Tag Archives: BRCA

by | October 7, 2019 · 6:06 PM

All For BRCA, BRCA For All?

Should all women undergo BRCA testing? This question has been an item for discussion once it was given the authoritative weight of Mary-Claire King, the widely respected genetics researcher who has made invaluable contributions to the discovery and elucidation of the BRCA genes. The appeal is clear. Under current protocols, many women at increased risk of carrying a pathogenic variant are not undergoing BRCA testing. It breaks my heart each time I meet with a 40 year old mother of young children who was just diagnosed with a preventible serous epithelial ovarian cancer or a triple negative breast cancer. Furthermore, a significant number of pathogenic variant carriers are missed by just about every set of testing guidelines. Not only that, guidelines are so complex, evolving, and variable that no one can keep track of them any more, except maybe the unsung  heroes among the support staff at commercial laboratories who are tasked with verifying insurance coverage for genetic testing all day every day. I half-jokingly tell my oncology colleagues at tumor boards that my new criteria for genetic testing are are simple: 1) Does the patient have cancer? 2) Does the patient have genes?

I understand the appeal of population BRCA screening. Risk mitigation strategies and enhanced screening have the potential to reduce morbidity and mortality, or, more simply put, it could reduce suffering and saves lives. This benefit looms particularly large in the face of that sly and nasty devil, fallopian tube/ovarian cancer. But the benefits – and I don’t mean to diminish them – can lead us to subconsciously overstate upsides and downplay downsides. As Guido Calabresi and Philip Bobbitt pointed out more than 40 years ago, allocating medical care is full of tragic choices, i.e., no matter what course of action we choose, some people will suffer and some people will benefit. The hard part is deciding who should benefit and who should suffer. Let me be clear, though, that if BRCA population screening were to be implemented, I hope that my concerns prove to be unfounded or are addressed up front.

So what are my worries? First off, I am not convinced that population BRCA screening is high on the list of public health priorities in the US. It doesn’t make the CDC’s list of pressing public health initiatives. About 100 million Americans are affected with one or more neurological diseases. According to the USDA, in 2018 about 37 million Americans lived in food-insecure households, including 6 million children. Eight hundred thousand Americans will have a stroke this year. Half a million Americans struggle with homelessness. About 380,000 children are born prematurely. Forty thousand people die from a gun shot each year.

In comparison, my back of the napkin calculations suggest that of the approximately 42,000 breast cancer deaths and 14,000 ovarian cancer deaths in the US each year, roughly  5% of breast cancer patients and 15-20% of ovarian cancer patients carry a BRCA mutation (I am not including other high risk breast cancer related genes such as PALB2 and TP53, but their inclusion would not substantively change the calculations). This would amount to theoretically saving about 5000 lives annually. This rough estimate is based on the very unlikely assumptions of full population participation in both genetic testing and follow up cancer screening and risk reducing strategies, and that these strategies save lives. While the evidence is pretty good that risk-reducing saplingo-oophorectomy reduces ovarian cancer mortality in unaffected BRCA mutation carriers, the mortality/morbidity reduction benefit of combined mammography and breast MRI is less well established. Risk-reducing mastectomy significantly reduces breast cancer risk and disease and treatment morbidity but the mortality reduction is not as great as one would hope, especially as a woman gets older. And many healthy BRCA pathogenic variant carriers delay or decline mastectomy. At most, about half of unaffected BRCA pathogenic variant carriers undergo risk-reducing mastectomy.

Would the resources devoted to  saving lives through population BRCA screening justify a reduction in allocation of resources to other far more common health problems or disparities within cancer care itself, such as racial and economic differences in access to care, morbidity, and mortality? Of course, numbers are not the only deciding factor for resource allocation, which is ultimately an ethical decision that society arrives at in a somewhat unpredictable and disorganized fashion. On the other hand, those numbers cannot be ignored. Population BRCA screening may prove to be cost-effective but that does not necessarily mean it would be the best use of limited health care dollars and resources. It is not exactly a zero sum game, but no matter how you slice and dice it, all health care problems cannot be covered with even the most generous allocation of resources. Eliminating the hundreds of billions of wasted health care dollars in the US might start to address resource limitations, but, realistically, drastic reductions in unnecessary spending are not likely to happen any time in the near future nor is it guaranteed that the saved dollars would be reapportioned to other areas of health care. Which lives “deserve” to be saved and which diseases “deserve” to be prevented? Tragic choices, indeed.

Then too there is the problem of health insurance, or, more precisely, the lack of it. BRCA testing on a population scale would presumably lower the cost of genetic analysis to affordable levels and labs would likely absorb the costs of those who can’t pay (or at least would figure it into their pricing). However, it is in the follow up of mutation carriers where the annual costs start to pile up. Annual mammography and breast MRI, mastectomy, reconstructive surgery, and salpingo-oophorectomy would not likely be available to the ~14% of the US population who lack health insurance, with even higher rates of non-insurance among young women, the very population who theoretically would benefit the most from BRCA testing. Yes, the cost of treating those women for cancer is much greater than the cost of screening and risk-reducing surgery, but if the women do not have the financial wherewithal to pay for surgery and screening then those interventions just aren’t going to happen. Before we even think too hard about implementing population BRCA screening, the national health insurance crisis must first be addressed. BRCA screening could unintentionally result in further health disparities for low income women.

Even among women identified at high risk of developing breast cancer and who have health insurance, uptake of MRI screening is low even in facilities where MRI screening is available, with some demographic variability in uptake. Thus, innovative efforts are needed to improve outreach, education, and motivation to participate in semi-annual screening that would likely last for decades. In addition, if population BRCA screening becomes a reality, more MRI machines will need to be purchased, more radiologists will need training if they don’t routinely read breast MRI images, and more surgeons will be needed to perform mastectomy and reconstruction. A commitment to BRCA screening requires a lot more resources than just increasing the availability of genetic testing.

I admit that I am a professional worrier, and maybe all of my concerns are just another expression of my character flaws. No doubt many of the Good Readers of The DNA Exchange will have strong differences of opinion with me. I want to save lives and avoid cancer treatments just as much as the next person, and maybe even more so than many others after having spent two plus decades watching women and their families go through the nasty physical and existentially threatening experience of chemotherapy, disfiguring surgery, radiation therapy, and dying all too young. On the other hand, there are many more people suffering from other serious and potentially preventible health problems. Are they less worthy? Tragic choices are so…..tragic.

