A Challenge for Personalized Medicine

Personalized medicine is the new Holy Grail of cancer therapy.  The drugs we currently use are stupid.  They don't actually target cancer cells, they target rapidly dividing cells.  Cancer cells divide rapidly, which is why chemotherapy works, but plenty of other cells in our bodies divide rapidly, and that is why chemotherapy causes so many side effects.

Not only that, but not every tumor of the same type responds similarly to the same chemotherapy.  For breast cancer, some tumors respond well to cyclophosphamide and doxorubicin, but others do not.

Cancer is, at its root, a genetic disease... meaning that changes in the genes within a cell cause it to transform from normal to cancer.  A lot of recent work has gone into identifying the specific mutations that lead to a particular tumor type, and using this information to gauge risk and make treatment decisions.

A by-product of this work has been the development of so-called targeted therapies... drugs that interfere with the abnormal function of a mutated enzyme, for example.  Because these drugs act only in cells that have that particular mutation, which presumably only happens in tumor cells, they are thought to be more specific and less prone to side effects.  The ultimate goal, then, of personalize cancer medicine would be to identify mutations in an individual's tumor and prescribe a regimen of targeted therapies that are specific for that tumor.  Not for the type of tumor... for the individual tumor.

An article in today's issue of the New England Journal of Medicine makes it clear that this approach is going to be more difficult than previously believed.

Most work aimed at identifying mutations in a specific tumor is based on a single biopsy of the tumor, the idea being that the important mutations will be present in every cell in the tumor.  Today's article addressed this issue directly by comparing the mutations found in multiple different biopsies from the same tumor.  What they found raises serious concerns.  Only about 1/3 of the mutations this group identified were present in every biopsy specimen from the same tumor.  The other 2/3 were found in only a subset of the biopsies.

At one level, this is not news.  Cancer scientists have been aware for years that tumors are heterogeneous... that is, not all of the cells are the same.  It stands to reason, then, that not every cell will have all of the mutations.  That there will be some cells with fewer mutations, and some with more.  And today's article does suggest that some mutations, probably the ones important for the original development of the tumor, are found throughout the mass.  However, if only a single biopsy is performed and used as the basis for making treatment decisions, most of the identified mutations will NOT be common throughout the tumor.

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It's not the end of the world, but it does mean that developing and testing this kind of treatment approach is going to be a lot messier than people have previously believed.

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This is not a drill!

 Today was the day.


I recently wrote about chemotherapy shortages.  They've been in the news more and more over the past 12 months.  But until today, at least in my practice, they were worries.

But now the drug in short supply is methotrexate.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children.  Cancer is the most common cause of death (other than trauma) in children.  Upwards of 80% of children with ALL are cured with modern treatment regimens.

But I don't know how to cure ALL without methotrexate.

Or osteosarcoma.

Or lymphoma.

There are several companies that supply methotrexate in the US, but all are experiencing production or distribution delays or suspensions.  The net result?  We had a meeting today to figure out if we have enough methotrexate to treat our current patients.  And, if we have a shortfall, to figure out who gets treated... and who doesn't.

The good news is we found a few vials we didn't know about yesterday, and for at least the next 2 weeks, all current patients can get treated on schedule.  But, if we don't get another shipment in 2 weeks, or if an adult-sized patient is diagnosed with Burkitt's lymphoma presents to the hospital tomorrow?  We won't have enough drug. 

And someone won't get treated.

I have already discussed the many reasons for drug shortages.  The list of drugs in short supply is mind-bogglingly long.  But we can work around a lack of Zofran.  We can find alternatives for Gentamicin.

But I can't cure ALL without methotrexate.

What's Sauce for the Goose May Not Be Sauce for the Gander

Avastin has been in the news a lot lately, and most of the press has been negative.  In November, the FDA revoked its approval of Avastin to treat newly diagnosed metastatic breast cancer.  Then, in December, Genentech, who manufactures Avastin, announced it would not seek FDA approval for the treatment of ovarian cancer, based on studies showing an improvement in progression-free survival but not overall survival.  Of course, whether Avastin helps women with ovarian cancer remains a controversial question, depending how you value progression-free survival. Compare this report with this one, for example. 

In tomorrow's New England Journal of Medicine, there are two reports of clinical trials evaluating Avastin for patients with newly diagnosed HER2-negative breast cancer.  In both this study and this one, women with newly diagnosed breast cancer were given chemotherapy with or without Avastin.  The women with HER2-negative tumors had a higher rate of "pathological complete response" if they received Avastin.  "Pathologic complete response" means that when it was time for surgery, not living tumor could be found.  Women with a "pathologic complete response" tend to live longer than women who do not respond as well.

What does all this mean?  Will these studies "reignite the debate" about Avastin in breast cancer?  I guess that depends on who is doing the debating.  I think the role of Avastin in breast cancer, indeed the role of Avastin in treating any cancer, remains unclear.  In the end, I believe it will be shown that Avastin helps some cancer patients and not others, and it will all depend on the biology of each tumor type.  Clearly, not all breast cancer is the same, and breast cancer is not the same as ovarian cancer, let alone osteosarcoma or lymphoma.  Today's studies simply reinforce the fallacy of extrapolating from one tumor type to another.  A drug may be very helpful for one type of cancer, and useless for another.


That's why we do clinical trials like this one, sponsored by St. Jude Children's Research Hospital, in which we are participating, trying to see if Avastin helps osteosarcoma patients.

These studies do raise another important point, which I will discuss very soon.  These studies relied on a "surrogate end point."  That is, the studies were designed to see an effect on "pathologic complete response," but only because that is thought to correspond with improved overall survival.  Only time will tell whether the women who received Avastin do actually live longer.

