“A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring.

At first glance, this is terrific news for patients world-wide. It means is that no company, university, other entity or individual can patent human genes.

Keep in mind – the case doesn’t just apply to BRCA and evaluating a person’s risk for breast and ovarian cancers. Rather, there are hundreds of human genes implicated in cancer that are potential targets for treatment, that might be evaluated, and thousands linked to other diseases. The decision continues:

“Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA. It found an important and useful gene, but groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the… <patent law>

West façade, U.S. Supreme Court (Franz Jantzen), gov’t image

What’s clear is that gene sequences, as they occur in human cells, can’t be owned just because they’re found, no matter how important they are. This circumstance should allow other researchers and firms to create cDNA from the natural sequences to develop new (competing and potentially less costly) assays and, even better – do their own work – tantamount to providing “second” and “third” opinions (etc. & n.b. IMO more is better!) research to understand how the genes lead cause disease in some people and might targeted for therapy. Great –

But the decision suggests that many lab-generated complementary DNA (cDNA) strands remain patentable, or up for grabs once created – which may be the reason some biotech stocks have rising values today. I’m neither a lawyer nor an analyst, but I do know from my experience as a researcher that it’s essentially trivial to generate cDNA from a short DNA segment, potentially with a mutation of interest. So how might the cDNA be patented, if anyone who has access to the original genetic sequence might form the cDNA by routine lab methods?

Near the end of the opinion, the justice writes:

“…but the lab technician unquestionably creates something new when cDNA is made. cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived. As a result, cDNA is not a ‘product of nature’ and is patent eligible under <patent law §101>, except insofar as very short series of DNA may have no intervening introns to remove when creating cDNA. In that situation, a short strand of cDNA may be indistinguishable from natural DNA.

The document clarifies the cDNA issue just slightly:

“It is important to note what is not implicated by this decision. First, there are no method claims before this Court… the processes used by Myriad to isolate DNA were well understood by geneticists at the time of Myriad’s patents ‘were well understood, widely used, and fairly uniform insofar as any scientist engaged in the search for a gene would likely have utilized a similar approach’…

Nor do we consider the patentability of DNA in which the order of the naturally occurring nucleotides has been altered. Scientific alteration of the genetic code presents a different inquiry, and we express no opinion about the application of <patent law §101> to such endeavors.

How I interpret this is that if a researcher generates a short cDNA segment based on a gene, that’s not patentable, but if it’s a long strand involving lots of clipped introns, that might be patentable.

Taking in all this, which is far from simple, I have a question and a wider point:

What goes unaddressed by the justices is the patentability of cDNA based on common genetic variants in cancer. Those are “naturally occurring” mutations, inasmuch as they arise in humans. But the cDNA generated from those sequences might remain patentable. There are loads of examples in this regard: Consider, for example, the genetic mutations in EGFR, and ALK, that are used in lung cancer diagnosis, treatment decisions and development of new targeted drugs. In the current issue of the New England Journal of Medicine, doctors report on SALL4, a gene that occurs in some liver cancers and might be a good, useful target for therapy in that disease.

The point is that the Supremes – and those would be lawyers – need to know about biology. Justice Scalia, sadly in my view, wrote his own opinion not because he disagreed with the others, but because he felt there was too much science in the decision. From the Scotus Blog today:

“Many readers no doubt will share the view of Justice Antonin Scalia, in a short, separate opinion refusing to join in a section “going into the fine details of molecular biology,” of which he said he had neither knowledge nor belief.  Scalia said he did understand enough …

This scares me, that one of the Justices, our most accomplished lawyers who might make decisions on cloning, and stem cells and who knows what in the future, copped out because he lacks science education – what should be required high school biology in  U.S. schools, public and private – to form an opinion that matters so much.

Yesterday I learned that a woman I know slightly, a journalist, has Stage 4 lung cancer. Debra Sherman is a reporter for Reuters and began a blog, Cancer in Context.  It’s a moving start of what I hope is a long journey.

What struck me is how Debra describes crossing a line, a bit the way I felt when I found out I had breast cancer. She writes:

I have been writing about medical technology and healthcare for more than a decade. I’ve covered the major medical meetings, including the big one on cancer. I’ve written stories about new cancer drugs and treatments…I wrote those stories objectively and never imagined any would ever apply to me.