 

” And tell me how does God choose,

Whose prayers does he refuse?”

– Tom Waits, “The Day After Tomorrow”

10 Comments

Filed under Robert Resta

Tagged as , , ,

by | March 18, 2018 · 6:27 PM

Medical Strategy or Marketing Strategy?

A well-known direct-to-consumer (DTC) genetic testing company now has FDA approval to include a very limited form of BRCA testing with its DNA genotyping product. I refrain from mentioning the company’s name because they already got enough free press from the announcement. You probably know what company I am referring to, and if you don’t, well, follow the above link. Sorry Unnamed Company, but I am not going to make the free advertising that easy for you, no matter how insignificant the source. Besides, I see it as a bigger issue than just one company’s policy.

For now, the analysis is limited to the three BRCA1&2 mutations that are more common among Ashkenazi Jews. Actually, the company offered the same 3 mutation test until they were slapped with a cease and desist letter from FDA in 2013 to stop all medically related testing. So this new announcement amounts to a resurrection of a nearly decade-old policy, not a groundbreaking innovation. Funny, though, that there was not this much to-do when the test was first offered.

The genetic counseling community is in a bit of a dither about this, including me, though admittedly part of the reason I am writing this blogpost is to help me figure out just what I am dithering about.

Some of the concerns are obvious. People may be under the misconception that a negative result = no increased risk of hereditary breast/ovarian cancer and thus some high risk women may forego potentially lifesaving surgery and appropriate screening strategies. Then there is the worry that patients will not follow through with genetic counseling if the testing is positive, or that high risk patients will not seek genetic counseling and more testing if the result is negative. If you are not Ashkenazi Jewish, the test does not seem to offer much benefit. And even for Ashkenazi Jews, the testing does not include the ~10 other genes linked to hereditary breast cancer and the ~10 other genes linked to hereditary ovarian cancer.

The company recommends verifying positive results with an experienced clinical lab.  For that matter, then, why not verify a negative result, if there is that much uncertainty? Why bother having a test if you can’t fully trust the result? I suspect though that there is probably little reason to doubt the test result and that the company makes this recommendation to keep FDA happy and to minimize their legal exposure rather than concerns about assay validity.

Incidentally, the cost of the company’s product is really not much different than the more comprehensive multigene hereditary cancer panels offered by some of the clinical testing labs, and in some cases more expensive.

Eight years ago I shared my first experience with a patient whose BRCA carrier status was detected through DTC testing. My patient’s experience and a few more cases I encountered since then have not been that different than my patients who went through the usual counseling and testing process. A 2013 study by the company  showed that the 11 women and 14 men who discovered their BRCA status through DTC testing had experiences similar to my patients. That last statement is brimming with caveats – small sample size, at least for my patients they were savvy enough to want to see a genetic counselor, personality traits of the earliest users of new products, no long-term follow-up, etc. But I am not aware of any independent, large-scale studies of patients who learned their BRCA status through DTC testing to more definitively address the pros and cons, other than studies offering BRCA testing that targeted all Ashkenazi Jewish women.

I readily admit that I may be proven wrong, but I am guessing that most of the consumers of this DTC product – note they are not patients because the test is not intended for clinical use – will opt to learn their BRCA status. After all, people have this testing to learn about their genetic makeup. I am also guessing that this may be the company’s proverbial toe-in-the-water; I would not be at all surprised if additional clinically useful testing is part of the company’s future product and marketing plans.

At heart, I don’t like the idea of DTC BRCA testing. I think about all the ways it can go wrong, and inevitably some of those ways will come to pass. But will it go right often enough, and go wrong infrequently enough, that there will be adequate benefit to justify offering DTC testing? Undoubtedly, some of my uneasiness stems from a professional conflict of interest; DTC eliminates my role as an interface between patients and testing. Personally, I think being a middleman is a good thing because it can help patients take a thoughtful deep breath before leaping into the gene pool. But that could be because I have been trained to think that way and because it supports the value of my professional career. What I really should want is for patients to have access to genetic information in a manner that is affordable, accurate, psychologically and emotionally appropriate, and medically useful. If DTC and other forms of offering BRCA testing works for many men and women, then I should swallow my professional pride and acknowledge it.

So having stewed on this for a while, I have come to the realization that my argument isn’t with this company per se. Other companies aggressively market hereditary cancer and other genetic testing to average risk people. For example, one company approached my institution with the idea of offering their product to all women coming in for breast imaging, with saliva kits kept in the mammography center along with a prescription pad with a genetic counselor’s name on it acting as an ordering provider for the test (legal in my state). Although many labs employ genetic counselors who work directly with patients to review test results, this is still not the same experience as meeting with a genetic counselor before undergoing testing to explore the complex medical and psychological issues surrounding genetic testing. And the highly respected Dr. Mary-Claire King has advocated for population based genetic screening for establishing hereditary breast cancer risk. Are DTC clinical testing and other consumer-friendly strategies disruptive ideas that will bring about much-needed change or are they just bad but well-intentioned ideas that will also fill company’s coffers and keep investors happy?

Having sifted through and weighed my thoughts and feelings about DTC testing or other genetic test delivery models, I have concluded that my problem is not with DTC or other models per se. My argument is with how these new testing approaches are introduced into clinical practice, typically under some version of the banner of liberating testing and bringing it to the people. I do not doubt the labs’ sincerity when they say they are trying to improve access to medical care and reduce the suffering from cancer and other illnesses. But these are as much marketing strategies as they are medical strategies. Labs should not be calling the shots on the introduction of new tests and practice models because, in the absence of well designed studies, we really have no idea if these new approaches are effective in reducing cancer risks and increasing high risk screening when indicated, or if they are in the patients’ best emotional and psychological interests. Just throwing a mess of tests out there and encouraging everyone to take one is, in my view, irresponsible.

A better approach is to first conduct controlled and ideally randomized studies that evaluate both new and novel testing strategies to determine the most beneficial one(s) for patients, or if different types of patients benefit differently from different strategies. For example, age, family history, medical history, psychological functioning, and socio-economic status could all conceivably affect outcomes, not too mention the all too real possibility that many Americans may lose health insurance in the near future. While labs should play a critical role in that evaluative process, to keep it as clean as possible the studies need to be conducted and overseen by researchers who have no financial benefit from the outcomes of such studies.

