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The future of cancer therapy?

I was contemplating writing a post along the same lines as Harriet’s post about evolutionary medicine last week, but then on Sunday morning I saw an article that piqued my interest. Sorry, Harriet, my response, if I get to it, might have to wait until next week, although we could always discuss the usefulness (versus the lack thereof) of evolutionary medicine over a beer or two at The Amazing Meeting in a few days. In the meantime, this week’s topic will revisit a topic near and dear to my heart, a topic that I tend to view (sort of) in a similar way as Harriet views evolutionary medicine, namely personalized medicine or the “individualization” of treatments. It’s a topic I’ve written about at least twice before and that Brennen McKenzie wrote about just last week. In essence, we both pointed out that when it comes to “complementary and alternative medicine” (CAM) or “integrative medicine” treatments for various conditions and diseases, what CAM practitioners claim to be able to do with respect to “individualized care” is nonsense based on fantasy. Science-based medicine already provides individualized care, but it’s individualized care based on science and clinical trials, not tooth fairy science.

Serendipitously, this point was driven home over the weekend in an article by Gina Kolata in the New York Times entitled In Treatment for Leukemia, Glimpses of the Future. While the story is basically one long anecdote that shows what can be done when new genomic technologies are applied to cancer, it also shows why we are a very long way from the true “individualization” of cancer care. It also turns out that I’ve discussed the same basic story before, but here I’ll try to discuss it in a bit more detail.

As hard as it is to believe, it’s been nine months since Steve Jobs succumbed to a metastatic neuroendocrine cancer of the pancreas. Last November, the authorized biography of Steve Jobs, written by Walter Isaacson, revealed that after his cancer recurred for the second (and final) time Jobs became one of the first twenty people in the world to have all the genes of his cancer and his normal tissues sequenced, which was done by a collaboration of research teams at Stanford, Johns Hopkins, and the Broad Institute. At the time (2010-2011), it cost $100,000 to do. Scientists and oncologists looked at this information and used it to choose various targeted therapies for Jobs throughout the remainder of his life, and Jobs met with all his doctors and researchers from the three institutions working on the DNA from his cancer at the Four Seasons Hotel in Palo Alto to discuss the genetic signatures found in Jobs’ cancer and how best to target them. Jobs’ case, as we now know, was, alas, a failure. However much Jobs’ team tried to stay one step ahead of his cancer, the cancer caught up and passed whatever they could do.

Kolata’s story, in contrast, appears to be that of a success. It is the story of Dr. Lukas Wartman, a recent graduate of the Washington University hematology-oncology fellowship who is now an Instructor in the Division of Oncology:

Genetics researchers at Washington University, one of the world’s leading centers for work on the human genome, were devastated. Dr. Lukas Wartman, a young, talented and beloved colleague, had the very cancer he had devoted his career to studying. He was deteriorating fast. No known treatment could save him. And no one, to their knowledge, had ever investigated the complete genetic makeup of a cancer like his.

So one day last July, Dr. Timothy Ley, associate director of the university’s genome institute, summoned his team. Why not throw everything we have at seeing if we can find a rogue gene spurring Dr. Wartman’s cancer, adult acute lymphoblastic leukemia, he asked? “It’s now or never,” he recalled telling them. “We will only get one shot.”

We learn later in the article that Dr. Wartman had first been diagnosed with acute lymphoblastic leukemia in 2002, when he was a fourth year medical student ready to finish up and move on to residency. During trip out to California for a job interview, he began to experience overwhelming fatigue. Upon his return, he found he couldn’t run anymore and started having night sweats. At first he thought it was mono, but then he started having bone pain. He finally went to an urgent care center, where at first it was thought that he might be suffering from depression, but it was also noticed that he had a low white blood cell count.

The rest of his story can be summarized in a manner that is still too common among leukemia patients. He underwent nine months of intensive chemotherapy, which was followed by 15 months of maintenance chemotherapy. Five years later, his leukemia recurred, and he underwent a bone marrow transplantation, which is the usual treatment for recurrent ALL. Thus far, he had beaten the odds, having not realized how bad they are for recurrent ALL:

Seven months after the transplant, feeling much stronger, he went to a major cancer meeting and sat in on a session on his type of leukemia. The speaker, a renowned researcher, reported that only 4 or 5 percent of those who relapsed survived.

“My stomach turned,” Dr. Wartman said. “I will never forget the shock of hearing that number.”

In the vast majority of cases, a patient like Dr. Wartman would be dead. As is pointed out in Kolata’s article, we are not even sure of the expected survival rate of someone who has relapsed twice with ALL, other than that the odds are clearly very, very low. However, Dr. Wartman was very fortunate to have friends who had access to technologies to which few have access. Because he is a researcher at the Washington University and knew Dr. Timothy Ley, a world-renowned leukemia researcher and Associate Director for Cancer Genomics for the The Genome Institute at Washington University and because he was apparently well-liked there, Dr. Ley offered to do what was described in the introduction of Kolata’s article. It was a massive undertaking, as well:

Dr. Ley’s team tried a type of analysis that they had never done before. They fully sequenced the genes of both his cancer cells and healthy cells for comparison, and at the same time analyzed his RNA, a close chemical cousin to DNA, for clues to what his genes were doing.

The researchers on the project put other work aside for weeks, running one of the university’s 26 sequencing machines and supercomputer around the clock. And they found a culprit — a normal gene that was in overdrive, churning out huge amounts of a protein that appeared to be spurring the cancer’s growth.