She’s shifted from what you might call a “straight” reporter to an i-reporter journalist. And although it’s true that Debra may be less objective than some other writers on the subject, she’s already knowledgeable – through her prior work – on many of the relevant terms and issues. Much of what she knows already, vocabulary included, may allow her to make more informed decisions. It’s possible it may enable her to write in a way that helps readers more than ever.

Earth, from space (NASA image, Wiki-commons

I wish her the best with her column, and with her health ahead.

The bigger issue, of which the story reminds me, is that we’re living among too many young and middle-aged people who have cancer. Every day I read or hear of another case among my neighbors, a friend, a blog. Each reminds me of the need for research, better drugs, and greater knowledge of why so many tumor types – including lung cancer in women who haven’t smoked much, and breast cancer in young women – are on the rise.

The ASCO meeting, where believe me I wish I could be but can’t now, offers a bright picture for targeted drugs, genomics, novel immunotherapy and better data access and analyses through a huge new platform called CancerLinQ, All good. Great, really.

In thinking about each new case in my “world” – if I could pick a field for future investigation that might lead to insight on cancer’s causes and, ultimately, reduce the cancer burden 30 and 50 years from now, I might choose the tiny, under-funded area of environmental oncology

That’s a tough field. Most oncologists want to work with patients. Researchers want to publish papers. Cause-and-effect is hard to demonstrate, especially when most of the data is untenable and you’re up against businesses, politics and people who, understandably, don’t recall precisely what they ingested years ago. But to stop cancer from happening so much, that’s where the money is. IMO, nothing more.

All for this week,

ES

tamoxifen binding an ER receptor (Wiki-Commons)

Why this matters so much is that ER+ tumors account for most BC cases. So if you’re a pre-menopausal woman who’s had a tumor removed by surgery, there’s a good chance your doctor will recommend adjuvant (“extra”) treatment with Tamoxifen for 5 or (probably) 10 years. The reasoning behind this recommendation is that the recently-published ATLAS study demonstrated a clear lengthening of life among women with ER+ tumors who took the longer course.

The usual dose of Tamoxifen (Nolvadex) is 20 milligrams per day. The bargain-rate cost is around $9 for a month’s supply GoodRx.com  - so we’re talking just over $110/year x 5 or 10 years. That’s small change as oncology drugs go, although the numbers add up over so many patients affected…

Tamoxifen carries a small but real risk for what most doctors consider side effects, like blood clots and occasional, typically low-grade uterine cancers. The problem with Tamoxifen – which is not so much a risk as a definite consequence of taking this medication – is that it has anti-estrogen effects that many young (and older) women consider undesirable. Already our breasts have been cut. Feeling “feminine” is not trivial. Many don’t want it!

(Mental exercise: imagine hundreds of thousands of men ages 35–55 agreeably accepting a prescription for partial chemical castration to reduce the chances of a tumor recurring, after they’ve already had significant treatment to reduce those odds)

Your author has been in rooms filled with doctors where the overwhelming consensus expressed was that hormonal treatments in women with BC are terrific. Indeed, they extend life and, in some cases – such as those with low Oncotype scores – afford women the option of skipping chemo. But how are they so sure we’d rather take an anti-estrogen for 5–10 years rather than 3–6 months of chemo? Answer: I don’t think anyone knows.

One limitation of the ATLAS study (and as best I can tell the same for aTTom) is that the trial doesn’t distinguish between women who got adjuvant chemo and those who didn’t get chemo. So it’s unclear whether Tamoxifen helps prevent recurrence, or extend life, in women who’ve also received chemotherapy for the disease.

Here are 2 questions for aTTom:

1. How do we know that women with small, node-negative (low risk) tumors who receive chemotherapy, as is standard in many communities, get additional benefit from Tamoxifen after chemo?

2. Should pre-menopausal women with small, ER+ tumors be given a choice between taking chemo or Tamoxifen?

In other words, is there evidence to support the combination – chemo followed by hormonal Rx – as the standard, adjuvant care for women with early-stage, ER+ tumors? or that women prefer hormonal pills over a short course, like 4 cycles, of chemo?

I’m eager to hear about the updated aTTom (adjuvant Tamoxifen Treatment offers more?) findings, to be published and presented on Sunday. I hope my colleagues – doctors, patients, advocates and journalists will ask good questions!

