End of October, Breast Cancer Fatigue

Today the author fears she is suffering from breast cancer fatigue syndrome, an unofficial and possibly infectious condition that she named this morning, that comes from too much thinking about breast cancer and the incidence of which peaks in October, and/or that she may be suffering from writing-about-breast-cancer fatigue syndrome, an affliction of some bloggers.

So she will take the rest of the afternoon and evening off, and do some reading and enjoy the weekend with her family.

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Crizotinib, An Experimental Drug for Some Lung Cancers and Other Tumors With Alk Mutations

ML is excited upon reading the latest New England Journal of Medicine (NEJM) which she still receives in print. Today’s issue includes four articles, if you count the accompanying editorial, on an experimental pill for treating some forms of lung cancer and other tumor types with distinct genetic profiles.

The new drug, called crizotinib, is manufactured by Pfizer and targets cellular enzymes including ALK (anaplastic lymphoma kinase). Sound like a mouthful? Well, it turns out that ALK acts up in some cases of non-small-cell lung cancer – an old-fashioned, catch-all oncology term that refers to most types of lung cancer in the U.S. that, literally, don’t comprise cells that look small when examined with a microscope. This tumor category, which affects nearly 200,000 people in the U.S. each year, includes three main subtypes: adenocarcinoma – the kind of lung cancer most common in non-smokers, squamous cell carcinoma and what’s called (seriously) “large cell” lung cancer.

In approximately 5% of non-small-cell lung cancers the malignant cells have a particular chromosomal defect that renders them vulnerable to crizotinib: the gene encoding ALK, on the short arm of human chromosome 2 (2p) is rearranged nearby the gene encoding EML-4 (echinoderm microtubule-associated protein like 4), such that an abnormally active, fusion protein is active in the tumor cells. This hybrid gene product, the result of a particular chromosomal abnormality, is implicated in tumor cell growth and proliferation. Some of these and other investigators have previously demonstrated that crizotinib inhibits ALK activity in cells in vitro and in some animal models.

OK, so in the first of the NEJM papers*, 31 authors (including 16 in Boston, at Harvard affiliated-medical institutions and 5 based at Pfizer, in La Jolla, CA),  report on the trial of 82 men and women with non-small-cell lung cancer who qualified for the study. All had “advanced” tumors, meaning tumors that couldn’t be removed surgically, and 94% had tried other treatments before starting crizotinib. Each enrolled patient had a chromosomal rearrangement, identified by a molecular FISH study, resulting in the EML-4-ALK fusion protein. After some initial phase I work to test tolerance to this new drug, the patients were prescribed 250 mg by mouth, twice daily.

The results were dramatic, as things go for clinical studies of advanced non-small-cell lung cancer: 57% of the subjects responded (partially in all but one apparent instance, meaning that the tumors shrank but didn’t disappear). In an additional 33% of patients enrolled, the disease stabilized (meaning that the tumors didn’t get significantly smaller, but stopped growing as they were before treatment). Upon 6 months of treatment, the probability of progression-free survival was estimated at 72%, but the median had not yet been reached.

According to the study authors, the drug was well-tolerated overall, and most of the patients elected to remain on treatment after completion of the planned protocol. Among the 82 patients, 34 reported “mild” visual disturbances, according to the authors: “the events were most frequently described as trails of light following objects moving relative to the observer, particularly noticed during changes in ambient lighting…” These were considered “Grade 1,” according to Table 2 in the paper. Grade 3 and 4 toxicities were few, and mainly included abnormal liver enzymes affecting 5 or 6% of the patients.

The second paper is a case report, astonishing firstly because there are 18 authors describing the drug’s activity in 2 patients, and secondly because of the interesting nature of the tumor described, a condition called inflammatory myofibroblastic tumor (IMT). I don’t think I’ve ever seen a case of this, either in real-life practice or in preparing for my oncology boards, so for now I’ll quote the paper and say that IMTs occur mainly in young people and consist of malignant myofibroblasts – cells that, when normal, usually form muscle and related soft tissue structures. The ALK gene is rearranged and abnormally expressed in about half of these tumors.