Even better, there was a promising new drug that might shut down the malfunctioning gene — a drug that had been tested and approved only for advanced kidney cancer. Dr. Wartman became the first person ever to take it for leukemia.

And now, against all odds, his cancer is in remission and has been since last fall.

As is often the case when I’m reading an article in the lay press, I sometimes have to read a bit between the lines and make an educated guess as to what exactly it was that Dr. Ley’s team did. The first analysis appears to be a next generation sequencing (NGS) analysis of both the leukemic cells and normal cells. NGS techniques allow the sequencing of complete genomes in a matter of weeks. In “old-fashioned” automated sequencing using Sanger techniques, the rate-limiting step in the sequencing process was the need to separate reaction products on a polyacrylamide gel in order for the sequence to be read. Next generation sequencing (NGS) techniques overcome this limitation by arraying DNA molecules on solid surfaces by anchoring and copying single DNA molecules on glass slides or or array of beads. Going into the details of these new sequencing techniques is beyond the scope of this particular post (maybe some day), but for interested readers who know a bit about sequencing and PCR, there is a decent general description here. The long and the short of it is that NGS techniques allow the massively parallel sequencing of a genome such that 30 gigabases of DNA sequence, which is the equivalent of approximately 10 haploid human genomes, can be obtained in a week at a cost of approximately $15,000. By way of comparison, the draft human genome reference that was reported in 2001 to six-fold redundancy took five years of sequencing by several laboratories and cost billions of dollars. That is how much technology has advanced in a single decade. It’s truly astonishing.

The second analysis that was performed is almost certainly another NGS techique known as RNAseq, which is the common name for whole genome shotgun sequencing (WTSS). Again, the details of the technique are beyond the scope of this post. However, RNAseq overcomes the major limitation of cDNA microarrays, which is that it is only possible to measure the mRNAs whose sequences are known and therefore have been placed on the gene chip. Consequently, cDNA microarrays can’t discover previously unknown transcript and in general do not cover noncoding RNAs, such as microRNAs and long noncoding RNAs (lncRNAs). RNAseq does. As a result, using RNAseq it is possible to identify every sequence of every mRNA transcript, coding and noncoding, being made by the cell and how much. Of course, cDNA microarray techniques are by no means dead yet, the primary reason being that RNAseq is a lot more expensive than cDNA microarray techniques, at least ten-fold more, and cDNA microarray experiments can be completed a lot faster.

Taking the results of the sequencing of the entire genome and RNAseq data and analyzing them allows scientists to probe the genome and transcriptome of cancers in a way that was never before possible. It produces an enormous amount of data, too, terabytes from a single experiment. At cancer meetings I’ve been to, investigators frequently refer to a “firehose” of data, petabytes in magnitude. Indeed, the sheer quantity of data from these experiments challenges the bandwidth of universities doing them, and, in fact, it’s not at all uncommon for the preferred means of sending experimental data to be to load up a hard drive with the data and send it by the quaint but effective method of overnight mail to other investigators because it’s faster and more reliable that way. Not surprisingly, serious computing power and major advancements in computer algorithms have been necessary to develop the methods of analyzing data from these experiments.

What I’m trying to convey is that what WUSTL did for Dr. Wartman was not a little deal. It was a big deal that took a lot of resources and effort and likely cost well over $100,000. Apparently it was paid for through research grants, and Dr. Ley claims that no patients were neglected while all that sequencing and computing firepower were transferred to sequencing Dr. Wartman’s cancer genome and transcriptome, having done the same thing for a previous patient. That might well be true, but does anyone believe that Dr. Wartman would have had access to so much genomics goodness if he hadn’t been a researcher at The Genome Institute? Be that as it may, Dr. Wartman’s luck didn’t end at having friends willing to go to such great lengths for him. Here’s what happened when all that sequencing was done and analyzed:

The cancer’s DNA had, as expected, many mutations, but there was nothing to be done about them. There were no drugs to attack them.

But the other analysis, of the cancer’s RNA, was different. There was something there, something unexpected.

The RNA sequencing showed that a normal gene, FLT3, was wildly active in the leukemia cells. Its normal role is to make cells grow and proliferate. An overactive FLT3 gene might be making Dr. Wartman’s cancer cells multiply so quickly.

Even better, there was a drug, sunitinib or Sutent, approved for treating advanced kidney cancer, that inhibits FLT3.

In brief, for whatever reason, Dr. Wartman’s leukemia cells appeared not to have any mutations in the FLT3 gene, which would have been found in the DNA sequencing, but for some reason (probably a mutation in a regulatory region) was making lots and lots of the kinase coded for by FLT3. FLT3 has also been implicated as a molecular target in acute myeloid leukemia (AML). Indeed, this is the very reason why sequencing the genome and transcriptome both are frequently needed to understand what is driving the cancer. Of course, as I’ve discussed before, the genome of your typical cancer cell is so messed up that it’s impossible to identify a single gene that is primarily responsible for the cancer, but in this case Dr. Wartman was again incredibly lucky. His recurrent ALL was being driven primarily by FLT3, a single gene, and there exists a good drug to target that oncogene. Even better, as predicted by the biology, treating Dr. Wartman with sunitinib worked! His blood cell counts started to normalize within days, and he rapidly went into remission.