All for now,

ES

And so I was struck by an essay in today’s Times by a woman who has dystonia, a neurological condition. She writes:

Long after “coming out” to my friends about my diagnosis, I realize now that what’s most important is telling people about the disease. Telling waiters why I’ve brought a special pillow with me to a restaurant; legislative aides who want to know what their bosses can do; and strangers who ask, almost rhetorically, if I am in pain.

The point of the article, as I understand it, is that big-name diseases like cancer get loads of media attention and sympathy from strangers. Relatively few people “get” the suffering of those with rare or less mortifying conditions. This is especially true when there’s no celebrity who speaks, writes, sings or otherwise whines or rails on it. People who don’t feel well want empathy, or at least a bit of consideration.

OK, now I’m going to say what’s hard, and I might regret, but I’m not sure that everyone needs to hear about all of our ailments: Sure, if you’re a writer, you can sort through your medical issues and feel better by expressing yourself, as I sometimes do here, and in principle and occasional reality help others facing similar disorders. And if you’re an employee somewhere and you need to take time off or accommodation for a disability, you may need to talk with your boss about what’s going on.

But do you need explain to the person on the checkout line or, say, a mother organizing a bake sale, why your back hurts? Why you frequent the women’s room? Or why you need a seat on the bus?

I am truly ambivalent about this.

My only way out is to tell you of an error I think I made, in withholding information. After my spine surgery, when I couldn’t sit up without assistance, or raise my arm to brush my teeth, and then eventually was practicing walking with a cane, wearing a brace in warm weather under modest clothing, I deliberately didn’t visit or walk by my place of work. I didn’t want my colleagues to see me looking frail. I wanted to return to work looking strong and standing straight up, as if nothing were wrong inside.

Already I’d had the cancer treatment – surgery and chemo – and they knew about that, although we didn’t speak of it much. Mainly it was women coworkers who visited me when I was hospitalized. That is understandable. Most of my colleagues didn’t know about my back. Not really. A lot of people have back pain, after all. What’s the difference, scoliosis, fusion, a revision, a clot, whatever…Or about my other conditions. It was TMI.

Over time I was becoming a burden to the group and – astonishingly in retrospect, I felt badly about that. I worked harder than most, to compensate for my disability (which I had trouble acknowledging, internally), and that further damaged my health. I sometimes wonder, now, if I had told my colleagues earlier, and let my non-cancerous conditions “show,” would I still be practicing medicine today?

Maybe.

Not everyone wants to hear about it. Or know. Besides, plenty of people have stuff they don’t mention -

“Everything is copy,” is a phrase Nora Ephron learned from her mother. That’s according to her son, Jacob Bernstein, who  detailed some of her final days in the New York Times Magazine. But Ephron kept quite a bit to herself. She was a sharp and successful lady.

Thoughts?

Angelina Jolie at Cannes in 2011 (Wikimedia Commons, attribution: Georges Biard)

Before this morning, I never wondered what it’s like to walk in Angelina Jolie’s shoes. Like many, I woke up to the news – presented in the form of an op-ed in the NYTimes – that one of the world’s most beautiful and famous women recently had bilateral mastectomies to reduce her risk of developing breast cancer.

It turns out the 37 year old actress carries a BRCA1 mutation, a genetic variant that dramatically ups her risk of developing breast and ovarian cancers. Her mother, Marcheline Bertrand, died of cancer at the age of 56 years. Jolie would have been 31 years old when her mother died.

As Jolie tells it, doctors estimated her risk of developing breast cancer to be 87 percent. As she points out, the risk is different in each woman’s case. As an oncologist-journalist-patient reading her narrative, I can’t help but know that each doctor might offer a different approximation of her chances. It’s likely, from all that Jolie has generously shared of her experience and circumstances, that her odds were high.

“Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness,” Jolie wrote in today’s paper. To take control of her fate, or at least to mitigate her risk as best she could upon consultation with her doctors, she had genetic testing for BRCA and, more recently, decided to undergo mastectomy.

The decision was hers to make, and it’s a tough one. I don’t know what I’d have done if I were 37 years old, if my mother died of cancer and I had a BRCA mutation. There’s no “correct” answer in my book, although some might be sounder than others –

I know physicians who’ve chosen, as did the celebrity, to have mastectomies upon finding out they carry BRCA mutations. And I’ve known “ordinary” women – moms, homemakers, librarians (that’s figurative, I’m just pulling a stereotype) who’ve elected to keep their breasts and take their chances with close monitoring.  I’ve known some women who have, perhaps rashly, chosen to ignore their risk and do nothing at all. At that opposite extreme, a woman might be so afraid, terrified, of finding cancer that she won’t even go to a doctor for a check-up, no less be tested, examined or screened.