More to come...

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The issue of chemotherapy drug shortages has made the news a lot over the past 6 months or so, including an OpEd piece in the New York Times last August that pointed out that the situation is so bad that, in effect, cancer care is being rationed in the US.


How did this happen?

Well, the situation is quite complex, but much of what is going on was summarized beautifully by my colleague Michelle Hudspeth, Director of Pediatric Hematology/Oncology at Medical University of South Carolina (and graduate of our residency and fellowship programs), when she testified before Congress (her testimony is here).  Briefly, the problem can be traced, in part, to a rule by The Centers for Medicare and Medicaid Services (CMS) called the ASP + 6 Rule.  This rule limits what a private oncologist can charge for a chemotherapy drug to the Average Sale Price plus 6%. 

Why does that matter?  An article by the Director of the National Library of Medicine, and one in the New England Journal of Medicine, outlines the financial issues.  Because so many of the older chemotherapy drugs are available as generics and are consequently very inexpensive.  Consider the case of carboplatin.  A vial of carboplatin once sold for $125, but recently the cost has fallen to $3.50.  Add 6% to that, and you certainly don't recoup the cost of administering the drug in your office. Similarly, paclitaxel costs $312 per vial, while Abraxane (albumin-bound paclitaxel) costs $5,824 (all cost data come from this article in the New England Journal of Medicine).  There is almost no financial incentive to pharmaceutical companies to make generic chemotherapy drugs, nor is there a financial incentive to private oncology practices to use generics.

But this is just part of the problem.  There is currently a nationwide shortage of Doxil (liposomal doxorubicin), which is not a generic.  Why?  Through industry consolidation, there are fewer and fewer plants that manufacture these drugs, so when something happens at even a single plant, the entire market is affected.  Quality control issues at the only plant in the world that makes Doxil shut the plant down and with it, all drug production. 

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So, it seems that industry consolidation, downward pressure on pricing of generics, as well as contamination, other quality control problems, and shortages of raw materials have conspired to create a perfect storm.

The consequences of these shortages go beyond just drug availability.  As the New York Times article discussed, and Dr. Hudspeth mentioned, medication errors are increasing as oncologists are forced to use less familiar drugs.  Research is affected, too. This article, published in the scientific journal Nature in October, discusses the effect of drug shortages on clinical trial enrollment.  Closer to home, the clinical trial I am running looking at Doxil and temsirolimus for sarcoma patients is on hold because Doxil is unavailable.  We haven't enrolled a new patient in months, and there is no end to the shortage in sight.

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The shortages are not limited to chemotherapy drugs (which, of course, is evidence that the problem is not due to the inability of oncologists to make a profit giving drugs to patients).  Drugs for ADHD, the components for iv nutrition, anesthetics, and many others are affected.  In fact, on Friday I was told our hospital has only a 5 day supply of Zofran, the mainstay anti-nausea drug used for patients receiving chemotherapy. 

I sure hope they get more.  I'm not looking forward to giving chemotherapy without it.


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Entering the Fray

The vast majority of biomedical research conducted in the United States is funded by taxpayers through grants distributed by the National Institutes of Health.  This includes investigator-initiated laboratory research (the work we do in our labs) as well as clinical trials, both large and small (NIH is a large supporter, for example, of the Children's Oncology Group).  In the not-too-distant past, the results of all of this research were published in scientific journals which were available to anyone who could gain entrance to a medical library.  With the rise of the internet, journals began publishing online, and charging a fee for viewing these articles on their websites.  Those of us who work at academic centers generally have free access to most (but not all) of these websites because our universities buy institutional subscriptions.  Others, including people who work at smaller centers and the general public, have less (or no) access to this work.

All of this changed in 2008, when the NIH instituted a Public Access Policy that stated, in brief, that results of research funded by the NIH had to be made freely available to the general public.  Along with NIH's Public Access Policy came the advent of the Public Library of Science, a non-profit organization co-founded by Michael Eisen, a professor at UC Berkley (and blogger), dedicated to open access to scientific research.  I have published in one of their journals, PLoS ONE.  I am a strong supporter of open access to the results of research, mine and everyone else's.

This concept of free access to taxpayer-funded research is under attack by a bill introduced into the House of Representatives last month, the Research Works Act.  In essence, this bill would forbid the NIH to require that its grantees provide copies of their papers to the National Library of Medicine for online, open access.  There are innumerable reasons to oppose this bill, and Dr. Eisen discussed them far more eloquently than I ever could in an Op-Ed piece published in the New York Times. 

If you agree that the results of research paid for by your tax dollars should be freely available, please contact your congressperson and express your opposition to the Research Works Act.  As the PLoS journals have demonstrated, high quality research can be published online and made freely available to all, and the research enterprise will flourish because of this, not suffer. 

"We need a better test"... or do we?

A study, published online January 6 in the Journal of the National Cancer Institute, claims to show that screening men 55 years old or older for prostate cancer does not significantly decrease mortality from the disease.

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This study made headlines, in large part because it  runs contrary to conventional wisdom -- that cancer screening tests, by detecting the disease at an early stage, save lives.  A number of things struck me about this study and the way it was reported.

This is one of several relatively recent studies that has called into question the premise behind cancer screening tests.  Two years ago, I had a post about a revision of the US Preventive Services Task Force's position on Pap smears and mammograms.  In that post, I talked more about how screening tests might be applied to particular patient populations.  But cervical cancer and breast cancer are very different from prostate cancer.  Women rarely die WITH breast cancer... they die OF breast cancer.  In contrast, many men die WITH prostate cancer, but not because they had prostate cancer.  This is a key difference, and strongly influences thoughts about screening tests.  KevinMD did a great job addressing this issue, highlighting the idea that screening tests are not without their costs.