We are in this together, so let’s work together.

2 Comments

Filed under Robert Resta

Tagged as , , , ,

by | December 27, 2016 · 10:42 AM

TOP TEN STORIES IN GENETICS, 2016: An Adolescent Science Meets the Big World

Clinical genetics is a young science, not yet come of age – a new discipline. It’s early days, say the small group of clinicians and researchers who have watched over its formative years, dreaming like proud parents of a future where genetics and genomics are integral to clinical medicine. And as for many parents, it may sometimes have seemed that the all-consuming, semi-hermetic little laboratory of childhood would go on forever.

But guess what, people? I believe we have entered the teenage years.  I believe baby has borrowed the car keys and taken it out for a spin.  I see a field boasting a few real accomplishments, and on the cusp of so many changes, from therapies for genetic disease and cancer to a suddenly burgeoning DTC marketplace. And like all parents, geneticists are poised to discover the limits of our ability to control what we have nurtured. That’s exciting, more than a little bit scary, and the theme of this year’s top ten.

  1. FDA CANCELS PLANS TO REGULATE LDT’s

Over the past two decades, a single technological advancement has revolutionized the way we practice medicine.

I am talking, of course, about overnight delivery of packages.

Years ago, laboratory testing services were divided into large companies that sold test kits and devices nationwide, and the small labs in hospitals and other clinical settings providing services to their local providers. With limited resources, government regulators focused on the tests that affected more people, and agreed by convention that ‘laboratory-developed tests’ would not be subject to the same scrutiny. Today these distinctions are virtually meaningless, as giant companies like LabCorp and Quest perform tests ‘in-house’ on samples gathered worldwide, tossed in a box and sent overnight. Still laboratory-developed tests (or LDT’s) – a category that includes virtually all genetic tests – remain in regulatory limbo.

In 2010, the FDA announced its intention to address this loophole. In July 2014, they issued draft guidance detailing their plan for a regulatory structure that divided the LDT universe into high, low and medium risk tests. While some professional organizations disputed the FDA’s right to have a role in regulation of LDT’s and threatened legal action, others approved the framework in principle but disagreed on specifics, including how to handle the thorny new territory of exome and genome sequencing. A dialogue ensued with representatives of labs, clinicians and patients that has lasted two years and included multiple workshops and public meetings. That process, it was widely assumed, was nearing its end, with the resulting draft guidance expected to be sent to Congress for approval in the near term.

And then came November 8th and the election of Donald J. Trump, ushering in an executive opposed to regulation on principle, to join a similarly inclined House and Senate. Ten days later, the FDA ran up the white flag, announcing that the agency would not take steps to finalize its existing plan and would instead reopen the discussion with a new administration and a new Congress. What this means precisely is a matter of some interesting speculation, but in general it suggests that an industry that has been struggling for years to avoid too much regulation will have to consider the consequences of living with none at all.

 

  1. IS THIS THE FUTURE? CRISPR EXPERIMENT ADDS RARE PROTECTIVE VARIANTS TO HUMAN EMBRYOS

The second experimental use of CRISPR technology to alter human embryos was reported in May of 2016, again by a group out of China. Again, the embryos used were not viable, and no attempt was made to transfer them for reproductive purposes. While this experiment did not produce the same ethical firestorm as the first, it was in several ways a more significant indicator of both the potential and the peril of human germline engineering using CRISPR.

In the first experiment investigators attempted to alter a gene variant responsible for causing hemoglobinopathy, with limited success – proof in principle that it could be done, but nothing to assure worried observers that it could be done safely. In version 2.0 there were fewer off target effects, but researchers were not able to consistently control the content of changes introduced in place of the edited DNA. This is not inconsistent with what we know so far about CRISPR: if we envision it as a word processing search-and-replace function, it is good at the finding and erasing part, but hit or miss when it comes to  putting in a replacement.

What stands out about the second experiment is that the goal was not to eliminate a disease-causing gene, but to insert a rare and protective one – in this case, the CCR5Δ32 allele that offers the bearer reduced susceptibility to AIDS. Gene editing is often envisioned as a way that individuals whose children are at risk can avoid or change genes that cause disease, but in the vast majority of these cases there are simpler and better established tools such as PGD if the goal is to obtain embryos that do not carry a specific variant associated with some catastrophic risk. Why use technology to substitute out a pathogenic BRCA variant or a double dose of the sickle cell genes when the parents are perfectly capable of producing a healthy embryo themselves? What CRISPR and related technologies can do that is not available through other means is to introduce a gene that neither parent carries. That is a powerful new option, and it is both exciting and scary in the manner of all things powerful and new.

 

8. GENETIC DISCRIMINATION MAKES A CAMEO

Many wise observers have noted that for all our deeply felt concerns about genetic discrimination, to date the examples are few, far between, and usually more clumsy than systemic (looking at you, Burlington Northern Santa Fe Railroad). These arguments, redux, were on display in 2016 as Canada debated and ultimately passed its own national genetic discrimination law. Yes, Globe and Mail Guy, there is little evidence of a big problem, and a look at law suits filed between 2010 and 2015 under GINA, America’s genetic discrimination law, proves the point. But one real unanswered question remains: is the absence of institutionalized discrimination a sign that it is destined to be a bit player in the big picture of genomics, or is it only too soon to tell? Big companies, whether they are offering insurance or providing employment, may not have had an incentive to weather a PR shitstorm in order to use genetic information to limit their exposure to risk when not that many people have been tested, and the reliability of the data is debatable – which it has been in these early days. Genetic discrimination, in other words, may be making an appearance in Act II.

Two stories got some attention in 2016; whether they are one off events or signs of the future – well, that’s crystal ball territory. Are they important? They are something to which we should be paying attention. Attention should be paid.

In January, Stephanie Lee at Buzzfeed published an account of a boy named Colman Chadam who was asked to leave his Palo Alto, CA school because he carried two mutations commonly associated with cystic fibrosis, although he did not have any signs or symptoms of the disease. The results of genetic testing, inappropriately revealed by a teacher at the school, were taken, also inappropriately, as diagnostic. The reason this got him thrown out of school was to avoid contact with another student who did have CF. The emphasis on keeping children with CF apart, which sounds weird if you don’t know much about the disease, was about the only appropriate thing that happened, because individuals with CF are at risk of passing one another dangerous and life-limiting infections.