What’s great about this piece, and what’s wrong about it, is that it comes from an individual woman. Whether she’s made the right or wrong decision, neither I nor anyone can say for sure. Jolie’s essay reflects the dilemma of any person making a medical choice based on their circumstances, values, test results and what information they’ve been given or otherwise found and interpreted.

How to conclude? Mainly and first, that I wish Ms. Jolie the best and a speedy recovery after surgery. And to thank you, Angelina, for raising this issue in such a candid fashion.

As for the future, Jolie’s decision demonstrates that we need better (and not just more) research, to understand what causes cancer in people who have BRCA mutations and otherwise. My hope is that future women – children now –needn’t resort to, nor even contemplate, such drastic procedures to avoid a potentially lethal condition as is breast cancer today.

river landscape, by Frits Thaulow

So when Dan Fagin’s book, Toms River, came out two months ago, I was drawn. The narrative opens with a gripping portrait of a young man whose frame was irrevocably altered by a childhood cancer. It moves on to the history of the small town in central NJ where Ciba, an international chemical company now subsumed by BASF, set up shop in the early 1950s.

The residents hadn’t a clue what was happening to their water. Fagin, an environmental journalist, wades through a half century of dumping, denial, Greenpeace efforts to expose the situation, local citizens’ mixed responses, real estate, some basic and theoretical chemistry, cancer registries and more.

I value this book highly. Toms River could be a lot of places – pretty much anywhere pollution goes unchecked. As the author points out near the end, the problem’s manifest in China now, and elsewhere. It’s a lesson in business ethics, among other things.

The tale intersperses epidemiology and statistics with local politics and individuals’ lives. It reveals just how hard it is to prove cause and effect when it comes to cancer – which, as I’ve said before, is no reason to let industry go unregulated. Because we’ll rarely if ever get definitive, 100%-style evidence that a particular compound causes cancer in humans. Rather, the story points to the need for lowering the threshold for chemicals on the list, and for regulating toxins in manufacturing.

A subtler point, deeper in some ways, is that there are people who don’t want to think about their neighborhood’s water supply or the food they like to eat…”Out of sight and out of mind,” Fagin says in the thick of it. He’s spot-on, there: when a toxic exposure is disconnected from its outcome by decades – and diluted, we tend not to notice or worry.

#humannature

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Cancer Genome Atlas Image, NIH

What does this mean if you’re a patient?

You might ask your oncologist if and in what lab your tumor’s been sequenced. Some mutations affect prognosis. Knowing your “status” could influence a decision to take aggressive therapy. Some genetic changes involve molecules that confer susceptibility to new drugs. You and your doctor would want to consider what targeted options apply to your case. If standard treatment isn’t working, you might want to see if there’s a clinical trial for tumors that have your cancer’s genetic pattern or variant. Keep in mind — testing for particular mutations is not the same as sequencing an entire gene or cancer genome.

Commercial tests don’t necessarily (nor usually) check for all possible mutations in a broad cancer type or gene of interest. For lung cancer, melanoma and other tumor types – the tests offered by one company, that your doctor or hospital may happen to use, vary in their scope, accuracy and methods. The recent BRCA patent case, now before the U.S. Supreme Court, highlights this issue.

What are the implications for doctors?

The cancer news points to the value of hard science education before, during and after medical school. Physicians need to know and “get” genetics – how DNA is sequenced and how mutations are evaluated, in the current era – so they can appreciate the limits and meaning of their patients’ test results.

Shortliffe emphasized the multidisciplinary nature of the field — that clinicians and computer science-oriented types need be involved for health information technology (HIT) to be effective. “Human health is at the core of it,” he said. The goal of biomedical informatics isn’t for computers to replace humans, he said, but for doctors to learn how to use it – as a tool – so that we (human doctors) can practice better medicine.

He reviewed the 50-year history of the field. The super-simple summary goes something like this: in the 1960s hospitals developed early information systems; in the 1970s, early decision support and electronic health records (EHRs) emerged at hospitals and large institutions; in the 1980s clinical research trials led to databases involving patients across medical centers; in the 1990s, progress in science (especially genetics) led to modern biomedical informatics. Now, the vast work includes clinical, imaging, biology (molecular, genomic, proteomic data) and public health.