This episode also demonstrates that it is important to read the whole article, not just the headline.  (Reading the original research is best, but only if you know how to interpret it appropriately).  The Washington Post's headline, for example, reads, "Routine prostate cancer testing does not save lives."  Only if you read deep into the article does it become clear that one group of men was screened by the study doctors with PSA blood tests and digital rectal exams, while the other group of men were cared for by their regular doctors.  Of course, the regular doctors were allowed to do PSA tests and digital rectal exams, too.  But those data were not recorded, making it challenging to know how different the screening of the two groups really was.  This is important, because the "screened" group had a higher rate of cancer than the "unscreened" group, but no difference in the rate of death from prostate cancer.



How can that be?

The answer may come from pediatric oncology.  Neuroblastoma, the most common solid tumor (other than brain cancer) in children, can be detected by a simple urine test.  Since neuroblastoma primarily strikes kids less than 3 years old, a population of children who see their pediatricians quite frequently, it seems sensible to do a urine screening test for neuroblastoma as part of routine well child care.  In fact, that was the routine in Japan for many years.  In the beginning of this century, though, two large studies showed that screening for neuroblastoma increased the rate of diagnosis, but did not change the death rate.  On the basis of those two studies, Japan no longer screens children for neuroblastoma.

How can a screening program increase detection but not decrease the death rate, especially if there are effective treatments available?

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In the case of neuroblastoma, we believe the answer lies in the biology of the tumor.  Some tumors are very aggressive, grow rapidly, and kill a high proportion of patients, while others are more slow growing and can be cured pretty easily, often with surgery alone.  If screening detects more of the low grade tumors, but the high grade tumors end up being detected because they cause symptoms, then screening programs won't change the rate of detection of the aggressive tumors... the ones that cause most of the deaths. 

If this same biological principle applies to prostate cancer, the findings of the screening trial make sense.  Which brings me to my last point:  at the end of the article in the Post, Dr. Jonathan W. Simons was quoted as saying, "We need a better test than PSA."  That may be true, but it needs to be better not because it can detect prostate cancer even earlier, but because it can detect aggressive prostate cancer earlier.  Screening for that may change death rates.  Maybe we don't need a "better" test... we need a different test.

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My name is FDA, and I approve of this message

As the new year begins and election season accelerates, we will be hearing phrases like that more and more.  In the context of a political commercial, it is often pretty clear what is being approved and the basis for the approval.

But what about new drugs?  How does the FDA decide whether or not to approve a new cancer drug, and what exactly is being approved?  In the era of targeted therapies, which are incredibly expensive to develop, and therefore incredibly expensive for patients and their insurance companies, these are crucial questions.

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I think the case of bevacizumab (Avastin) is a perfect example.  Avastin was the first of a new class of drugs that treats cancer not by directly killing tumor cells, but instead by attacking the blood vessels that feed a growing tumor, essentially attempting to starve the tumor of oxygen and nutrients.  Avastin was approved by the FDA for the treatment of renal cell carcinoma (kidney cancer) based on its ability to prolong the life of patients with this disease.   Avastin was given a provisional FDA approval to treat metastatic breast cancer, based on its ability to delay progression of the tumor.  It was big news last month, however, when further studies failed to show an improvement in "overall survival" (meaning how long the patient lives from the time she begins treatment) in women with metastatic breast cancer, and the FDA withdrew its approval.

Avastin is in the news again today.  In today's issue of the New England Journal of Medicine there are two reports (links here and here) showing that Avastin prolongs Progression-free Survival (PFS; the time from beginning treatment until the tumor gets worse) but not Overall Survival (OS) in women with newly diagnosed ovarian cancer.  Based on these results, Genentech, the manufacturer of Avastin, declared that they will not seek approval from the FDA to treat women with ovarian cancer using Avastin, because they know approval will not be granted without an effect on OS.

Overall survival, an extension of life expectancy, is clearly the ideal for a cancer drug.  I certainly treat all of my patients with drugs that I expect will allow them to live longer (hopefully to cure, but even in patients who are not likely to be cured, I would like them to live longer).  But is that the only goal of cancer treatment?  Perhaps there is a benefit to an increase in PFS.  If I told you that your child was going to die in 10 months no matter what I did, but that there is a treatment that will keep his tumor from growing for 7 of those months, and that during those 7 months he would develop no new tumor-related symptoms, would you want him treated with it?  Probably that would depend on the side effects the drug causes, right?  If the drug was very toxic, you might decide that treatment isn't worth it, but if all that happened to your child was high blood pressure that was easily controlled by medication, you might say yes.

The primary result the FDA wants to see before approving a new cancer drug is an improvement in OS.  Although FDA guidelines do allow for approval based on an improvement in PFS, the degree of improvement required for PFS-based approval is much more strict than what is required for OS-based approval.  I believe that there may be cases where even a modest change in PFS would be a more appropriate standard.  Demonstrating a change in OS requires large studies enrolling many patients.  For rare diseases, studies like this may not be feasible.  In that circumstance, FDA approval based on a change in OS may be an unattainable standard, and PFS may be a reasonable alternative.

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Some may ask whether lowering the standard will change the entire drug approval process, because PFS is an easier standard to reach.  Concerns could be raised that no pharmaceutical company will ever try to reach the OS standard (which is more expensive and more time-consuming) if PFS is sufficient to be granted FDA approval, and thus we will never know which, if any, drugs prolong patient survival. 