Although Colman did not have to leave the school, and the Chadam’s lawsuit against the school district has settled, the case continues to raise issues about how genotype as distinct from phenotype can be used under the law. In addition, it may signal the need for measures to protect personal privacy (no such thing, I know, I know) in an age when genetic testing is commonplace.

Three weeks later, Christina Farr wrote an article for Fast Company about a woman who was turned down for life insurance because she had a risk-conferring BRCA1 variant. Unlike the Chadam case, this is not a result of genetic illiteracy, and it is not a violation of any law: GINA does not cover insurance for life or long-term care. It is, in fact, exactly the kind of genetic discrimination that ethicists and patients thinking about genetic testing have worried about over the years, and if systemic, would certainly be an important point for genetic counselors to raise in pretest counseling (if pretest counseling is still something we do, which is an issue unto itself…but related). According to the article, genetic testing for cancer susceptibility is not required by any insurance company, although nothing stops them from doing that, but companies are starting to request to see test results when they exist. Failure to answer questions honestly can invalidate policies if you are caught.

If this becomes the status quo, it may affect uptake of genetic testing. If it is curbed through regulation, genetic testing may change the way the insurance industry operates. Act II is going to be interesting! I am having a couple of stiff drinks and heading back to my seat.

 

7. TYPE II DIABETES: RESISTANT TO INSULIN AND EASY ANSWERS

Genome wide association studies (GWAS), a way of looking at common variants in the gene pool to identify genetic susceptibility to common diseases, have been unable to explain the degree to which liability to these common diseases is inherited, although it clearly is. If you are in genetics and this is news to you, you have not been paying attention.

Many reasons for this have been proposed, and many are likely a part of the answer. One thought was that individually rare variants might be collectively common enough to play a big role in generating risk, which would not be picked up by GWAS, as it traditionally looked only at variants carried by at least 5% of the population (“the population,” as though there was only one!). Looking at rare variants takes a village, but that is what a googleplex of Type II Diabetes researchers did to produce an epic July 2016 paper in Nature.

Okay 300 authors on the paper so close enough.

The report by first author Christian Fuchsberger showed that MEGA*GWAS produced the most GWAS-y result possible: intellectually interesting, informative and ultimately inadequate. Using exome and whole genome data to capture a broader range of variation, the study found significant association to a handful of previously unknown common variants, and then failed to replicate a good chunk of what we thought we knew. Uncommon variation? The researchers found 23 loci that appeared significant, which was meaningful, but nowhere near enough to validate the rare variant hypothesis as the smoking gun in the Mystery of the Missing Heritability. “A comprehensive and extremely well written paper,” said Dan Koboldt at MassGenomics, and you can almost hear him sigh.

 

6. DATABASES: IT’S NOT JUST FOR WHITE PEOPLE ANYMORE

We don’t have enough diversity in our databases. It’s not exactly news, and yet publication of an article called “Genetic Misdiagnoses and the Potential for Health Disparities” in the August issue of the New England Journal of Medicine felt like a slap in the face.

The methodology was not complex. For hypertrophic cardiomyopathy patients, doctors use genotyping to identify individuals and family members at risk for sudden and catastrophic cardiac events. Identification as ‘at risk’ is a traumatic and often life changing event, requiring ongoing medical screening and behavioral modifications. For these families, a lot rides on whether or not a variant is considered pathogenic. One bioinformatics tool is to look at databases, because there are limits on how bad a variant can be if it shows up regularly in healthy individuals. The study checked variants labeled pathogenic against an increasing wealth of exome data available in public databases and found that a number were common in the African-American population. Result: reclassification from pathogenic to benign of multiple variants affecting primarily African-American families.

“Simulations,” said the authors, “showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications.

 

5. IMMUNOTHERAPY: A NEW STAR BURNS BRIGHT AND HOT

Earlier this week, my sister-in-law was telling me about a friend with a cancer deemed treatable but not curable. “But if they get it in remission,” she said, “and he has more time, maybe there will be something new.” There it was – the cancer prayer. May There Be Something New. And I thought, has there ever been a moment when those words felt more hopeful than right now?

Hopes have been raised before, by promises that money would bring answers, and we wandered down blind alleys and into mazes waving cash as though the scent of it would draw the answers to us, but this time, progress is lighting the way like street lamps, and money follows hope instead of the other way round. Immunotherapy – engineered cells meant to light the bodies own defenses into a controlled burn that destroys cancer cells and leaves the rest untouched – has burst onto the scene since 2015. Cancer researchers report on progress in Hemingway stories, terse narratives of a few more days, an extra month or two, and that’s a win, but suddenly we are getting Gabriel Garcia-Marquez fables of magic beans and people rising from their deathbed.

So which story is more 2016: Sean Parker’s 250 million dollar cancer institute, connecting Silicon Valley money with Car-T cells that he describes as “little computers,” and presenting to the NIH in comic sans? Or the unexpected lethal immune response that shut down a Car-T trial by Juno Therapeutics in November, after four people died of cerebral edema?

It’s the two in conjunction that tell the tale. Immunotherapy is truly a candle in the wilderness, but it’s a candle that burns rocket fuel. Or perhaps I should say, in the spirit of the season: catch a falling star and put it in your pocket – bet it burns a hole in your ass.

 

4. A NEW DTC GENETICS EMERGES WITH HELIX

In October, Helix announced the first fruit of its partnership with DNA-lifestyle start-up Exploragen and it’s grapes: Vinome, a company that promises to sell you wine tailored to your genetic profile for something like fifty bucks a bottle. I’m not a wine drinker and that sounds like a lot of money but, hey, you do you.

For Helix, the Illumina spinoff that debuted in 2015, this was one of a series of 2016 announcements giving us a more concrete vision of their plans for a sequence-once-access-often platform for DTC genomics. The structure of it is like Apple, if your IPhone didn’t even pretend to be a phone, and existed entirely as a vehicle for apps. With your first purchase, Helix will underwrite the cost of sequencing and storing your entire exome, and then sell it back to you bit by bit in the guise of applications created by partners.