There was a hitch, however. Sunitinib is very, expensive ($330 per day), and Dr. Wartman’s insurance company wouldn’t pay for it, given that it was being used off-label. Basically, Dr. Wartman scraped together enough money to buy a week’s worth of the drug, and that’s what demonstrated such remarkable effects. Later, the doctors in his division pitched in to buy him more drug. After a few weeks, Dr. Wartman was in complete remission. Fantastic news, but it presented a dilemma: Should Dr. Wartman keep taking the drug, or should he undergo another bone marrow transplant? Ultimately, the decision was made to do another bone marrow transplant because of fear that the leukemia would soon evolve resistance. When evolution meets modern medicine, evolution nearly always wins. In another stroke of luck, Pfizer decided to supply Dr. Wartman with the drug free of charge until he underwent a bone marrow transplant. As of the running of the story, Dr. Wartman remains, as far as the best tools of modern medicine can tell, free of cancer, although he is suffering from graft versus host disease due to his transplant.

There’s no doubt that “individualized” medicine will become increasingly a part of modern medical care, with the individualization based on sequencing the genomes and transcriptomes of patients. In just a few years, the price of a complete genome sequence has fallen from hundreds of thousands of dollars to around $15,000. True, that doesn’t count all the analysis and that’s $15,000 per genome, which means at least $30,000 to sequence a normal and cancerous genome. There are, however, lots of things we do in medicine that cost $15,000. The price doesn’t have to come down much more before whole genome sequencing starts to look doable for individual patients. After all, gene tests like the OncoType DX cost on the order of $3,000 to $4,000, and we now order this test fairly routinely for patients with estrogen receptor-positive, node-negative breast cancer because in the end it saves a lot of patients from unnecessary chemotherapy.

The problem with the individualization of care based on genomics are well-illustrated in this article, which, let’s not forget, is nothing more than anecdote. The question of its generalizability remains to be determined. Using genomics to individualize treatment worked in Dr. Wartman’s case. What his odds of long-term survival are now, no one really knows, but we do know this much. There’s little doubt that, without the discovery that sunitinib would be an appropriate drug to treat his cancer, he would almost certainly be dead by now. Unfortunately, his example can be countered with that of Steve Jobs, whom sequencing his tumor ultimately didn’t help, and Christopher Hitchens, who according to this article also had his cancer sequenced.

How many will have results like Dr. Wartman’s and how many will have results like those of Steve Jobs or Christopher Hitchens? Most cancers are not driven by just one gene that can be targeted, nor are most other diseases and conditions that we might wish to use genome and transcriptome sequencing as a guide to therapy. We’re drowning in genomic data right now, and we just don’t know how to use it yet. Nor will we know until a lot more research is done. The problem is that, with a relatively few exceptions like the case of Dr. Wartman, we don’t know enough yet to translate genome and transcriptome sequences into therapies. We also don’t have drugs for anywhere near all the potential molecular targets that can be identified this way, and the targeted drugs that we do have tend to be enormously expensive. For all the promise it shows and for the now occasional success story like that of Dr. Wartman, the genomics revolution will, like most revolutions, be messy.

Posted in: Cancer, Clinical Trials, Medical Ethics

Leave a Comment (18) ↓

18 thoughts on “The future of cancer therapy?

  1. Janet Camp says:

    An interesting opening to my road trip. While my portable WiFi is working here in my little trailer, I couldn’t bring up the NYTimes article so I came here instead and probably saved myself some data. Fascinating stuff Dr. Gorski and I could almost follow the technical explanations. I find that in casual conversations, most people don’t even know that cancer is many diseases, let alone how difficult and complex the treatments are and how much more so they will become. The Times article seems to miss this and instead builds up the idea that this story will soon be the norm.

    I’m on my way to Portland (OR), so if I pick up a nasty enough bug, perhaps I’ll get to meet Dr. Crislip!

  2. rork says:

    So they could have just done a cheaper, ordinary array to measure mRNAs to find increased FLT3.
    Note to nerds: They might have done exon-capture rather than whole-genome for the DNA-seq part. But I haven’t looked into it. Also, I’m not used to doing mRNA and stuff without poly-A as part of the same assay, so that’s not really an advantage of using sequencing.

    As with the previous McKenzie SBM post, I don’t like this fuzzy use of individualized. And I think Gorski feels like I do. Has it become shorthand jargon, merely meaning we used some data, or more data than we did 20 years ago?
    Varmus has asked that it stop too. If I measure tumor ERBB2 protein expression and decide to give you herceptin based on that, is it individualized? If not, change the name of the gene and the drug and try again. Maybe it means the doctor sees one patient at a time.

  3. Patrick says:

    Well, Dr. Gorski, I really hope that you dig into the topic of evolutionary medicine and respond to the claims Dr. Hall presented. I am a staunch Darwinist and have always touted the efficiency of Darwinian medicine. I have always agreed with Dan Dennett’s contention that Darwinism is a universal acid that erodes traditional concepts; it has already altered the face of genetics, biochemistry, and even psychology—now it appears that it has altered the face of medicine quite a bit.

    However, despite the contention by evolutionary biologists—professor Dawkins, Dr. Nesse, Dr. Shubin, etc.—that medical science should be rearranged and placed under a Darwinian umbrella, it appears that Dr. Hall has provided a strong case to the contrary. Her criticism is actually refreshing and unbiased and breaks away from the “poisoning the well” tactics that creationists doctors use to criticize Darwinian medicine.

    I just want as much information as possible. I am still a student working on my BS in Biology, so it is really hard to set down my homework and study patters to investigate all of the claims, so it really helps seeing condensed arguments at sciencebasedmedicine.org.