These are valid concerns, but I believe they can be addressed.  Perhaps a two-tiered approval process, with a lower tier for drugs that affect PFS and a higher tier for drugs that affect OS, with financial incentives for reaching the OS standard, would be a solution.  I'm sure there are others.  But the status quo gives the impression that if a drug doesn't change total survival time, it has no benefit.  And I'm quite sure that's not true.

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Why Study Rare Diseases?

The times they are a-changin’!  When I began my career as a scientist, NIH funded 25% of the applications they received.   That number is now down to less than 10%, and if there really are radical cuts in the discretionary federal budget, that number could fall even further.  Many of my colleagues (including myself) are concerned that this would lead to an emphasis on funding projects directly related to common problems (heart disease, breast cancer, emphysema) at the expense of less common diseases (like childhood cancer).

An article published on my birthday by Science:  Translational Medicine demonstrates the danger in cutting off funding for rare disorders.

In this study, Dr. Jaime Guevara-Aguirre and his colleagues published the results of their 22 year study of an isolated population of individuals living in a remote village in Ecuador.  The 99 subjects all have Growth Hormone Receptor Deficiency, or Laron Syndrome.  This is not a public health menace, even in Ecuador.  This article states that there are only 250 known people with Laron Syndrome worldwide.

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So why study such a rare disorder?  Well, interestingly, people with Laron Syndrome don’t get cancer (they also don’t get diabetes, but this is a blog about cancer, so we’ll focus on that).  This interesting observation raises a really obvious question:  Why not?

At first blush, there could be a very simplistic answer:  IGF-1 makes your body grow.  For you to grow from the size of an infant to the size of an adult, your cells have to divide many, many times.  Each time a cell divides, it risks developing a mutation, and the accumulation of mutations leads to cancer.  If you don’t grow any larger than a 7-year old, there are fewer cell divisions.  Fewer cell divisions means fewer mutations.

But if that were the answer, people with Laron Syndrome would have a lower than average rate of cancer.  That is not what was observed, however.  What was observed was an almost complete lack of cancer.  This must tell us something profound about how cancer develops.

It turns out that Growth Hormone Receptor Deficiency results in low circulating levels of insulin-like growth factor-1 (IGF-1; also called somatomedin C because it mediates the effects of growth hormone, or somatotrophin).  IGF-1 has been in the news a lot recently because its receptor appears to be important for the growth and survival of a wide variety of tumors, making it a darling of drug developers.   The fact that people with Laron Syndrome don’t get cancer suggests that IGF-1 signaling through its receptor probably plays a role in cancer development, not just the survival of cancer cells once the tumor develops.  More importantly, this must be a general property of cancers, because it’s not the case that people with Laron Syndrome are protected from just one or a few types of cancer.  They don’t develop cancer at all.

This sort of insight could never have come about from a focused study of a particular tumor type, nor could it have been derived from studying cells in a lab.  Only because someone was interested in the biology of a rare disorder was this discovery made.  I can only hope that the people in charge of the federal government’s medical research budget consider this when deciding how much research we can afford, and whether to focus on the common disorders, or whether we can let scientists study what is interesting… because we never know where the next important discovery will come from.

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What is Life?

Life is hard to define.  Perhaps former Supreme Court Justice Potter Stewart summed it up best (though he was referring to hard-core pornography, not living organisms) when he said, "I shall not today attempt further to define [it]... and perhaps I could never succeed in intelligibly doing so. But I know it when I see it."  

Erwin Schrodinger gave a series of lectures in 1943 that were published under the title "What is Life?" 

NASA has an Astrobiology group that is charged with searching for evidence that there is life on other planets.  Key to that mission is understanding what life is.  How else would they know what to look for?

Up until today, living organisms were thought to require four elements:  oxygen, carbon, hydrogen, nitrogen, sulfur, and phosphorus.  A paper published today by the NASA Astrobiology group has challenged that belief.  NASA scientists discovered a bacterium that can live without phosphorus, using arsenic instead.

The bacterium, designated GFAJ-1, can build the molecules of life, including DNA, proteins, and the energy molecule ATP, with either phosphorus or arsenic.  This is very handy, considering the organism was found in a lake with an extraordinarily high concentration of arsenic in its water.

Up until this discovery, life forms were the stuff of science fiction novels.  I've read novels about silicon-based life forms, based on the idea that silicon, being just below carbon on the periodic table, could take the place of carbon in the building blocks of life.  This is actually the basis for how GFAJ-1 uses arsenic.  Arsenic is just below phosphorus on the periodic table of the elements.  So the bacterium just substitutes arsenic for phosphorus.

This finding has important implications for the search for life away from earth.  Clearly phosphorus is not a requirement for life.  Perhaps neither is carbon.  Maybe not even oxygen is needed.  Life can take many forms, so finding it is going to require knowing it when we see it.

Question to ponder:  if ATP is the main energy molecule in a cell, and the P stands for phosphate, does GFAJ-1 have ATA instead?

Yoga – Not Just for Skinny, Pretty Women Anymore?

This post is dedicated to a close friend of mine, a budding scientist with an aversion to yoga.

The benefits of yoga for cancer patients were plastered throughout the popular press recently, in anticipation of a presentation by Dr. Karen Mustian from the University of Rochester Medical Center at this year’s meeting of the American Society for Clinical Oncology in Chicago. This study enrolled 410 cancer survivors (96% female, 75% had breast cancer) suffering from moderate or worse sleep disturbance. The participants were randomized to standard monitoring versus a 4 week yoga intervention. Participants in the yoga program had improvements in sleep quality, fatigue, and various measures of Quality of Life compared with the control arm (no intervention). The benefit was significant enough to be covered by mainstream media outlets like CNN as well as web-based media like Breastcancer.org. ASCO president Douglas Blayney, MD, stated that the results are “readily applicable” for a huge patient population.