Effectively, the Helix model lowers the barrier of entry for any product based on DNA testing, by spreading out the cost over a myriad of marketing opportunities. Some current players in the DTC universe have signaled their interest in playing in Helix’s playground; Geno 2.0, National Geographic’s version of ancestry testing, is already available on the Helix website. Others may take their toys and stay at home. Daniel MacArthur of the Broad Institute once penned an April Fool’s Day account of a company named Helix Health’s plans for a hostile takeover of 23andMe using Somali pirates, but for real the entry of an Illumina-backed company into the DTC space must have some Mountain View observers concerned that the current industry thought leader might end up the Blockbuster Video of the genomics world.

The uncorking of Vinome raises a few questions that existing partnerships with, say, the Mayo Clinic or the Icahn School of Medicine at Mt Sinai do not. One role that Helix could potentially play is to provide the vetting service much needed in the consumer genomics world, with its mishmash of pharmacogenetics and Warrior Gene testing and supplements designed just for your DNA.

As for Vinome, the eminently quotable Jim Evans called it “silly” in an article by Rebecca Robbins in STAT. “Their motto of ‘A little science and a lot of fun’ would be more accurately put as ‘No science and a lot of fun,’” said Evans — which I guess is true, if paying fifty dollars for a bottle of wine is your idea of fun. But like Apple, Helix is going to have to make some hard decisions about how much it takes responsibility for the quality of the partners it allows to come play in its sandbox.

 

3. GENOMES OF MASS DESTRUCTION

In February, for the first time but probably not the last, the U.S. Director of National Intelligence’s assessment of worldwide threats included genome editing as a weapon of mass destruction. Congratulations, genetics: we’ve made the big time.

The report pointed to the widespread use of new genetic technologies like CRISPR in countries with different regulatory and ethical standards, its low cost and the rapid pace of change as pre-conditions that might lead to intentional or unintentional misuse, though it was vague as to what form they thought the threat might take. More specific concerns were articulated later in the year by the Pentagon’s Defense Advanced Research Projects Agency (called DARPA of course, because…government) in announcing a program called Safe Genes intended to establish a military response to of dangerous uses engineered genes. DARPA, which Scientific American reports has been a major funder of synthetic biology, will support projects that look at ways to remove engineered genes from a variety of habitats and in a variety of circumstances, including those spread through gene drive.

 

2. A BREAKTHROUGH DEFIES CONVENTION AND GEOGRAPHY

On April 6, 2016, a baby was born after the transfer of his mother’s nuclear DNA into an enucleated donor egg in an effort to avoid the mitochondrial disease that killed the couple’s two previous children. The success of mitochondrial transfer therapy itself was not a shock, since earlier experiments had demonstrated good outcomes in animal models and in in vitro human embryos. The circumstances, however, were startling: the procedure was done in Mexico, for Jordanian parents, with the help of a New York-based fertility doctor with no known expertise in mitochondrial disease.

Some have argued that mitochondrial transfer therapy represents a violation of international norms forbidding any germline genetic change, which were meant to provide a clear dividing line between somatic changes associated with gene therapy and genetic engineering with the potential to impact future generations. Pretty clear in theory, but all of these divisions are less clear in reality – there are no guarantees that gene therapy doesn’t affect eggs or sperm, and mitochondrial DNA itself challenges any simple equivalence between the molecular structure of DNA and the intellectual concept of our ‘germline’.

Mitochondrial transfer is illegal in the United States but permitted in Great Britain under a 2015 law, and applications for clinical use have been approved for 2017. Its apparent success – independent sources confirm that the baby appears to have traces of maternal mt DNA associated with Leigh syndrome but no sign of disease – is a cause for celebration for the families whose children are at risk. The step forward is a milestone, but so is the way in which it occurred, which demonstrates the extent to which geography and national laws are no match for money and access in determining what is possible.

Personal note: on my wish list for 2017, can we PLEASE stop cheapening the concept of parenthood by using the term ‘3-parent babies’? If I donated a kidney, that person would have some of my DNA, but it wouldn’t make me their momma.

 

1. WHITE SUPREMACISTS LOVE GENETICS, BUT GENETICS DOES NOT LOVE THEM BACK

Nothing about the year 2016 was more disturbing than the empowerment of the alt right, an all-purpose term for the angry souls that crept out from under rocks to preach hate and division. Here at home and all around the world, narratives of race and ancestry emerged as powerful drivers in political and social movements based on appeals to base and tribal instincts – fear mongering about immigrants, Islamaphobia, white supremacy. In October, Elspeth Reeve at Vice ran a story about white supremacists posting their 23andMe results to prove their whiteness.

This embrace of a science that does not love them back is evident even without a deep dive into the world of Stormfront and 4chan.  Twitter trolls talk about ‘founder effects’ and ‘genetic drift’. A Breitbart tech editor, now barred from twitter, writes gleefully about associations between race, behavior and intelligence, mocking disbelievers as prisoners of an “all-consuming cult of equality.”  The L.A. Times describes the alt-right as “young, web-savvy racists who are trying to intellectualize and mainstream bigotry.”   These viewpoints aren’t mainstream, but their proponents can no longer be dismissed as fringe, with Breitbart’s founder about to be ensconced in the White House as chief strategist, and reports suggesting that the presumptive next National Security Advisor Michael Flynn taking meetings with the head of an Austrian political party founded by former Nazis.

The connection between white nationalism and population genetics is proof once again that genetics as a field is uniquely susceptible to misuse by agenda-driven movements intent on the subjugation of others. Donald Trump ran against political correctness, but his rise has proven the importance of language. As Michelle Obama says, “words matter.” Push back against the misuse of genetics to fuel ‘racialist’ theory. Ancestry sites should think very hard about the manner in which they present their findings, which stress differences without acknowledging the greater than 99% of DNA that we all share. Scientists need to address and refute the ways in which their work can be misconstrued to reinforce prejudice and unsubstantiated visions of racial differences. We all have to be careful not to promote explanations of genetic effects that oversell the determinative power of genes.

Genetics is a science of the future. Let’s not let it be used to drag us back into a tribal past. Peace out, Genetics, and here’s to a better year in 2017.