    Finally, you are a physician with an incredible command of evolutionary theory, a decided advantage all by itself because I do not know to many people who can comprehend the fact that all organisms on planet earth—from bacteria, bats, and baboons—share common ancestry.

  4. Patrick says:

    And I just read this entire post about Dr. Wartman’s cancer that he battled throughout his medical career. This was a very emotional read for me and I am happy to see a happy ending, but I nobody knows what the future holds. But is this really not a fantastic read about how scientific energy, harnessed by humanity, kicked mother nature’s ass in this case (metaphorically speaking). The CAM clowns should be ashamed of themselves; what the hell have they done over the years to help anybody of this nature? Imagine Dr. Wartman prognosis under the command of CAM. This single blog entry demonstrates just how enormously complex cancer is; if we listen to the crank CAM crowd, grandma could cure even the most complex diseases with a blow of soup!

  5. Patrick says:

    Pardon me, but I meant to type “bowl of soup.”.

  6. cervantes says:

    All this, of course, raises the $64,000 question that Americans seem unwilling to confront. At the heart of the problem is the so-called Rule of Rescue. We have an individual before us, who is in dire straits. We feel compelled to do all we can to save him. How can you put a price on a young man’s life?

    But we forget that there are millions of people who have no health insurance at all, and that even if we do achieve universal coverage, continuing increases in the cost of medical care will eventually make it impossible to sustain. We need to ask whether the best use of resources is to develop more and more extremely expensive treatments that ultimately, it will be impossible to offer to everybody; or to do a better job of inclusion, prevention and maintenance of good health.

    Devoting more research dollars to figure out how to do more for the same amount of money, or less money, rather than figuring out how to spend more and more money for marginal gain, might make sense.

  7. cervantes says:

    And one more thing – it’s impossible to actually save anybody’s life. We are all mortal. We seem unwilling to confront the most basic fact of human existence.

  8. mousethatroared says:

    Janet Camp “I’m on my way to Portland (OR), so if I pick up a nasty enough bug, perhaps I’ll get to meet Dr. Crislip!”

    HaH! I thought it was hard to get tickets to see Stephen Colbert, to see Mark Crislip you need to have a dreadful infection.

    If that’s the case I’m hoping to never meet David Gorski, (no offense intended DG) unless I recognize him at a local coffee house or restaurant, which is unlikely, since I have familiar face syndrome.

  9. Janet Camp says:

    @mousethatroared

    I met Dr. Gorski and it only cost me a tank of gas to Chicago–not his office, happily! :-)

    I just did the “black” tank dump, so maybe I’ll catch something from that. It’s impossible to simply ask Crislip if you can buy him a beer when you’re in town because he never answers email. I’ll just have to get on that tram thing up the hill to the hospital and wander around–or maybe I can get him paged!

  10. Janet,

    Go to his hospital and start yelling that you have multiple drug resistant tuberculosis. That should get his attention!

  11. Very well written article, even in most details of genetics and molecular biology in general. I can tell that because I am biomedical research that already worked both with genetics and biotechnology. Every new tech comes with the emotion and promise to resolve our modern humans problems. And that moment is that we need most to apply Skepticism and critical thinking

    The most important part of the article is when it’s says that the abnormality was found in the RNA production. That is much more common than a mutation in a DNA ny itself. The reason is that natural selection found ways to buffer the effects of minor mutations, such as signals that point a wrong decoded RNA or DNA. The protein Chaperone can fix protein even when DNA and RNA aren’t correct. There is a huge number of mechanism, you can easly find many on the book “Molecular Biology of The Cell (new edition) ”

    The more molecular biology and genetics get complex, the more medical student need to understand the basic of DNA/RNA/Protein regulation. Most of professionals don’t have this knowledge due the rapid increase of medical complexity. In my opinion the application of knowledge in molecular biology to clinical care is far way from reality, even in developed countries.

    Thanks for the post !

  12. I forget to ask my question about the cancer of FLT3 (CD) . It wouldn’t be easier to start by the analyses of the cells by flow cytometry instead of spending time and money on genetics ? This method is already common on diagnostic of “blood diseases”. Genetics and RNAtics” arent accurate to show the phenotype as flow cytometry…

  13. rork says:

    Rafael: You can screen for common events (like Her2/neu overexpression in breast) by staining. Don’t even need flow. You could do an ELISA instead, but you don’t get to see localization that way. If you are trying to screen for hundreds of things though, doing it in parallel helps. You don’t want to stain for every protein separately when you aren’t sure what you are looking for. Massive proteomics attacks are possible, but are currently still messy. Some proteins are at high concentrations, others low. This makes it harder. Finding novel point mutations by massive proteomics is hard too.
    Today it was an overexpressed transcript, but for other patients the DNA might tell you what you wanted to know. Mutant APC1 or BRCA1 for example. There’d be a telling change in some downstream proteins there, it’s true, and we could detect it that way. But like I say, that’s still pretty hard. Maybe in our future though.

  14. agitato says:

    @cervantes

    “We need to ask whether the best use of resources is to develop more and more extremely expensive treatments that ultimately, it will be impossible to offer to everybody; or to do a better job of inclusion, prevention and maintenance of good health.”

    Well-stated. I have just returned from a lengthy road trip throughout the the US. I was overwhelmed by the number of people I saw who appeared to be in poor health from preventable causes. After what I’ve just observed, massively more resources need to be directed toward inclusion, prevention and maintenance of good health. In fact at various times, I was convinced that ALL resources for the foreseeable future should be directed this way. The US has become a nation of lumbering behemoths many of whom still smoke! But in a profit-driven approach to health care, how do you make prevention of disease appealing to shareholders? This debate has no easy answer but it’s definitely worth having…repeatedly.