But wait. As we scientists often ask, do the results support the conclusions?

I think the answer is a resounding “Maybe.”

There is mounting evidence that cancer survivors benefit from participating in yoga programs. Although this study is the largest thus far reported, it is certainly not the first to show a benefit to yoga. Back in 2003 a study presented at the ASCO meeting showed that participation in a yoga intervention improved the Quality of Life of women newly diagnosed with breast cancer.

But is it yoga, per se, that helps? So far none of the studies have compared participation in yoga with any other exercise program. This study, for example, published in 2001, demonstrated that a home-based walking exercise program improved fatigue and other Quality of Life measures in women being treated for breast cancer. The studies cited on this page of the American Cancer Society’s website demonstrate a benefit to using a treadmill or an outpatient wellness program involving aerobic exercise, strength training, flexibility and relaxation. So maybe it’s exercise in general, and not specifically yoga, that helps cancer survivors live better.

Are the results of the yoga study “readily applicable” to a huge patient population, as suggested by Dr. Blayney? Again, I think the answer is “Maybe.” It depends on how you define “a huge patient population.” Dr. Mustian’s study is certainly applicable to the very large number of women diagnosed with breast cancer every year, but her study involved essentially only women with breast cancer. Given the variety of ways various cancers are treated, it may be premature to conclude that because yoga helped these women, that it would make a difference for young adults being treated with intensive chemotherapy for leukemia.

So what can we conclude? I think it is safe to conclude that some degree of exercise is beneficial for cancer patients, probably regardless of where they are in the course of their therapy. But before we can state that yoga is the best form of exercise, the right study has to be performed: patients need to be randomized to various forms of exercise, and research participants need to include men as well. Perhaps for a relatively inflexible man like me, the frustration of not being able to do “downward dog” will make yoga a poor choice, while the feeling of accomplishment associated with being able to last 5 more minutes on the treadmill will make that form of exercise a much better choice. Only a well-designed experiment can tell us for sure.

 
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Genomic Medicine – The Hope and the Hype

Ten years ago this month, President Clinton, along with Drs. Craig Venter and Francis Collins, announced the completion of the Human Genome Project – the complete DNA sequence of the human genome. As is typical of such announcements, there was much pomp and circumstance, as the President declared it a “day for the ages.”

Why the excitement? It was fully expected by participants in the struggle to sequence our genome that achieving this goal would rapidly lead to a new understanding of the genetics of common disease, and would yield new genomic treatments that would revolutionize the practice of medicine. In fact, Dr. Collins predicted that the genetic diagnosis of disease would be accomplished within 10 years, and treatments would begin to appear 5 years later.

This, sadly, has not happened.

So does that mean the Human Genome Project was a bust? Hardly. While medicine has not been revolutionized, basic biology has been. The complete sequence of the human genome has shed tremendous new light on a variety of ways that genes are regulated, especially by RNA, which would never have been understood without sequence information.

So why has the sequence of the human genome not revolutionized medicine? As discussed in an article from The New York Times, there are several reasons. One reason cited by The Times is that many of the sequence variations associated with common diseases are not found within genes. This raises the possibility that these sequence variations are a statistical fluke, not really associated with the disease at all… or by anything other than chance. More disconcerting, if your goal is to develop a new treatment, is that common diseases may be caused by a large number of very rare sequence variations, so that individuals with a particular disease may have very little in common with each other, and nothing amenable to a drug.

Is this result entirely a surprise? To any serious student of human genetics, the answer has to be, “Not really.”

The First Genetic Disease

After reading any article in the popular press about genomic medicine, one would get the impression that the genetics of human disease is a new field, and that before the human genome was sequenced, there was nothing known about how gene mutations cause disease. This, however, is not true. In a paper published in Science in 1949, Linus Pauling and his colleagues demonstrated that sickle cell anemia is caused by a mutant form of hemoglobin, the protein that carries oxygen in red blood cells. In 1956, Vernon Ingram and his colleagues proved that this mutation was at the 6th amino acid of the protein. This change was soon shown to be the result of a single DNA base pair change.

For more than 50 years now, physicians and scientists have understood Sickle Cell Disease in molecular detail. Nevertheless, we are still unable to explain how this molecular defect causes any of the symptoms of the disease, and we are unable to do anything about it. To this day, despite how long we have understood the molecular biology of the disease, treatment remains supportive (meaning prophylactic antibiotics, pain medicine, and transfusions) or aimed at changing the way the hemoglobin genes are controlled (using a medicine called hydroxyurea). There is no treatment available that is directly related to the genetic cause of the disease, the mutation at amino acid 6.

I think this should be a warning to those who think that the path from the molecular understanding of a disease to a treatment will be straightforward. The era of genomic medicine may be upon us, but it is probably going to be a very slow change, not an overnight revolution.

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More What You'd Call "Guidelines" than Actual Rules

Of course, Captain Barbossa was referring to The Pirate Code, but he could just as easily have been referring to documents released last month by the US Preventive Services Task Force or the American Congress of Obstetricians and Gynecologists (ACOG).

In an unanticipated coincidence, these two groups, operating independently, reached similar conclusions about commonly utilized screening tests: mammograms and Pap smears. Both groups reviewed the data and concluded that routine use of these screening tests, as currently recommended, may not be warranted.

Much newsprint has been expended since then discussing the political implications of these new recommendations. As this is not a political blog, I will leave that discussion to others.