Summary of the second paper: the investigators tried crizotinib in 2 patients with difficult cases of chemo-refractory IMT. One, a 44 year old man with a distinct ALK abnormality who’d undergone extensive abdominal surgery and received multiple chemotherapies, responded fabulously. The other IMT patient, a 21 year old man without evidence for an ALK rearrangement, didn’t respond to the drug.

The third paper, by a Japanese group with a corresponding author based at Jichi Medical University in Tochigi, Japan, describes the development of two secondary, acquired and resistance-conferring mutations in ALK in one lung cancer patient who was taking crizotinib. Among other methods, they performed deep sequencing to check the ALK sequence in many of the patients’ cells, and then confirmed the presence of 2 (but not 3, as were found by this method) mutations using Sanger sequencing. They performed some neat PCR tricks to amplify DNA that was specific to the tumor’s EML4-ALK hybrid, and determined that the two de novo mutations within the tumor cells were mutually exclusive: the patient seems to have developed two resistant tumor clones while on treatment with the ALK inhibitor.

Finally there’s an editorial, by two molecular biologists, Drs. B. Hallberg and R. Palmer, based in Sweden’s Umeå University. This drug has a lot of potential, is the gist of it. ALK mutations don’t just occur in some lung tumors and IMTs, but also in some childhood tumors called neuroblastomas and, more than occasionally, in some anaplastic lymphomas.

I am aware, also, from the NCI’s website and by reading, including some of the above articles, that crizotinib has activity against some other kinases, including c-MET and other signaling receptor molecules, some of which are implicated in cancer growth.

I contacted Pfizer today, and a representative informed me by email that pricing for crizotinib has not yet been determined. I asked about FDA plans, and he wrote: “Pfizer plans to submit crizotinib (PF-02341066) data in the first half of next year to the U.S. Food and Drug Administration (FDA) for regulatory approval.”

Now, there are several ongoing clinical trials of this drug, some for patients with non-small-cell lung cancer and some for patients with other “ALK+” tumors, meaning cancers that bear a mutation in the ALK gene.

Why am I blogging about this drug, a pill, that works imperfectly in perhaps most of 5% of non-small-cell lung cancer patients and, maybe, in some other rare tumors? Because this is the future of oncology and, ultimately I think, will provide cost-effective medicine that’s based in evidence and science.

The key is that the investigators tried the experimental drug in lung cancer patients with a specific genetic profile, one that predicts a response to this agent. If, in 3 or 5 or 10 years we could sequence a patient’s tumor and check for specific mutations, we could give medications tailored to what they’ve got, and avoid treating them with drugs that are unlikely to work. This kind of approach should, if done properly, reduce the costs of cancer care, if the drugs are reasonably-priced.

How drugs like crizotinib could save money:

1. This drug is a pill; slash the costs of IVs, pumps, bags of saline, nurses to administer…

2. Don’t give it to patients without a relevant genetic mutation;

3. Monitor patients for resistance and stop giving drugs when they no longer help the individuals for whom their prescribed.


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Annals of Pink: Chilean Miners Don Ribbons

The Santiago Times reports that the rescued Chilean miners donned suits and pink ribbons, the latter in honor of breast cancer awareness month, at a ceremony at the the presidential palace, la Moneda.

Sure, the pink scene’s getting to be a bit much around here. But I don’t belittle this gesture; the miners’ intentions are surely well-meaning, and in places like northern Chile where they lived and worked, BC doesn’t get the overblown attention it does here, at least not yet. Not even close.

So kudos to the miners, from this one blogger in NYC.

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Stem Cells, Breast Reconstruction and a Magazine Cover

The cover of the November print edition of Wired features large, unnatural-appearing cleavage. Inside and toward the back of the issue, a curious article ties together stem cells and the future of breast reconstruction. It got my attention.