  15. RE: YES: The future of cancer therapy is The individualized therapy — just as One that has been executed strategically and preemptively in the Wartman case, as reported in the biomedical literature and public media above!?

    Preamble: First do no harm; and let me elaborate the individualized cancer therapy (ICT) by itemizing, italicizing, and commenting on the several (7) critical queries, that have had been raised and concluded in David Gorski’s interesting article above, specifically pertaining to the last 2 paragraphs of his conclusion above, as follows:

    1] The problem with the individualization of care based on genomics are well-illustrated in this article, which, let’s not forget, is nothing more than anecdote.

    No, on the contrary, the individualization of care and treatment of cancers — for each case — has not been fully elaborated in the above article, at all; and genomics — or the genomic technology (GT) — is only an integral part of the materials and methods, that are being applied, and used, in a systemic series of steps in an ICT strategy, process, evaluation, progress, prognostication, outcome, etc, of the respective patient and disease in treatment!?

    2] The question of its generalizability remains to be determined. Using genomics to individualize treatment worked in Dr. Wartman’s case. What his odds of long-term survival are now, no one really knows, but we do know this much. There’s little doubt that, without the discovery that sunitinib would be an appropriate drug to treat his cancer, he would almost certainly be dead by now.

    Yes, the ongoing Wartman case represents a classic test-case history of a comprehensive and systemic practice with an accurate attention being paid on the ICT concepts, strategies, and progresses since the 1980s: at a time — decades before the GT era — when the ICT concepts, principles, and disciplines, were first introduced to the general public by offering the individual cancer patients, with a series of steps of ongoing, best-effort, intensive, clinical and scientific research and development (R&D) and treatment protocols, and services, that had emerged during and at the revolutionary times of the increasingly-progressive, biotechnological and genetic engineering (BGE) methodologies since the 1980s, worldwide!

    These pre-GT commercialized BGE labor-intensive services — from bedside to bench-top, and vice versa — had included a full series of cancer patient care and treatment protocols, steps, and measures, which typically and systemically would begin with 1) the disease diagnosis and prognosis (ie, at the bedside); 2) the tumor acquisition and processing (on the bench-top); 3) the creation of specific monoclonal antibodies (mAbs) and/or modified antibody-drug conjugates (mADCs) against the individualized cancer-types and specificities, as processed and identified in the labs (or in today’s GT labs); and 4) the monitoring of the subsequent or ultimate ICT with clinically-prescreened mAbs and/or mADCs in patients! — All these BGE services were offered at a cost of $35,000 per patient in the 1980s!

    I have since 1990s retired from the laborious and rigorous or time-compressed and labor-intensive ICT industry; and as far as I could review: The appropriate drug, sunitinib or brand name Sutent (of Pfizer) used in the Wartman case, was in fact one of the 1990s-2000s (or second to third wave) generation of BGE-based biotherapeutics, that has had been derived and/or modified from the initial ICT concepts and/or the specific anti-cancer mAbs and mADCs engineering and creating methodologies, since the pre-GT 1980s — and — luckily Wartman has had been saved by this specific anti-FLT3/leukemia/kidney cancer drug or Sutent, as indicated by his subsequently more elaborated ICT strategy with a full series of exceptional genomic and proteomic screenings that were executed at The Genome Institute at Washington University; or the GT-based ICT protocols and practice that are now available to Wartman since 2007; especially at a critical time when his leukemia case had had relapsed, despite the fact that he had had been successfully treated with a bone marrow transplantation; and been chronically maintained by a traditional chemotherapeutic control of leukemia remission, since 2002, when Wartman was first diagnosed with ALL!?

    3] Unfortunately, his example can be countered with that of Steve Jobs, whom sequencing his tumor ultimately didn’t help, and Christopher Hitchens, who according to this article also had his cancer sequenced.

    I thought that is a very gross generalization of the ICT characterization and specification criteria, and comparison: whether of GT-based, or of classic mAbs-based, clinical characterization and comparison pronouncements; or of the scientific R&D protocols and practice, as well as the ICT principles and concepts identification and specification measures, etc since the BGE 1980s (see Comment 2 above)!? With regard to the more complex cases, as related to both Jobs and Hitchens, I shall address them appropriately as I continue to comment on more of Gorski’s queries below.

    4] How many will have results like Dr. Wartman’s and how many will have results like those of Steve Jobs or Christopher Hitchens?

    None, as No cases of the elaborated ICT strategy and practice will mirror the same results or outcomes as those that have had been reported in the case of Wartman, or of Jobs, or of Hitchens, at all! This is Why a series of steps of any elaborated ICT characterization, specification, and individualization strategies, processes, treatments, and protocols must First be fully in preparation and attention and put in place — especially early on — in Each case! And, not all elaborated ICT cases will react or respond the same ways as those in any other ICT cases! Thus, the future of cancer therapy is the elaborated ICT strategy and practice that shall be widely and increasingly researched, specialized, trained, experienced, and applied in our Modern Oncology and Healthcare services and practices of the 21st or the GT century* to come!?