What I want to talk about is how guidelines (should) influence patient care.


I think a lot of the worry surrounding these guidelines stems from concerns that they will be interpreted by those who pay the bills in our system (meaning the Federal Government, through Medicare reimbursement regulations, and the private insurance industry) as “Actual Rules” rather than “Guidelines,” meaning that if you get a mammogram or a Pap smear but don’t meet the “Guidelines” your service won’t be covered. In the current environment, this may be true, but it shouldn’t be.

The key to my argument is the highlighted words above: “routine use” and “as currently recommended.”

The key to understanding why both groups reviewed the published data and reached similar conclusions is an understanding of the nature of screening tests as well as a bit on biostatistics. My work colleagues who read this will laugh at the idea that I am trying to teach anyone statistics, but that’s what I’m going to do.

To start, the accuracy and usefulness of any medical test can be described by the terms “sensitivity” and “specificity.” Sensitivity refers to how likely the test is to be positive if the condition is present. So a sensitive test will pick up every case. Specificity is the mirror image – if the test is positive, how likely is it that the condition is present. Screening tests are designed to be very sensitive, even if they are not very specific – that way, no cases are missed (very sensitive), but sometimes the test is positive even if the patient does not have the disease (not very specific).

The other statistical consideration is the concept of positive- and negative-predictive value. This means, how likely is a positive test to mean the disease is there, or how likely is a negative test to mean the disease is absent? Two concepts factor into the positive- and negative-predictive values of a test: the sensitivity and specificity AND how common the condition is in the population being tested.

These considerations underlie the new recommendations. Mammograms save lives. No one disputes that. Early detection of breast cancer saves lives. No one disputes that. But mammograms are not very specific, and the positive-predictive value of a positive mammogram is MUCH more if the woman is at risk of developing breast cancer than if the woman is at relatively low risk. Since a woman with a strong family history of breast or ovarian cancer is at higher risk of developing breast cancer in her 40’s than a woman with no such history. Thus, the positive-predictive value of a mammogram in a 40 year old woman is higher if the woman is at higher risk. This is why the Task Force no longer recommended ROUTINE mammograms for women under 50.


This is where the practice of medicine comes in. As the doctor treating a 40 year old woman, it is important to remember that a mammogram will be valuable if the woman is at risk, but far less valuable if the woman is NOT at high risk. So blindly refusing to order a mammogram simply because the patient is 40 makes no sense (and an insurance company refusing to pay for it based solely on age makes equally little sense). A 40 year old woman whose mother had breast cancer should have a mammogram and it should be covered. A 40 year old woman with no relatives who have ever had cancer may not need a mammogram. Determining whether a screening test is needed is a decision for the doctor and the patient to make together.

This isn’t rationing care, this is good medicine.


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Is the Medical Community Complicit?

A Smarter War on Cancer

The headline in the Washington Post caught my eye: “Fighting a smarter war on cancer,” [sorry, you must register to read the article] an opinion piece by Dr. John Marshall, a faculty member at the Lombardi Cancer Center in Georgetown. It is about the intersection between health care reform and cancer care - it seemed like just the thing to read while drinking my morning coffee. But halfway through the article I found myself feeling marginalized, and that got me thinking. Although Dr. Marshall makes some good points, I think he missed a golden opportunity to propose changes that could make a real difference in our lifetimes.


How did Dr. Marshall make me feel marginalized? He wrote the following about chemotherapy:

“The most common approach to treatment involves exposing large populations of patients to highly toxic poisons in the hopes that the treatment will kill the cancer cells and not the patient. This strategy has succeeded with several types of less-common cancers, curing some patients with leukemia, lymphoma, testicular cancer and most childhood cancers [emphasis is mine]. But it has not worked for more common forms of the disease, including breast, prostate, lung, colon, pancreas, stomach and ovarian cancers. These cancers represent an enormous public health problem, consuming the majority of our cancer-specific health-care costs and research dollars.”

I realize that childhood cancer is rare, and that to make an impact on the total health care system in our country will require real progress against such public health menaces as breast and lung cancer. However, I believe that rather than brushing aside the approach that transformed childhood cancer from a death sentence to a treatable disease, the medical oncology world needs to embrace it.

Most oncologists know this, but in a single generation, collaborative clinical research in pediatric oncology, exemplified now by the Children’s Oncology Group, has revolutionized the way childhood cancer is treated in this country. Once uniformly fatal, there are now some types of childhood cancer that are cured 95% of the time. This transformation did not come about by chance. It came about because of a culture change that is now a huge gulf between pediatric oncology and medical oncology: the role of the clinical trial.

Dr. Marshall hints at this in his article: “In cancer medicine, fewer than 5 percent of all patients in the United States enter clinical trials. That means more than 95 percent are treated with the ‘standard of care’ -- a legal term denoting a minimum level of care for an ill or injured person.” In contrast, being entered on a clinical trial IS the standard of care in pediatric oncology. Partly this is born out of necessity – childhood cancer is rare enough that unless nearly every child with cancer is treated on a trial, not enough patients can be studied to yield reliable results, making progress impossible.

The cultural difference in the view of clinical trials between medical and pediatric oncology is readily apparent in my every day practice, particularly when I have to approach an insurance company about enrolling a patient of mine on a trial. In the “adult” world, a clinical trial is something offered when there is nothing “standard” to offer, just as Dr. Marshall implies. What this means is that insurance companies often feel justified in denying coverage for trials, since these are “experimental therapies” and “not standard.” In the “pediatric” world, everyone goes on a clinical trial. Coverage is routine, because the trial IS the standard.

