of the population for whom it might be most beneficial - those who can't afford yearly exams and screenings. But then again, given the recent study that showed how many cases of cancer radiologists miss, it would still be a good thing - just for a more limited group.
-Kelly

Study Finds Detecting Breast Cancer Depends on Radiologist

There is a new study on the effectiveness of diagnostic mammograms in actually detecting cancerous masses, and the news is sadly grim. Previous studies have shown substantial differences of opinion in radiologists when viewing screening mammograms (up to 25% of cases), but no one knew if this inaccuracy extended to diagnostic mammograms, situations where women have lumps or other symptoms.

The results are not good - radiologists miss an average of 2 in every 10 cases, with some missing as much as 7 out of every 10. The numbers, for those inclined, from the Chicago Tribune article (registration required), are:

123 radiologists who interpreted nearly 36,000 diagnostic mammograms between 1996 and 2003 at 72 U.S. facilities. All the mammograms had been ordered for women who found a lump themselves or whose doctors discovered something of concern.

The researchers found that sensitivity—the ability to detect cancer when it's present—ranged from 27 percent to 100 percent, with a median of 79 percent. The false-positive rate—women who got a tentative diagnosis of cancer when they didn't have it—ranged from zero to 16 percent, with a median of 4.3 percent.

But even for radiologists at teaching hospitals, median sensitivity was only 88 percent, which means that on average 12 out of every 100 cases of breast cancer in symptomatic patients were not detected.

This is kind of scary. These are women who already have cause to consider breast cancer a risk, be it lump or pain or leaking fluids, and they are still receiving false negatives. And given that the rate of breast cancer is 10fold higher among women with physical symptoms who go in for diagnostic (as opposed to screening) mammograms, you have to wonder how many women who receive those false negatives actually go and get a second opinion? How many primary care doctors insist on a second opinion, period, regardless of the result (but especially if the test result appears to disagree with physical symptoms)?

The results do suggest one clear thing: it's better to have your images read by someone who specializes in diagnostic breast imaging. The radiologists with the highest and most consistent correct reads were those in academic medical centers, and then those who spend at least 20% of their time on breast imaging. Unfortunately, most women in America have their images read by general radiologists in their community; in this study, 1/4 of those radiologists see less than 1,000 mammograms a year.

I haven't been able to access the article itself to read (but Andrea provided the link to the abstract, thanks!), but one other question does come strongly to mind. In the cases where the researchers found radiologists missing as many as 7 out of 10 cases of breast cancer, did the researchers say anything to the radiologists? To the center the radiologists work at? To someone, anyone? Did they track down those women with missed cancer cases who haven't already found out they were mis-diagnosed?

I realize this is a common question when it comes to research ethics, and perhaps my point of view is just too badly skewed by watching my mother die from cancer, but I can't imagine how you could know that people were out there without receiving treatment, going to die because of a missed diagnosis that you know about. And how can you not say anything about the person(s) continuing to risk lives by not being good at their jobs?

-Kelly

Racial disparity among breast cancer patients

A blue ribbon panel in Chicago released a report yesterday outlining recommendations to help decrease health disparities, after it was found that the breast cancer mortality rate for black women in Chicago is 68 percent higher than that for white women, a disparity that cannot be explained by genetics alone. One of the key recommendations is to create a "universal, transparent quality-control system for mammograms, which are specialized X-rays that can detect breast cancer earlier." Full article can be accessed here (free registration may be required).
The panel's report is available at http://www.chicagobreastcancer.org.

Four More Breast Cancer Genes, and Nary a Genetic Counselor in Sight

In a season two episode designed to coincide with a pink ribbon, breast cancer awareness campaign, Grey's Anatomy depicted a woman seeking a prophylactic oopherectomy and double mastectomy in reaction to the news she tested positive for BRCA-1 mutation after her mother died from ovarian cancer. Of course, being Grey's Anatomy, the storyline was played for maximum drama - but that doesn't mean we should simply roll our eyes and assume it creative writing at its best. Women do pursue prophylactic double mastectomies after testing positive for BRCA mutations, even though science is still out on the potential medical benefits.

With the news that four more genetic mutations have been linked to breast cancer, we are going to have to seriously consider what it means to have a genetic mutation, to look beyond the lab at the actual impact the geneticization of medicine is having on how patients are both viewed and treated, and consider what appropriate treatment actually means.