    [*These ICT conceptual and practical analyses and predictions are primarily based on the fact that It took over a century (since 1860s) for the Mendelian genetics -- [and not the neo-Darwinist geneticism or the reductionist sophist “evolutionary rhetoric” that has had been derived from the formulaic mathematics of “evolutionary theory of population geneticism” since 1930s] — to test, develop, advance, and establish to be the foundational scientific discipline of our modern or developmental cell biology and diseases, including tumor biology or oncology; It may take another century (if not decades since 1980s) for the BGE and GT-based ICT concepts and practices to assimilate, test, refine, advance, strategize, and establish to be the generally-accepted or prescribed or subscribed strategy for, and in, any cases of the specifically-targeted, screened, and elaborated ICT practice in our Modern Oncology — but Not — in the neo-Darwinist “Evolutionary Medicine” or the neo-Darwinist, reductionist, sophist pseudoscience dogma or “evolutionary biomedical rhetoric” that Harriet Hal and other SBM readers or critics have had just begun to seriously query and refute here: “Do We Need “Evolutionary Medicine”? — RE: Science-based Medicine vs Evolutionary (neo-Darwinist) Medicine!?” (SciencebasedMedicineUSA; August 4, 2012).]

    Specifically, in Each elaborated ICT case, the oncological and clinical expertise; efficiency; diagnosis; prognosis; treatment; pre-therapeutic intervention (eg, tumor surgery, local irradiation, etc); post-biopsy anticipation of metastases, etc; and patient cooperation and level of education and motivation — [as one that could lead to meaningful ICT evaluations and experiences] — are all but a systemic series of very important, ongoing, patient-clinician interactive dynamics; dynamics that could hopefully culminate in and/or arrive at the best outcomes of a targeted and elaborated ICT possible: As one that any fully-strategized ICT practice would have had expected to achieve, in full accordance with the best of our biomedical knowledge and R&D efforts to date — as those that have had been experienced in and from the BGE and R&D strategy and practice since 1980s — whether in the high academia or in the biopharmaceutical industry today and beyond!?

    The Wartman case has exemplified all of the above criteria — conventional as well as GT-based — especially in and with the biomedical and oncological knowledge and R&D practices of an ICT strategy, that has had been preemptively pursued, identified, and tested in Wartman — himself — as one of the oncology-savvy and cooperative patient attitude and cancer researcher experience and expertise, since the relapse of his leukemia case in 2007!?

    Whereas without accessing to their actual biomedical records: reportedly, both Jobs and Hitchens were 2 among the few exceptional intellectuals in the US, who were rather quite uneducated, nor motivated, and extremely ignorant of the immediate and subsequent conditions and expectations of the cancers that they were Each had had been diagnosed with. Thus, in Both cases, None of an elaborated ICT strategy had had been initiated nor applied early on, in Either case, at all — until it was too late!?

    Furthermore, to be fair to All cases mentioned and discussed herein: Unlike the leukemia case (that of Wartman or the white blood cell cancer), Both the neuroendocrine cancer of the pancreas (that of Jobs) and the esophageal cancer (that of Hitchens) have had not been in any lists of the actively or widely or systemically researched, targeted, and/or tested diseases (or cancers of the soft tissues) at all; nor such similar organ-site tumor cases been commonly reported or communicated in the US biomedical literature (since the 1980s ICT concepts and practice) whether in the BGE and R&D biotherapeutic industry or in the high academia, at all!?

    As far as I could follow and recall from the public media: “Hunters of Myths: Why Our Brains Love Origins — RE: Mythbusting Journalism 101 — First do no harm: Never attempt to insinuate more Myths (or frivolous Memes) in the 21st-century Biology and/or Psychology literature!?” (ScientificAmericanUSA; April 16, 2012) — and my brief but focus biomedical review of the Walter Isaacson’s scanty and scattered accounts of the Jobs case in his recent book “Steve Jobs” (2011): I could conclude that it was the sad Jobs electronic-gadgets entrepreneurial genius and his super-egotism complex: including his innate fear, denial, and ignorance of his initial (2004) diagnosed tumor biology; and of its acute and critical prognostications, without following-up with any post-biopsy preemptive anti-metastatic measures; and his subsequent refusal of an immediate tumor surgery thereof and cancer therapy thereafter, that might have had sealed his own fate!? — As it was his initial refusal of the instant tumor removal and therapy, that might have had opened up a “vital physiological window of opportunities” which had had thereof and thereafter enabled Jobs initially-diagnosed tumor cell-type, and its malignant aggressiveness, to be continuously and safely “incubated, harbored, and spread subsequently and systematically” in his vital abdominal cavity; or, in effects, Jobs body had had soon thereafter become a vital physiological “incubator and harbor” for his aggressive tumor to grow and spread in the following weeks, if not months, to come, as approximately chronicled** below!?

    [**In all seriousness and with all due respect, this critical analysis-in-retrospect has been based on the scientific fact that In animal models, the artificially-seeded tumor metastases can be established and evaluated in a matter of Several weeks (not months) after tumor cell implantation; In the Jobs case, the potential and tendency for tumor metastases and spread, would have had been No exception, especially at a time, immediately, after its initial "invasive" endoscopic biopsy (or tumor perturbation, that is) while without following-up with any tumor removal measures, nor therapy thereof nor thereafter the primary tumor surgery, at all!? Instead, Jobs had had decided to take an unconventional “cancer treatment” course -- an untimely nor clinically tested Naturopathy -- until it was too late (or proven to be inefficacious during the next 9 months)! As such, even the best ICT strategy (be it GT-based or otherwise) -- or as one that Jobs had had only decided to assemble at his late and advanced stages of tumor progression and metastases (2010-2011) -- would not have had been able to reverse the course that he had had set himself up (as a physiological incubator and harbor) immediately after his initial tumor biopsy and diagnosis in 2004!]

