Prostate cancer advances – The Oscars are in…

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I have been attending the ASCO led GU oncology symposium for the last 48 hours. As usual, it is somewhat of a “firehose to take a drink” scenario with great presentations, more posters than you can possibly absorb, and lots of progress on many fronts. I remember when there were only about 50 “GU oncologists” 30 years ago, and about 300 attended this meeting when it first started. The attendance is 2900 from around the world. As one of my patients likes to put on his blog, “help is on the way”, which is really encouraging. There is more to report than I can possibly do in a blog, so I will just poach from existing internet info and highlight some of the existing posts.

Chemotherapy for newly diagnosed patients with many metastases is now the “standard of care” following the CHAARTED trial that I previously discussed. The French completed a smaller study that did NOT show an advantage for using docetaxel “up front”. There are a number of possible explanations that you can read about here. Not mentioned in that discussion is a moderately complex explanation that came up in the discussion period after the presentation. It turns out that ADT leads to changes in the way docetaxel is metabolized. Thus, the approval of the use of docetaxel in the setting of castrate resistant pca (which has been the usual situation) is different from using docetaxel when a patient hasn’t been on ADT for very long. The French study had more toxicity, and potentially more delays in treatment but the relationship of when the ADT started may have been different from the CHAARTED trial and could explain differences. Nevertheless, CHAARTED was larger and I think the trial still sets a new standard.

The optimal duration of ADT when given to enhance radiation was covered extensively by Anthony D’amico. The details are pretty complex, and if you want to wade into these weeds, you can start with his JCO article. Basically, the issue is this: ADT helps radiation therapy be more effective. But it is clearly “toxic” in terms of quality of life, and possibly increases cardiac events in men with a history of heart disease. Both of these factors make it questionable to use at all in men with “low intermediate risk” disease, and we would certainly like to use for as little time as necessary to get the benefit so that quality of life is preserved. In the higher risk patients there is no doubt that it should be used, but the duration is still up for discussion, with the existing “definitive” study showing 36 months is better than 6 months. Generally in such patients, I go over this, and then say, “let’s see how well you tolerate ADT before we reach any final decision on how long to continue”. Certainly a minimum of 4 months is required, and possibly the longer the better, but I suspect 36 months is too long. And really no one has taken into account the factor that a single 3 month leuprolide injection can result in quite variable overall duration of testosterone suppression with older men generally not recovering as quickly as the younger guys.

On the vaccine front, data were presented on Prostvac in combination with the immune checkpoint inhibitor, ipilumimab. The exciting findings in using checkpoint inhibitors (including the PD1 and PDL1 drugs in other diseases has lagged somewhat in prostate cancer because it isn’t clear that the ongoing immune response is very good. (For example ipi alone in prostate cancer didn’t work) However, given the promising data on using Prostvac in the phase II trials, the phase III trial has now accrued all of its patients and we await the result. Meanwhile, investigators have begun to look at whether adding a checkpoint inhibitor to a vaccine can make further headway. An abstract presented at the meeting reported on the early results of this approach. Dr. Singh from the NCI GU oncology team stated “In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months.” This certainly means that if the Phase III trial of Prostvac leads to approval by the FDA, there will quickly be more studies of how to make this vaccine even more effective.

Many of us have been talking at this meeting and other recent meetings about a “kitchen sink” approach combining all of the newer drugs to get a biochemical complete response in metastatic patients and then using a vaccine to “clean up” the microscopic disease that is clearly left behind. I’m looking forward to these trials which are probably a year or two away, but optimism abounds. Example: A new man with metastatic disease who had prostate radiation or surgery 5 years ago is found because of a rising PSA. We do fancy scans with C-11 acetate or choline, radiate the known disease, treat with second generation ADT plus docetaxel x 6, then use the vaccine with a checkpoint inhibitor. (read that link by the way – terrific) Given that prostate cancer is generally a “slow cancer”, there are many men alive today with lurking metastases that will only become apparent 5 or 10 years from now. These guys will almost certainly be able to take advantage of such an approach – never fast enough, but never more promising prospects, either.