Wired, November 2010 issue

The detailed and admittedly interesting piece, by Sharon Begley, describes what’s science or science fiction: first humans, such as some plastic surgeons, remove adipose tissue, a.k.a. fat, by a well-established cosmetic surgery procedure called liposuction, from a body part where there’s a fat surplus – such as the belly or backside; next, laboratory workers purify and grow what are said to be stem cells from that that fat; finally, they use a nifty, calibrated and expensive device to inject those fatty stem cells where women want, such as in a hole or dimpled breast where a tumor’s been removed.

The story starts, unfortunately and distractingly, with a portrait of a male, enterprising and PowerPoint presentation-giving CEO of a biotech company, Cytori Therapeutics. Toward the end of the article, the author provides stats to support the potential business. Ultimately, improved breast cancer survival means that greater numbers of women will live more years after a lumpectomy or mastectomy, she explains. The reconstruction market may expand further, still, because some women opt for prophylactic mastectomies upon positive genetic testing for a BRCA mutation. Others, without cancer or high risk, might simply want to use these adipose-derived stem cells for cosmetic breast augmentation. What’s clear, if nothing else, is that women’s breasts are perceived as a commodity.

In between the money elements of the discussion, there’s some cool science about adipose-derived stem cells, which according to the cited scientists are quite prevalent in fatty tissue and relatively easy to grow if you give them some blood to feed on in the lab. A putative advantage of the cells is that they draw blood vessels to the area of engraftment, which is a concern to this oncologist (me) and, evidently, to an FDA panel that has not yet approved of this innovative method of breast reconstruction in women who’ve had breast tumors.

I’m not convinced, at least from what’s reported in this Wired article, that the cells used in this process are true stem cells, based on the high numbers the scientists describe finding so readily, and in rich proportions, in human fat tissues. It could be, for example, that what they’re isolating are really primitive adipose cells that can, indeed blend into the breast tissue and even recruit blood vessels as described, but aren’t true, pluripotent stem cells – the kind that can form any kind of blood cell or heart cell or neuron. Perhaps stem cells just sound sexy, at least to investors.

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Notes on Cholera, Old and New

Cholera was a far-away kind of affliction, almost an abstraction, when I first studied microbiology in 1984. The legendary, infectious scourge still affected people in places like Bangladesh or Indonesia, but was a treatable condition that, surely, would be eradicated within a decade or so through progress, if you could call it that, like basic plumbing and sanitation.

The tiny comma-shaped bacteria, Vibrio cholerae, tend to thrive in brackish water, the kind that’s just a bit salty from a mix of ocean and fresh sources. These sometimes stagnant watery places crop up in river deltas, like the Ganges, and coastal estuaries such as those along the U.S. Gulf Coast. We learned that you might, very rarely, pick up a case of cholera by eating contaminated shellfish like crabs or oysters.

The most common symptom of cholera is diarrhea, so rapid and voluminous that a person can die, quickly if without remedy, by straightforward dehydration. The diagnosis of cholera can be tricky, as many people are afflicted with severe gastrointestinal diseases worldwide, but most don’t have this particular, potent toxic germ. Cholera spreads by contamination of infected human feces in the water supply. The disease can afflict people who drink tainted water, who touch it and then put unclean fingers into their mouths, as children do, and who eat food prepared by those with affected hands.

illustration by Robert Seymour (1831), image from the National Library of Medicine, image A021786

Choleraphoby, illustration by Robert Seymour (1831), lithograph from the National Library of Medicine, Image #A021786

Dr. John Snow, an anesthesiologist and founder of public health, recognized the means of cholera’s spread more than 150 years ago in London, where he became famous for mandating the closure of the Broad Street Pump. Snow died at the age of 45, of what was said to be apoplexy, old jargon for a stroke.

In 2009, there were 221,226 cholera cases reported and 4,946 cholera deaths in 45 countries, according to the CDC. Based on information put together by the World Health Organization, the case-fatality rate is 2.24%. A trend in recent years is that the overwhelming majority of cases, roughly 99 percent, are reported in Africa.

According to the 17th edition of Harrison’s Principles of Internal Medicine, there have been seven global cholera pandemics since 1817. The current rage, attributed primarily to the El Tor biotype, started in Indonesia around 1961. That strain spread, eventually, as far as coastal Peru in the early 1990s. There have been no cholera epidemics in North America since the middle of the 19th Century.