 

 

Follow me on twitter

7 Comments

Filed under Laura Hercher

Tagged as , , , , , , , , , , , , , , , , , , , , , ,

by | September 10, 2014 · 1:40 PM

Mary-Claire King (winner of the 2014 Lasker Prize!) proposes a plan for universal BRCA 1/2 testing that is both TOO MUCH and TOO LITTLE

First things first: congratulations to Mary-Claire King, who this week won the Lasker Prize in Medicine for “bold, imaginative, and diverse contributions to medical science and human rights”. The award acknowledges King’s work in the 1980’s, reuniting families with the biological children taken from them during Argentina’s “Dirty War”, and it highlights her role in the pursuit and identification of genes implicated in familial breast cancer. Myriad’s Mormon database may have won them the patent race, but their Rosie Ruiz victory belied the long history of the chase, which King pursued for more than 20 years, stubbornly refusing to believe that pedigrees strewn with cancer were simply bad luck. What seems like common sense now was iconoclasm at the time, and it begs the conclusion that it took a woman in science to take these women’s stories seriously. King’s role in the discovery of BRCA1 was a triumph of independent thinking, as well as brilliance and persistence. You go, girl scientist!!!

 

King used the occasion of the Lasker Foundation’s announcement to publish a call for BRCA 1 and 2 testing for all women at age 30. The manifesto, published in JAMA, decries the current state of affairs, where women are frequently tested only after they get cancer. “To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention.” This is a bold challenge, and given the source, one that demands some careful consideration.

 

There are some negatives to universal screening, many of which King discusses. A diminished but enduring problem with BRCA testing is the tendency to produce variants of uncertain significance (the dreaded VUS!). King suggests that for this purpose, we report only unambiguous loss-of-function mutations. Another concern is that our empiric data about the risk of cancer associated with these genetic findings comes primarily from families with a history of cancer – suggesting a possible ascertainment bias. For that reason, the US Preventative Services Task Force recommends testing only in at-risk populations. In response King cites a new study out of Israel documenting increased cancer risk in women with one of three Ashkenazi Jewish founder mutations even among women with no family history of cancer (and amazingly, 50% of all women identified with a mutation had no history of breast or ovarian cancer that would have brought them to clinical attention).

 

But, as King herself recognizes, “major questions arise in generalizing from the results of the study in Israel to population-based screening in the United States or any other country.” That study reviewed only 3 very well-characterized mutations in a single ethnic group with an equally well-characterized risk for breast cancer. It is a leap to assume the results are valid for all variants and all populations. Still the likelihood is high that mutations that disable BRCA 1 or 2 will cause at least some significant increase in cancer risk. Should we be advocating for universal screening?

 

Well, there are a couple of negatives to consider. First, King rightly notes that we can’t hand out results on a huge scale when we aren’t certain what they mean. So that means we are only looking at a subset of BRCA results with the potential to increase cancer risk. Furthermore, her plan reduces the complexities involved in cancer counseling in that it looks only at BRCA 1 and 2, and not at any of the other genes that contribute to overall cancer risk. While this makes universal screening much simpler, it also limits the effectiveness. So while you might make a ‘something is better than nothing’ argument for screening, you have to wonder if this quick and dirty approach will end up replacing a more thorough risk analysis for many women in the higher risk categories. It’s not easy getting women in for cancer counseling now – are they not less likely to seek out genetic counseling if they have already been ‘screened”? Similarly, will physicians be less likely to refer and insurance companies less likely to pay for a more thorough breast cancer risk assessment and panel testing? Not an issue, perhaps, for families with a striking, definitive cancer history– and never an issue for those with their own resources — but beyond this we run the risk of cannibalizing the cancer counseling programs that we have built, which provide a fuller and deeper approach to of risk assessment.

 

Second, the program King describes will not generate the data we need to improve our ability to interpret results of genetic testing for breast cancer predisposition. One of the goals if universal testing ought to be that an investment now would get us out of the too-much-data-too-little-interpretation hole we are stuck in today. On Twitter, response to King’s essay buzzed about the prospect of a massive database of variants:

 Screen Shot 2014-09-10 at 9.12.34 AM

But returning only information on variants we have already characterized will not enable us to make any headway on classifying the rest.

 

Universal BRCA 1 and 2 screening is an enticing idea, and there is no doubt that it will identify tens of thousands of women at increased risk for breast and ovarian cancer, for which we have preventative measures with proven efficacy. But a program at this scale will not provide assessment or counseling at anything like our current standard of care, and the potential harm that could cause for families with mutations in BRCA 1 and 2 as well as the other cancer-related genes that will not be reported must be weighed against what we can accomplish; to that end, a pilot study would put some numbers on the scale. Furthermore, as a project universal screening represents a significant investment in public health. It makes sense for us to consider whether or not such an investment moves the ball forward in terms of improving genomic interpretation, and King’s plan, as envisioned, does not.

 

 

Follow me on Twitter!   

 

5 Comments

Filed under Laura Hercher

Tagged as , , , ,

by | November 29, 2012 · 11:10 AM

To Improve Care for Your High Risk HBOC Patients, You Don’t Need the Supreme Court: It Is All in Your Hands — and In Your Files

What happens in 2015 when the essential Myriad patents on BRCA 1 and 2 expire? 

Think about it a while.   What are you imagining?  Lower costs, better tests, quicker turn-around times?  A single panel covering all breast cancer susceptibility genes?  An end to unhappy conversations with patients trying to explain why the process can’t be simpler and cheaper?

While you mull over your utopian fantasies of a patent-free universe, keep this in mind: Myriad has been thinking about it for a while now.  After all, BRACAnalysis remains close to 90% of their total revenue, so it’s probably on the minds of Myriad executives.  It certainly was on their minds at Goldman Sachs when they listed Myriad Genetics as a sell in February 2011. 

Does Myriad have a plan?  It sure looks like it.  In 2006, Myriad ceased to publish BRCA variant information, and ended their relationship with the open-access Breast Cancer Information Core (BIC) database.  Since then, they have assembled a private repository of genotype-phenotype information that seems to be a central component of its strategy for future earnings.  How central?  Well, Dan Vorhaus et al at the Genomics Law Report speculated back in 2011 that a strategy of relying on their “vast—and currently proprietary—database of BRCA test data, including VUS data” was behind the company’s decision not to even bother fighting patent infringement in Europe, citing Myriad CEO Peter Meldrum’s emphasis on “other competitive factors” as an alternate strategy for competitive advantage.