    Specifically, in mid 2004 Jobs was diagnosed with a neuroendocrine tumor of the pancreas via an “invasively-extracted” endoscopic biopsy; in lieu of a conventional procedure that Jobs had had feared and avoided: the exploratory laparotomy, a procedure that could have had provided a better overview and a fuller assessment of the pancreatic tumor conditions in situ, including the tumor vascularization and its potential for metastases, etc!? Nonetheless, the endoscopic biopsy prognosis was fair; and it had indicated an immediate tumor surgery and therapy. Whereas because of his personal philosophy, beliefs, and control (of his own body, mind, spirit, diet, etc), Jobs had resisted the standard treatments of the pancreatic tumor surgery and therapy; but insisted on an “alternative treatment of naturopathy” in and for the next critical 9 months — or over 35 weeks — after his initial tumor biopsy and diagnosis — and — during which time (2005) it became clear that his ongoing physical conditions, pains, and appetite, had had not improved, at all; totally going against to what he might have had expected of his misconstrued “anti-cancer” naturopathy!?

    Also — being one of the uneducated and/or ignorant of the progressive biomedical oncological processes, or the cancer cell biology, development, spread, etc — Jobs might have had never expected this: From the perspective of a metastatic tumor cell dynamics and with the benefit of hindsight, the Jobs interim naturopathy-detour and the preciously-wasted time (9 months); or the critical time (over 35 weeks) that had had elapsed since the initial endoscopic biopsy-diagnosis of his cancer-type — to — the eventual primary tumor removal in and from his pancreas, might have had provided an “amble time and physiological opportunities” for the Jobs case to have had turned out — to — what it actually had become, in the next few years to come (2005-2011): with a series of severe, unexpected, inoperable, tumor spread and metastatic consequences; all had arisen within his vital abdominal incubator and physiological harbor, that he might have had unknowingly, unfortunately, untimely, and unexpectedly set himself up to be, especially during the first critical time period (2004-2005) immediately after his pancreatic tumor diagnosis (see the doubly-asterisked [**] footnote above)!?

    Although in early 2005 not only had he decided to undergo the 2004 advised tumor surgery of his pancreas, Jobs had also intended to follow up with the standard, conventional, cancer care and treatment regimens, as well. Unfortunately, in 2008, the Jobs cancer-related physical symptoms had returned; and in 2009, he successfully received a liver transplant and his health soon began to recover. Sadly, at this time, it was soon confirmed that his pancreatic cancer had had already spread multiply, regionally, and especially, to his liver and the peritoneum — and — that’s why he needed an impromptu liver transplantation in the first place in 2009, as observed above!?

    In 2010-2011, the Jobs physical symptoms again reappeared and began to deteriorate quite rapidly; as it was soon found out that his pancreatic tumor had already, and systemically, metastasized to the bones — as well as to other parts of his body-incubator — although Isaacson has had not fully recounted, nor disclosed, in his 2011 book at all!? Meanwhile, it was at this time, just a few months before his death, that Jobs had had decided to have his entire genome (of his cancerous and normal tissues) sequenced by the GT; just as duly observed by Gorski above! — I shall conclude the Jobs case shortly below.

    Speculations abound: In the Hitchens case, not much biomedical details were reported on his initial diagnosis of his esophageal tumor (July 2010); as this cancer incidence rate — though rising and killing about 15,000 Americans a year — has had been quite a rare occurrence in the West. Hitchens might have had received a conventional care and treatment regimen: one which normally may be indicative of an immediate tumor surgery, and follow ups with chemo and/or irradiation therapy thereafter — then again — he might have had received only chemo, without surgery; as he soon died in December 2011 — only 17 months after his initial tumor diagnosis!? Because of the complexity in Each cancer-type, idiosyncratic-malignancy, metastatic-potential and tendency, tissue-type, and organ-site variations and involvements, etc — even today — there has had been No universal or standard ICT regimen developed as yet, for All tumor-types possible — except leukemia — be it GT-based ICT or otherwise since the 1990s (see Comment 2 above and more below).

    In conclusion, Both cases of Jobs and Hitchens might have had followed, received, and followed-up with their Each respective, standard, conventional, cancer care and treatment regimens and biomedical advices. Particularly, the Jobs naturopathy detour aside: Had had Jobs been an oncology-savvy and cancer care cooperative patient — or Had had he Not opted for an alternative naturopathy detour during the first critical 9 months of his tumor treatment (2004-2005) — or Had had an “elaborated” ICT strategy been available or applied early on (2004) in the Jobs pancreatic cancer case — his “unexpected”, inoperable, successive, tumor metastases Could have had been systematically screened, detected, prevented, arrested, and/or treated accordingly — in and with the best ICT efforts, of course — during the interim of 7 years, before he eventually but “untimely” succumbed to his “unexpected”, systematic, metastatic (not recurrent) cancer of the pancreas in October 2011!?

    Unfortunately, and more educated speculations abound: With Jobs deep pocket, he Could have had been able to assemble the world’s best biomedical team of the time (2004), only if he Had had been an educated, motivated, anti-cancer entrepreneur-genius — and — he Could have had immediately ordered an “elaborated” ICT strategy (for himself, of course, in lieu of Naturopathy in 2004) to be specifically screened, tested, tailored, and preemptively applied to his Very complex (but rare) case of a neuroendocrine cancer of the pancreas!? — RIP Steve Jobs (1955-2011) and Christopher Hitchens (1949-2011) RIP!