What’s happening in Haiti now is the real deal, says the CDC. Thousands are infected, mainly in towns along the Artibonite River, which squiggles on the map and in real terrain through the western section of Hispaniola, north of Haiti’s capital, Port-Au-Prince. Among other concerns are the vast numbers of people living without toilets in tent cities and slums outside of the capital, especially since an earthquake devastated the region last January.

The CDC offers some very practical tips for people who live or travel in areas where cholera is endemic. Most people who are exposed to cholera and survive become immune, although infectious strains vary and immunity may not be long-lasting. In the U.S. there is no available vaccine for cholera, according to the CDC. Treatment consists primarily of giving electrolyte solutions, for rehydration, and antibiotics in some cases.

Now, the mortality rate from cholera in Haiti is running just under 10 percent, according to today’s news. Hopefully, doctors from MSF and other agencies working in the region will get this epidemic under control. But already it’s clear that hundreds of lives have been lost to an illness that it seems should have been eradicated long ago.

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New Findings on Postmenopausal Hormone Replacement Therapy and Breast Cancer

This week the Journal of the American Medical Association (JAMA) published results of a large study with significant implications for women who consider taking hormone replacement therapy (HRT). The new findings are based on careful examination over 16,000 individuals, part of the larger Women’s Health Initiative, who were randomly assigned to take either a placebo, or Prempro – a combination pill that includes estrogen, extracted from equine (horse) urine, and medroxyprogesterone acetate, a synthetic progesterone compound.

The extended data confirm that women who take hormone replacement therapy are more likely to develop breast cancer than those who don’t take it. But this finding has been seen previously, and was one of the reasons why the randomization was halted earlier on –

What’s new is that the breast cancers in women who took hormone replacement therapy are more invasive, with greater extension to the lymph nodes, and more deadly. Women ages of 50 to 79 years who take hormones are roughly twice as likely to die from breast cancer as those who don’t take hormones, and are more likely to die earlier, of any cause.*

In 2002, JAMA published a landmark report on an earlier analysis of the same trial, which was halted because of the evident toxicity, then, of hormone replacement therapy. Before that time, the treatment was thought – on theoretical grounds – to reduce the risk of heart disease.

The drugs were marketed heavily throughout the 1990s, particularly through gynecologists and primary care physicians, and later to women directly – an “ask your doctor” kind of thing. In tangible ways, these drugs tend to make women feel younger and suppler, with fewer hot flashes. Many women I knew were eager to try these hormone supplements.

My perspective is that of an oncologist. Knowing that most breast cancer cells have receptors on their surfaces for estrogen and progesterone – steroid hormones that stimulate growth of normal mammary (breast) tissue cells in healthy women – the findings seem entirely plausible. . Besides that the hormones can bind receptors on cancer cells’ surfaces and trigger growth pathways, there may be other effects. The authors of the new JAMA article suggest, for example, that the hormones can enhance the blood vessels that “feed” breast tumors, and so might make them worse.

Denise Grady provides a thorough report in the Times on this topic. As she points out, approximately 3 million women in the U.S. still take hormone replacement therapy. Before the 2002 report, as many as 6 million postmenopausal American women were prescribed this kind of medication. The incidence of breast cancer in North America has declined since 2002, and most oncologists and epidemiologists ascribe much of that improvement to reduced use hormone replacement therapy.

Still, many doctors still prescribe hormone replacement therapy. There’s a huge potential market for these drugs, and so a lot of money’s at stake, besides women’s health. Based on U.S. census data from 2000, the number of women between the ages of 50 and 79 approached 40 million and, today, is likely larger still.


*The absolute numbers run like this:

Among the 8506 women randomized to take hormone replacement therapy (HRT), there were 385 BC cases detected; among the 8102 assigned to placebo, there were 293 cases identified. (This was a statistically significant difference.) These numbers can be whittled down, then, to a total of 678 BC cases – out of 16,000 women on the trial – who developed BC. The pathology was similar between the two groups, in terms of molecular subtypes. But the invasiveness – in terms of lymph node involvement – was higher in the HRT group, as was the mortality: 25 women died from BC in the HRT group; 12 women died from BC in the placebo group. (This was also significant, but with a p value of just 0.049).