Dr. Marshall makes an excellent point about where the future of cancer therapy lies. He believes, as do I, that the future is in “personalized medicine,” meaning treatments that are individualized for each patient, based on the molecular and cellular composition of their individual cancer. Unfortunately, therein lies the problem. In the world of “personalized medicine,” there will be no standard. What works for Patient A will not necessarily help Patient B. Destruction of the concept of “standard of care” in oncology will make coverage decisions by insurance companies far more complex. This will need to be accounted for as we move towards a reformed health insurance system.

More importantly, demonstrating the value of “personalized medicine” will require more clinical trials. Only by enrolling patients in such trials, painstakingly dissecting the molecular changes in each patient’s tumor, and carefully proving that tailoring therapy based on these changes dramatically improves outcomes can real progress be made. Because these molecular changes will, by definition, vary widely from patient to patient, treating only 5% of adults with cancer on clinical trials will never get us to where we need to be. The medical oncology world needs to learn from the successes of pediatric oncology. Being treated on a clinical trial needs to be the standard, not something that is reserved for use when “standard of care” fails.

Instead of marginalizing pediatric oncology, hold our system up as the model. Only then will real progress be made in the war on cancer.

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Is the Medical Community Complicit?

When Bad Things Happen to Famous People

In a press release issued earlier this week, former NBA star and actor Kareem Abdul-Jabbar announced that he has been diagnosed with leukemia. Specifically, he has chronic myeloid leukemia (CML). Abdul-Jabbar went on to say that his disease can be managed by taking daily oral medication and he expects to live a long healthy life.

With leukemia? How is that possible?

Abdul-Jabbar has benefited from one of the first and most exciting applications of the translational research I have blogged about in the past.

Before 2000, CML was treated with a combination of a chemotherapy drug called cytarabine and another drug called alpha-interferon. Patients treated with this combination usually responded well, but none were cured. The only curative treatment was a bone marrow transplant, and in adults, bone marrow transplantation carries a significant risk of death.

So how will Kareem Abdul-Jabbar lead a long healthy life by just taking a daily oral medication?

The answer lies in the molecular biology of CML. It shows how basic research, undertaken for no reason other than to understand the biology of cancer, can lead to unexpected therapeutic breakthroughs. Such research can transform a disease like CML from one that kills without a bone marrow transplant into one that is managed just like high blood pressure.

Here’s how it happened:

Working in Chicago in the 1970’s, Janet Rowley discovered that the “Philadelphia Chromosome,” an abnormal chromosome seen only in the leukemia cells of patients with CML, is actually composed of pieces of two different chromosomes. Her idea, that so-called chromosome translocations could result in the creation of new genes that can cause disease, was heretical at the time, but is now a part of the standard dogma of oncology. She was rewarded with a Lasker Award (often called the “American Nobel”) in 1998.

Subsequent research demonstrated that the Philadelphia Chromosome instructs the leukemia cells to make a new enzyme (called a tyrosine kinase) that causes the leukemia.

Researchers led by Brian Druker eventually developed a drug that blocks the activity of the tyrosine kinase that results from the Philadelphia chromosome. This drug, called imatinib (the trade name is Gleevec), is a pill that, taken daily, kills CML leukemia cells. This work was also rewarded with a Lasker Award in 2009.

The net result of the work of Dr. Janet Rowley, Dr. Brian Druker, and a host of others is that CML has been transformed from a disease curable only by bone marrow transplantation, into a disease that can be managed as a chronic condition, by taking pills every day. An incredible change over a short period of time!

This is the model of basic and translational research those of us in the field emulate, and the prime example of targeted therapy for cancer.

Work that started out as very basic science, motivated only by a desire to understand biology, has led to a transformative new medicine, and now Kareem Abdul-Jabbar (and many people far less famous than him) should be able to lead a healthy, active life taking daily oral medication, despite having leukemia.

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When Translational Research Really Translates

As Breast Cancer Awareness Month Draws to a Close

As breast cancer awareness month draws to a close, I wanted to highlight a few breast cancer posts from other medical bloggers:

Suture For a Living asks: "Is Breast Cancer Over-Diagnosed?"

Bayblab writes about research on a diabetes medication killing breast cancer stem cells.

Science Update Blog discusses claims that we are "Two years from breast cancer cure".

Highlight Health's Allison Bland says "The Review is in: Lifestyle Changes Prevent Breast Cancer
and Healthcare Hacks discuss the benefits of weightlifting in breast cancer survivors.

If you've found any interesting breast cancer blogs or posts, link to them in the comments!

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Therapeutic Cloning Takes A Big Step Forward

Leber’s Hereditary Optic Neuropathy
Leigh Syndrome
Myoneurogenic Gastrointestinal Encephalopathy

What do these disorders have in common? They are all mitochondrial diseases.



What is a mitochondrial disease? Mitochondria are the parts of a cell that are responsible for generating energy. Mitochondria contain DNA, just like the nucleus does. Mutations in mitochondrial DNA can cause them not to function correctly, and some of these mutations cause the diseases listed above (and others).

When a baby is conceived, we think of the baby’s DNA as coming half from the mother and half from the father. That is true for the DNA in the nucleus, but not true for mitochondrial DNA. All mitochondrial DNA is inherited from your mother.

As a side note, the fact that all mitochondrial DNA is inherited from the mother is the basis for anthropological studies that allow scientists to trace the origins of humanity back to “Mitochondrial Eve” in Africa.


Since all mitochondrial DNA is inherited from the mother, replacing mitochondrial DNA that carries a disease-causing mutation with mitochondrial DNA from another source would prevent a woman from passing on such a disease to her children.