Forget about the ACLU lawsuit, and next-gen sequencing and all the other changes you have read about that may affect genetic testing going forward.  Get the DNA sequence data wherever you want, and however you want, and as cheaply as you can, but as long as Myriad has sole control of the information needed to provide analysis, no other company will be able to challenge them on a competitive basis.

 Is this fair?  Well, it is an end run around the philosophical basis of patent protection, which is meant to provide a 20 year window of unfettered commercial use in return for a free and open sharing of information to stimulate further innovation.  But it is not illegal.  Myriad controls their database, and can’t be compelled to share.  They own the database – but NOT the information.  The information is out there – in report after report after report, languishing in the files of thousands of clinical cancer specialists.  In other words, YOU HAVE IT.

 So now, some exciting news.  Dr. Robert Nussbaum at UCSF is spearheading an effort to collect BRCA 1 and 2 variant data in ClinVar, an accessible archive of anonymized genotype/phenotype information hosted by the National Center for Biotechnology Information (NCBI).  While the goals of ClinVar are very broad – to aggregate information about sequence variation and its relationship to human health – Dr. Nussbaum’s goal are quite specific: to assemble a list of BRCA 1 and 2 variants found since 2005, along with information classifying them as benign, pathogenic, or unknown. 

 But THIS ONLY WORKS AS A COLLABORATIVE EFFORT.  Dr. Nussbaum has contacted 600 clinicians involved in clinical care of HBOC patients (so far, 26 centers have contributed over 3000 BRCA 1/2 variants).  With their cooperation and yours, ClinVar could amass a database to rival that of Myriad, ushering in an era of genuine access to unrestricted, competitively priced information for our patients.  How great is that? 

 To get involved, contact Dawn Lee, a genetic counselor at Partners Center for Personalized Genetic Medicine who is working with Dr. Nussbaum.  Here is her contact information:

Dawn Lee

DLEE30@PARTNERS.ORG

617-768-8548

You can get all the important specifics from Dawn, but for those of you who are interested, I’ve made a stab at some FAQ’s:

 WHAT EXACTLY IS BEING COLLECTED?

This project is limited to collecting information on the variant, identifying it using cDNA and/or genomic numbering, and its classification in a 3-tier scale as benign, pathogenic/deleterious or unknown (some reports use a 5-tier scale including possibly benign and possibly pathogenic, which is also good).  The goal is to capture each variant one time per family.

 IS THIS OK?  ISN’T IT A HIPAA VIOLATION?

Great question!  HIPAA does not place any restrictions on the disclosure of information that is de-identified.  For this reason, no names or other identifiers will be collected, including familial information or the name of the facility where the patient was seen.  Does this mean that the clinician who orders the test has the right to use it in this way?  “Ownership of Information’ issues are governed by state laws, and you can check out your state regulations in this 50-state survey of state laws governing the  collection, storage and use of human tissue specimens by the National Cancer Institute but – spoiler alert – Dr. Nussbaum thinks the answer is yes, in all states.

DO WE NEED IRB APPROVAL?

Poor IRB’s!  Everybody hates them so much.  Don’t you think that is hurtful to their feelings?  Sure, lots of people are doing this data collection without IRB approval.  Those people are following Federal Regulation 46.101(4) from the Office for Human Research Protections, which specifies as exempt: “Research involving the collection or study of existing data,documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.”  But does anyone ask the IRB how this makes them feel? 

IS THIS GOING TO BE A HUGE PAIN IN THE ASS?

First of all, if you have the reports in electronic form, it should be pretty straightforward.  If you have them on paper, you have to make de-identified copies, which means masking the names in two places (Dr. Nussbaum suggests post-it notes).  Dawn reports that there is a small stipend available for paying someone (contact her) – I suggest genetic counseling students (if you are in the NY area, contact me).  And – wait this is exciting! – the next 20 centers to provide >200 variants will receive an Ipad mini. 

 WHY NOT COLLECT MORE PHENOTYPIC INFORMATION?

Why indeed?  Why not report age of onset or bilaterality?  And if you are going to do that, you might as well check for hormone status.  It’s like that child’s book, “If You Give a Mouse a Cookie.”  If you give a researcher laterality, he is going to want oncogene status.  If you give her oncogene status, she is going to want response to treatment data.  The limited goals of this project make it easier for more people to participate (see IS THIS GOING TO BE A HUGE PAIN IN THE ASS?, above), and thus  to advance the primary goal.

 

2 Comments

Filed under Laura Hercher

Tagged as , , ,

by | March 31, 2010 · 9:37 AM

Sweet!! The Judge Rules on the Myriad Patent Case

On Monday, Judge Robert Sweet of the Federal District Court in Southern New York shocked the world by ruling against Myriad Genetics, invalidating claims with regard to patents on BRCA 1 and 2.  This morning, the genetic counselors, oncologists, patients and their families as well as other interested parties like patent lawyers and venture capitalists are wondering: what does it mean, really?

 The ACLU and other parties sued Myriad in 2009, claiming their patents interfered with medical care for families concerned about hereditary breast and ovarian cancer by stifling innovation that might lead to better tests and denying them access to an alternate lab to double check or compare results.  In addition, the lawsuit challenged the idea of gene patenting, suggesting that DNA sequences were a part of nature and that they were discovered rather than invented, and therefore were not in their essence eligible for patenting.  For their part, Myriad maintained that the patent covered not DNA as it appeared in nature, but the isolated gene product that was tested in the laboratory.  This is concept – that purified or isolated DNA is effectively a chemical made by man — underlies many, many patents granted over the past 20 years or so, and Myriad was widely expected to win the case easily.

 But they did not.  Not to get too carried away – the case will be appealed and all the same experts who predicted that it would be dismissed are now predicting that it will be overturned.  But were it to stand, would it change the facts on the ground for consumers of BRCA 1 and 2 testing?  The short answer is, probably not.  The ruling struck down parts of 7 patents relating to BRCA testing; Myriad holds an additional 16 patents on BRCA testing (this might shed some light on the bewildering fact that there are over 40,000 patents on human genes, meaning that gene patents outnumber genes by a factor of nearly two to one).