One caveat, or limitation, to the study is that the authors didn’t have access to detailed information on the women’s treatments, which may or may not have differed between the groups. A strength of the study is the relatively long follow-up, of 11 years on average.

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Copiapó Dreaming – The Copper Miners’ Tale

This week it seemed at least half the world was captivated by the uplifting story of the Chilean miners. The 33 men – mainly middle-aged and of modest means – zoomed up in high-tech capsules from the deep, would-be tomb where they’d been waiting for 69 days underground in the southern Atacama, not far from the industrial, northern Chilean city of Copiapó.

The amazing and nearly-too-good-to-be true news is that a top-notch team of engineers, doctors including the NASA/Johnson Space Center Deputy Chief Medical Officer, nurses, psychologists and others pulled off this fantastic rescue by which each and every one of these real men were delivered to Camp Hope (Esperanza) a tent city swelling with media and enthusiastic politicians, clergy, miners’ families and, presumably, support staff – cooks, washers and others who helped people there cope with the situation.

It’s inconceivable that any human with a heart would not be gladdened upon learning of the miners’ safe arrival – all more-or-less in good shape, no less – on firm ground. A rabbi said this of the affair: we too-often take this world for granted; but after their ordeal in the darkness, the Chilean men kissed the earth and thanked god for simply returning them to what they’d had before – a place filled with sunlight, air, loved ones, friends, food, music and, well, everything they had and have again. So there’s a religious message here, if you’re open to that. At the same time, an atheist would see clear evidence in this fantastic episode for the power of humans and science, technology and coordinating resources.

The medical issues are rich, including: risk of fatigue and dehydration in an inescapable, 90 degree hot and humid environment; vitamin deficiency and possible eye damage upon exiting, from lack of sunlight; lung problems from metal dust exposure; infections like pneumonia, potentially shared in a small communal space or gut-related, if hygiene is poor and human waste is not stashed properly; emotional downers – like fear and depression – may affect men who don’t articulate those sorts of concerns.

Some environmentally-minded thinkers point out that this true tale isn’t representative, reducing the story like this: “For every miner who was rescued before the cameras this week, more than 400 others will die this year.” Indeed, the International Federation of Chemical, Energy, Mine and General Workers’ Unions, estimates that worldwide, approximately 12,000 miners will lose their lives this year, while on the job. They’re right, I know – mining is a risky, under-regulated occupation.

Nonetheless, I’m thrilled by this remarkable story, at two levels: first, that the “patients” are all right, and second – what’s even more awesome – is that people around the world cared so much about the miners’ well-being. I’ve been wondering what if the outcome hadn’t been so successful. The news coverage would have been less intense, and the President of Chile would have had more difficulty maintaining his political position, and maybe there’d be more regulation of copper-mining in the future. Still, it would have been OK, good and maybe great, I think – even without the happy ending – that the engineers and international top-docs with their expertise, and miners’ families and lovers’ with their food and good cheer, did everything they could.

The outcome matters, but so does the effort, in itself. If we don’t as much as offer care to humans who need it, there’s little chance they’ll get better. This news is about health care, delivered. So the next, logical question is this: Can we take this up to another level by providing high-quality, coordinated care to every group of 33 patients with a guarded prognosis, and do whatever it takes to make them well using existent technology and medicines? This story is a fantasy, as much as it’s real.

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Word of the Week: floccinaucinihilipilificationism

ML learned a new word upon reading the newspaper: floccinaucinihilipilificationism. According to the New York Times now, the late Senator Patrick Moynihan prided himself on coining the 32-letter mouthful, by which he meant “the futility of making estimates on the accuracy of public data.”