That is the basis for the work by Shoukhrat Mitalipov’s group at the Oregon Health and Science University published online in Nature on August 26. This group took an egg from a female monkey and removed the nucleus, replacing it with the nucleus from a different female. This hybrid egg, with nuclear DNA from one female and mitochondrial DNA from another female, was fertilized, and the resulting embryo was allowed to develop. Not every embryo developed normally, but some developed into seemingly normal monkeys like the ones shown above.

This approach would allow a couple with a family history of mitochondrial disease on the mother’s side to have children with mitochondria donated by an unrelated woman, and they could have children with no risk of developing the disease.

The monkeys described in the paper have genetic contributions from 3 adults. Does that mean there are three parents? I guess that depends on how you define “parent.” If you are a parent simply by virtue of having contributed DNA to a child, then yes, these monkeys have 3 parents. Of course, if a parent is defined as the adults who raise you, then a child conceived in this way would have 2 parents. The ones who raise the child.

Experiments like these raise huge ethical issues. Therapeutic cloning like this introduces changes directly into the germline (the DNA that is passed from parent to offspring), something that has long been taboo in the mainstream scientific community. It also raises interesting custody issues (does the donor of the mitochondrial DNA have any parental rights?). I’d be interested to hear what people think about this.

Like it or not, we are on the verge of a new era of genetic medicine. Some aspects of genetic medicine will not be controversial (tailoring medical treatments based on the presence of specific mutations), but other aspects are sure to raise questions (like the experiments described in this paper). It is critical that we begin to have serious, society-wide discussions about these issues, before it is too late and the discussions become arguments.

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Vitamin D in the Spotlight -- Again

Last year, I blogged about vitamin D as an agent to prevent breast cancer. My interest in vitamin D began when I found an ad promoting the health benefits of tanning salons because the exposure to ultraviolet light increases production of vitamin D, something most adults get too little of. Mostly, vitamin D is thought of as important for bone strength, and as something helpful in preventing osteoporosis.

Research presented at the 2008 meeting of the American Society of Clinical Oncology demonstrating that vitamin D may play a role in preventing breast cancer caused a huge sensation. There is also evidence that vitamin D may prevent colon cancer. Of course, everything about nutrition is complicated, including vitamin D needs – too much vitamin D can be a bad thing. Proper balance is everything. Moderation in all things.

As complicated as understanding the role of a vitamin in the health of an adult can be, it is even harder in children, who are growing and therefore can have changing needs. An important study investigating the prevalence of vitamin D deficiency in children and the implications for heart disease was just published in the journal Pediatrics, the official journal of the American Academy of Pediatrics.

A team led by Michal Melamed, from Albert Einstein College of Medicine in New York, surveyed the vitamin D levels of over 6,000 children registered in the National Health and Nutrition Examination Survey and correlated these levels with various cardiovascular risk factors. Their surprising results? Almost 10% of children in the US are vitamin D deficient, and fully 61% were vitamin D insufficient (meaning their levels were too low, but not low enough to be called deficient).

Why is this a problem? Low vitamin D levels were correlated with higher blood pressures and lower levels of high-density lipoprotein (HDL, or “good” cholesterol). Both of these are significant risk factors for heart disease in adults. This finding provides a key link between childhood nutrition and the development of heart disease in adulthood.



This is potentially a very important study. The question of why some adults develop heart disease while others do not is a complicated one, and many of us have long believed that adult disorders can have their roots in childhood. This study supports that belief, and also strongly supports the idea that intervention in the health of a child can have profound implications throughout her life.

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When Translational Research Really Translates

All of us who work in a lab and see patients say the same thing: “I do this because I hope one day to be able to discover something in the lab that will really help patients.” This is the essence of what is called “Translational Research.”

Our laboratory studies cancer stem cells. I have blogged about these cells before. Cancer stem cells are thought to be a small population of cells within a tumor that are resistant to chemotherapy and are capable of regenerating a new tumor. Thus, these cells are thought to be responsible for local relapses and for metastatic disease. Because they are resistant to chemotherapy, our usual treatments don’t get rid of them, so finding ways to kill these cells is critical to the further advancement of cancer treatment.

There are many theories to explain the resistance of cancer stem cells to chemotherapy. One of these is that there are important metabolic differences between cancer stem cells and most other cancer cells. One such difference might involve a signaling pathway called mTOR. mTOR stands for “mammalian target of rapamycin.” Rapamycin is a drug that is used primarily to prevent the rejection of transplanted organs. It turns out that rapamycin works by interfering with the function of a specific enzyme that was given the name mTOR.

For a variety of reasons, inhibiting mTOR activity has been predicted to make cells more sensitive to chemotherapy. In collaboration with another researcher at Johns Hopkins, Jonathan Powell, our laboratory has done some experiments that seem to show that inhibiting mTOR increases the sensitivity of cancer stem cells to chemotherapy.

Last winter, we responded to a call from the National Comprehensive Cancer Network for research proposals utilizing an mTOR inhibitor for the treatment of cancer. Based on our laboratory data, we proposed a clinical trial that would treat patients with a combination of a chemotherapy drug (liposomal doxorubicin, or Doxil) and an mTOR inhibitor (in this case temsirolimus, or Torisel).

In March we learned that our proposal would be funded.

On Monday, I signed the contract that will allow our clinical trial, now approved by the Institutional Review Board, the Food and Drug Administration, and the Johns Hopkins Clinical Research Committee, to begin to enroll patients. We hope to treat our first patients in late August.

I can’t wait to see whether we are able to help the patients willing to enroll in this trial! How gratifying it would be to know that work in our lab led to a new way to treat cancer patients. That, after all, is why we do this.

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