Clinical informatics is the newest field supported by the American Board of Medical Specialties.  The first boards will be offered in October of this year, he mentioned.

If you’re interested in the future of health IT, as I am, you might want to take a glance at a perspective published recently by Dr. Shortcliffe and two coauthors, Putting Health IT on the Path to Success, in JAMA. The authors consider the slow pace of implementing HIT, and suggest that the solution rests with patient-centric Health Record Banks (HRBs):

“…Health record banks are community organizations that put patients in charge of a comprehensive copy of all their personal, private health information, including both medical records and additional data that optionally may be added by the patient. The patient explicitly controls who may access which parts of the information in his or her individual account.

I’d like to see these emerge.

Dementia affects nearly 15 percent of people over 70 of age in the U.S, these researchers found. They used various statistical tools, adjustments, estimates etc. to estimate the costs of care for an individual with dementia: it typically ranges between $41,600 and $52,300 per year. The tallies are huge for the population, involving some $109 billion per year for “care purchased in the market” or $215 billion if you include the “estimated monetary value of informal care” – i.e. home care by relatives, days off from work and things people do all the time to assist old friends, family members and others in their communities.

The Times headline – about dementia-related expenses doubling between now and 2040 – and the NEJM article, focus on dollars and cents. And that’s fair enough. Unless we’re going to leave aging folks  to die of thirst in a metaphorical woods, or purposively give them a woefully large dose of painkillers in a clinical setting, or otherwise kill them, we’ve got to find a way to take care of elderly people who need help.

But – and I hope this doesn’t come across as heartless – I don’t think it’s reasonable to consider dementia in the very elderly along the same lines as illnesses that affect younger people, like lethal viruses, brain cancer or multiple sclerosis, to (randomly) name a few. Some degree of cognitive decline is normal, and aging is normal. It’s natural, if you will – like grief, distraction and other aspects of the human experience.I don’t really see the costs of dementia, when it doesn’t occur prematurely, as “medical.” Rather, it’s the price we pay for extending human life by feeding tubes, screening for and treating cancers, placing pacemakers, performing dialysis and giving other treatments that so many live beyond a ripe old age.

What’s not considered, left unaddressed, untended…is whether a legitimate goal of health care is to prolong life beyond a certain point. Few may be willing to mark that point, but I do think we’re missing it. If we can afford the research, technology and consequences of extending life by what some might consider unnatural processes – is a really tough question.

I was moved to read one of Rakoff’s books, Half Empty, and in that discovered a man who, I like to think, might have been a friend had I known him. It’s possible our lives did cross, perhaps in a hospital ward when I was a resident or oncology fellow, or in Central Park, or through a mutual friend.

The last essay, “Another Shoe,” is my favorite. Rakoff learns he has a sarcoma, another cancer, near his shoulder – a likely consequence of the radiation he received for Hodgkin’s in 1987. He runs through mental and physical calisthenics to prepare for a possible amputation of his arm. He half-blames himself for choosing the radiation years before: “I am angry that I ever got the radiation for my Hodgkin’s back in 1987, although if it’s anybody’s fault, it is mine,” he wrote. “It had been presented to me as an easier option than chemotherapy.” He reflects on his decision as cowardly and notes, also, that it didn’t work.

He wound up getting chemo anyway, a combination – as any oncologist might tell you, but not in the book –that’s a recipe for a later tumor.  So one take-away from this sort-of funny book, among many, is that how doctors explain treatments and options to patients – the words we use – matter enormously, not just in clinical outcomes, but in how people with cancer feel about the decisions they’ve made, years later.

The other part on words, which I love, is a section on the kinds of things ordinary people – friends, neighbors, relatives, teachers…tell people who have cancer. It appears on pages 216–217 of the paperback edition:

“But here’s the point I want to make about the stuff people say. Unless someone looks you in the eye and hisses, ‘You fucking asshole, I can’t wait until you die of this,’ people are really trying their best. Just like being happy and sad, you will find yourself on both sides of the equation over your lifetime, either saying or hearing the wrong thing. Let’s all give each other a pass, shall we?

I look forward to reading more of Rakoff’s essays, and appreciate that he’s given me so much to think about, on living now.
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