Some brief history:

Sometime around 1981, Moynihan invented the word by adding “ism” to an older, 29-letter English word, floccinaucinihilipilification – defined as “the action or habit as estimating as worthless” in a 1971 edition of the Oxford English Dictionary:

from the Oxford English Dictionary (1971)

You can find an open discussion of the roots of floccinaucinihilipilificationism on Wiktionary, which includes hard-to-decipher, clickable audiofiles – just in case you want to try saying the word out loud. Moynihan used the word in the title of his 1981 New Yorker review of a book by economist John Kenneth Galbraith.

More accessible is a somewhat dull, but worth-a-listen clip of the Moynihan discussing the word’s history in a debate on the budget deficit in July, 1999, on C-SPAN. From the Congressional Record:

“Floccinaucinihilipilification is now the second longest word in the Oxford Dictionary. It is from a debate in the House of Commons in the 18th century meaning the futility of budgets. They never come out straight…I added “ism” to refer to the institutional nature of this, so it became floccinaucinihilipilificationism. It is no joke. One never gets it right. It is not because one cannot, one does not try…

It seems to me the term, which was intended for the realm of economics, and projections in that, might bear also on the intricacies of vast amounts of data in science and health, data mining, and understanding the limitations of medical studies and related analyses. But I’m extrapolating here, for sure.

As I read the late Senator’s words, about his word, it seems maybe he’s suggesting that we could “get it right,” i.e. sort out data in a way that has real value, if we try harder to do so.

But who knows?

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October 13 Would Be National Metastatic Breast Cancer Awareness Day

According to the most recent figures available, roughly 160,000 people are living with metastatic breast cancer in the U.S. The number may be higher now, based on progressive availability of new drugs – especially in the past decade – that are slowly extending the average life-expectancy of women with Stage IV disease.

Last October, the U.S. Senate (on 10/13/09) and House (retroactively, on 10/28/09) voted to support the designation of October 13, 2009, as a National Metastatic Breast Cancer Awareness Day. The point was to draw public attention to the distinct needs of metastatic BC patients: women who live every day with this condition but, for the most part, are not heralded in pink.

My hope is that before October 2011, President Obama will make this day official: October 13 should be National Metastatic BC Awareness Day – so that women with advanced disease will know they’re not forgotten and, rather, will catch the public’s eye.

My pick for NMBCA Day’s official color: gray, to signify seriousness and uncertainty; but of course every woman should choose her own style!

Please see a related HuffPo piece; that includes patients’ and others’ viewpoints on this topic.

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Everybody’s Talking About Stem Cells

Last week, doctors injected embryonic stem cells into a human patient with an acute spinal cord injury. The procedure took place at Shepherd Center, a hospital and research center for spinal cord and brain injury in Atlanta, GA. The patient was the first to receive human stem cells derived from an embryo in an FDA-approved research protocol in the U.S.

The phase I trial, sponsored by Geron Corporation of Menlo Park, CA, is primarily intended to evaluate the treatment’s safety. The company has developed a way to culture and purify oligodendrocyte progenitor cells (OPCs – primitive neuronal cells) from human embryonic stem cells (h-ESCs). These precursor cells, obtained from human embryonic tissue, can be coaxed, at least in vitro, to develop into one of various mature cell types, including neurons).

So what defines stem cells?

Stem cells are considered pluripotent, meaning that they have the capacity to differentiate, or mature, into specialized, distinct cell forms depending on nearby cells and stimulatory molecules in their environment. Mature cells, by contrast, have already “decided” what kind of tissue they’ll grow into – whether that’s part of the eye, or the heart, liver tissue, nervous system or any other body component.

The idea behind stem cell therapy for spinal cord injury is to provide the wounded spine with fresh, primitive cells that might grow into neurons and replace those that have been damaged. The protocol is highly-experimental.

There are three major sources of human stem cells:

1. Adult stem cells are relatively abundant in the bone marrow.

2. Cord blood cells; as are found in the placenta and umbilical cord after delivery of a newborn;

3. Embryonic stem cells, as were used in this protocol, are typically removed from surplus material after IVF.

You can learn more about human stem cells on the NIH website here.

(and belated happy birthday, JL!)

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