    5] Most cancers are not driven by just one gene that can be targeted, nor are most other diseases and conditions that we might wish to use genome and transcriptome sequencing as a guide to therapy. We’re drowning in genomic data right now, and we just don’t know how to use it yet. Nor will we know until a lot more research is done.

    That is true: However, unlike the diagnosis and treatment of cancers at the cellular level, the GT has indeed deepened, broadened, and advanced our diagnostic tools and skills to, and at, the specific molecular or genetic level! This GT will only help accelerate the diagnosis and treatment of cancer protocols in and for any well-equipped and elaborated ICT strategy and practice, as one that has been systemically, strategically, and preemptively achieved in the Wartman relapse case above (since 2007; see Comment 4 above). In the clinical practice of an elaborated ICT strategy, the trained and prepared clinicians shall not sweat on the pre-clinically-tested details — or sweat on the proven results in the labs or the biopharmas or the regulatory FDA, etc — but shall duly focus on the ongoing outcomes of the patient and disease conditions under therapy!?

    Lest the bedside clinicians are also the bench-top scientists, researchers, themselves, like the Wartman case; in which he has indeed been thrust upon a series of urgent, biomedical and pertinent Oncology training process — in the many a functionalist, specialist, experimentalist, case-analyst, and survivalist roles, in the cancer battlefield, so to speak — in himself (since 2002): First as an educated and motivated biomedical student; then as a cancer patient-survivor; and currently, as an Oncology Instructor and a GT-based leukemia ICT researcher, scientist, patient, and survivor — all specialized roles or ICT steps of the specific screening and testing of an elaborated ICT concept and practice, are being thrust, encapsulated, entrusted, experienced, treasured, and treated in 1 single but precious individual — himself, that is, with lots of GT-based Oncology expertise, coordination, and collaboration, etc — at The Genome Institute at Washington University!?

    As such, under a persistent self-discipline of multidisciplinary education, motivation, and aspiration in our Modern Oncology and Healthcare practice today (especially since 1980s), I won’t be surprised, If someday Wartman should turn out to be an all-rounded, empathetic, well-trained, competent, knowledgeable ICT bedside as well as bench-top researcher and practitioner in himself, so that his specifically-experienced and elaborated anti-ALL case could thus exemplify and serve as a standard ICT concept and practice for other potential cases to emulate, strategize, or model on: all elaborated steps are to be modified in full accordance with their each respective cases, and conditions, of course (see also Comments 2-4 above)!?

    6] The problem is that, with a relatively few exceptions like the case of Dr. Wartman, we don’t know enough yet to translate genome and transcriptome sequences into therapies. We also don’t have drugs for anywhere near all the potential molecular targets that can be identified this way, and the targeted drugs that we do have tend to be enormously expensive.

    That is all true: Although the ICT concepts have been around since the 1980s, the GT (including transcriptome, proteome, etc) will only refine and accelerate the application of any elaborated ICT strategy and protocols on a case by case basis, as exemplified in Comments 1-5 above.

    7] For all the promise it shows and for the now occasional success story like that of Dr. Wartman, the genomics revolution will, like most revolutions, be messy.

    That is not entirely true: On the contrary, with the concurrent advents in the computer-electronics, digital informatics, and nanotechnology R&D academic-industrial complex arena worldwide, the 21st-century GT is the natural, progressive, outcome of the BGE and R&D pursuits and practices since the 1980s: at a time when the BGE revolution and methodology had also given rise to the concurrent stem cell, cloning, and tissue engineering technologies at the end of the 20th century!

    Furthermore, the BGE cum GT revolution has also helped clarify, expand, extend, and delineate the Mendelian “organic developmental genetics” (since 1860s) from the neo-Darwinist “evolutionary geneticism rhetoric” including its concomitant pseudoscientific rhetoric “biologism” or the reductionist “evolutionary biology” dogma or “evolutionism” culminated in the 1970s pop-science literature (also since 1860s; at which time, even to Charles Darwin’s chagrin, Evolutionism was feverishly championed by the first-ever neo-Darwinist Thomas Huxley, so as to rail against the Victorian-era religious Creationism)!

    Whereas more critically and scientifically, the GT revolution and methodology will further, elaborately and consistently, establish our Modern or Molecular Genetics (including epigenetics, microbiomes, etc) as the Foundational Discipline of our Modern or Developmental Biology and Medicine in years, if not decades, to come: including specifically the GT-based translational biomedicine — but not the elusive or alternative, metaphor-laden or rhetoric-driven, explanatory evolutionism of “evolutionary medicine” (since 1990s) — in our Modern Oncology and Healthcare services and practice, or in the specifically elaborated ICT strategy and practice, that is, once and for all, in the 21st century and beyond (see Comment 4 above, especially the asterisked [*] footnote above)!?

    Nonetheless: How well or How cost-effective Will the GT refine, develop, expedite, and consolidate the elaborated ICT strategy and treatment for any other diseases, so as to be able to offer on a low-cost basis and best-effort service to patients — and — that is the concurrent, burning, “socioeconomic, politico-analytical, and academic-industrial-regulatory healthcare complex” Question, in mine, as well as in other SBM readers, practitioners, or critics Mind!?

    Best wishes, Mong 9/1/12usct2:32p; practical science-philosophy critic; author “Decoding Scientism” and “Consciousness & the Subconscious” (works in progress since July 2007), Gods, Genes, Conscience (iUniverse; 2006) and Gods, Genes, Conscience: Global Dialogues Now (blogging avidly since 2006).

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