 Still, the ruling is likely to have a profound effect long term, as it puts industry and investors on notice that the law surrounding patent protection of genes and gene tests is far from settled.  One question that has been debated since the beginning of this lawsuit is whether or not patents on gene sequence (or their moral equivalent, patents on cDNA sequence, which the judge correctly identified as being different only in a petty and legalistic sense) promote or interfere with development of diagnostics, treatments, or cures for genetic disease.

 This is really the million dollar question.  Promoting innovation is the point of patents; it is the sine qua non of the whole patent deal.  It is tempting, but fatally wrong, to think of patenting as a system of social justice, ensuring that the deserving individuals receive the benefits of their labor and/or inspiration.  This is lovely, but false. A patent is not a right, like free speech or pursuit of happiness.  An individual or a corporation has no right to demand that the government throw its weight behind protecting their intellectual property.  Without a patent, they can protect their intellectual property simply by keeping it secret, like the formula for Coke.  In fact, one part of the deal when you get a patent is that you agree to make the information public.  This, in addition to making new ideas lucrative, is how patents are designed to promote innovation.  In this way, it is reasoned, we are spared the wasted energy of reinventing the wheel, and can go on to the society-enhancing process of improving our brakes, or our steering, or our floor mats.  (Are you listening, Toyota?)

 This ruling (maybe temporarily) invalidates sequence as the point at which a patent can be applied, a standard that might then be considered in other patent cases (or it might not.  Judge Sweet’s decision sets a precedent, but it doesn’t change any laws).  It leaves the door open for patents to be acquired for subsequent steps, such as testing methods or diagnostic algorithms (think Mammoprint).  The hope of many who argue against patents on sequence is that by eliminating the obstacle of a patent at this early stage, it will allow for more open and vigorous research to continue after the gene discovery phase, leading to more success in the development of diagnostics and treatments.  Which is, after all, what the whole thing is supposed to be about.

 For many years, the research system was divided, roughly, into basic science, which was generally funded by government or philanthropic sources and generally took place in academic settings, and commercial applications, which were generally funded by industry with a profit motive.  In 1980, Congress passed the Bayh-Dole Act, which actively encouraged universities to pursue patents and academic-industry partnerships, so that more of the government investment in science might be translated into advancements available to consumers.  As hoped, the number of patents resulting from NIH-backed science soared.  Bayh-Dole was very successful in promoting commercial use of scientific research; at the same time, it broke down the imaginary wall between academia and commercial interests, with consequences for everything from collegial information sharing to the dynamics of peer review that we are still sorting out today.  For example, it used to be a given that patents were not enforced in research settings.  Today, however, academics are routinely vested in companies, while companies often fund joint ventures with universities.  Companies are less inclined to wink at patent infringement in research when they see Washington University or UCSF as proxies for Monsanto or Genentech.

 But theoretically, a changing patent landscape could shift genetic research back in the direction of earlier models, with basic gene identification done mainly in academic settings using NIH or other public funding.  Detractors say that academic curiosity alone cannot drive discovery at the same pace as the dangling of dollar signs; others point to examples where research has been robust even without the financial inducement of an exclusive, patent-protected, market edge.  I am inclined to believe that intellectual curiosity and the desire to discover can do great things among the science-minded, but then, hell, I have always been a crazy optimist.  I mean, against all the odds in the world, I thought we could pass health care reform just because it was the right thing to do.

 Crazy, right?

1 Comment

Filed under Laura Hercher

Tagged as , , , ,

by | July 2, 2009 · 7:34 AM

Guest Post: Gene Patents- Why should genetic counselors care?

By Ellen T. Matloff

Ellen T. Matloff, M.S. received a Bachelor of Science degree cum laude from Union College, and a Master’s in Genetic Counseling from Northwestern University. Ms. Matloff currently serves as the Director of Cancer Genetic Counseling at Yale Cancer Center in New Haven, Connecticut and previously worked at SUNY Health Sciences Center in Syracuse, NY. She is board certified by the American Board of Genetic Counseling and is a member of the National Society of Genetic Counselors, the American Society of Human Genetics and the American Society of Clinical Oncology.

Should we, as genetic counselors, care about gene patents?

We have plenty of other things to worry about: patient care, publication pressures, administrative responsibilities, growing caseloads, shrinking health care budgets (I could go on, but why raise our collective blood pressure?) — so why, oh why, would we add gene patents to this list?

Because gene patents have a major impact on many things that affect our practice. This includes, but is not limited to:

  • Cost of genetic testing, which influences: Patient access and insurability
  • Market competition, or lack thereof, which affects: Cost (see above), our ability as practitioners (or as a Society) to drive change within commercial genetic laboratories regarding issues such as price setting, marketing, advertising, turnaround time, reporting mechanisms, etc.
  • Clinical research, clinical research, clinical research. It is pretty hard to enroll patients in a study with an extra $3000 price tag per subject. Even a small study of 100 patients would cost more than $300,000 in genetic testing costs alone if patients were to receive their genetic testing results. And as those of us who have written grants know all too well, 100 subjects is a small ‘n’ and $300k is a huge chunk of most available grants.

In short, a strictly enforced patent creates a monopoly. Our patients need a test, we have to order it from one company, and they hold all of the cards. Lump it or leave it.

In the case of BRCA1 and BRCA2 testing, the cost of testing was $1600 in private laboratories in 1997. Twelve years later with the advent of more efficient and less expensive technology, the cost of the testing has not dropped, but soared: $3120 for full sequencing + an additional $650 for BART analysis = >$3770 per patient. Cha ching!

Perhaps in response to rising costs and direct-to-consumer advertising, many insurance companies have tightened their belts and their inclusion criteria for testing. HealthNet tried to drop coverage for genetic testing altogether two years ago, before an angry mob of rioters (also called genetic counselors) bled the story to the press. Medicare will now only pay for testing in a person who already has cancer. Kind of obliterates the whole preventive healthcare angle, doesn’t it?

For all of the above reasons, genetic counselors should care about gene patenting. This is important, its effects are far-reaching, and this is precedent-setting. Educate yourself and educate others.

———-

Here is a great clip about Myriad’s BRCA patent from the documentary film In the Family.

11 Comments

Filed under Guest Blogger

Tagged as , , , , ,