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Predicting a cancer’s behavior – the cloudy crystal ball.

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In the past decade, a number of labs and companies have developed techniques to further define how a patient with prostate cancer, or suspected cancer is likely to do. There are at least a dozen tests that are in various stages of commercialization and it would be difficult to do justice to all of them here. However, I will at least describe the general approach and the potential utility and hazards of some of them.

First the mechanics: If you take a needle biopsy or a prostate that has been removed, you can microdissect the cancer out of the paraffin and extract RNA from the specimen. If you quantitate the amount of RNA for each gene you can get some idea of whether certain genes are being over-expressed or under-expressed in that specimen. Now let’s suppose you do that for 500 patients who have Gleason 7 cancer, a PSA between 3 and 10, and no lymph node involvement, negative margins, no extracapsular extension, etc. (We already have some idea of how this patient with intermediate risk will do using nomograms such as the CAPRA-S score (there is an app for this calculator) or Dr. Kattan’s at MSKI). If we look at all 500 patients who have a similar prognosis based on the nomograms, we can then ask whether a gene expression profile could further separate patient with similar a priori risk into “high intermediate” or “low intermediate” risk. (The same could be done for patients with low or high risk based on nomogram prediction of course). Now let us look at 50 patients who do much worse than expected and another 50 that do much better than expected. In these two groups, among the 30,000 genes tested suppose there are 500 that are overexpressed by 3-fold and another 500 that are underexpressed by 3-fold in the “bad outcome” group and similar findings for the “good outcome” group. Many of the genes will be telling us the same thing – for example that a certain characteristic like “rapid proliferation” is associated with a bad outcome and overexpression of those genes predicts a bad outcome. But, you don’t need all of the genes in that characteristic to tell you that. So you ask the computer to recalculate a prediction by leaving one of the genes out. If it makes no difference, then the remaining genes stay in until you reach a smaller subset of genes that are either over or under-expressed but suffice to make the prediction. You put those genes (from the “learning set”) on a chip that can quantitate expression and find another 500 patients from a different institution to see if the chip can accurately predict what happens to those 500 patients (the “validation set”) for whom you don’t know the outcome. If the chip performs well, you have a new test that could be a valuable clinical tool.

Examples of this sort of work that are now commercially available include the Prolaris™ and Decipher™ tests. As you might expect, the time/effort that has gone into making these tests has been considerable, and they are not inexpensive. Another such test, ConfirmMdx, evaluates gene hypermethylation (a way that genes are turned off) in prostate biopsy specimens and can help predict whether there was cancer NEAR a negative biopsy (a false negative biopsy result). Because the test might help avoid repeat biopsies, this is an example of the complexity in assessing cost. Saving cost/risk of further biopsies, if validated prospectively, could show that the test saves money. Similarly, using these kinds of tests to avoid overtreating a patient with “intermediate risk” who might actually have low risk based on a molecular analysis could save costs and morbidity.

What a purist would want to know is whether making a recommendation to an individual patient based on the outcome of one of these tests has been validated. In other words, how often when I tell a patient he has nothing to worry about in spite of having a Gleason 7 cancer on a biopsy, am I correct? Clearly no test is perfect, and patients themselves may differ in their risk tolerance. One patient who has a favorable genetic profile (say a test that says only 7% risk of metastases at 5 years) might be inclined to simply watch and do nothing more, while another would find that risk intolerable and opt for further treatment. Further, few doctors or patients are using the FREE analysis of overall health risk called the Charlson tool to put such risk into context (we wonder why not – no marketing is likely one answer). In this wonderful world of blogs and mobile devices, I am hoping someone will create an app for that! Meanwhile, the molecular testing of prostate cancer is a step forward, and hopefully how to use it will become clearer over time. We will, however, always have the challenge of heterogeneity and plasticity of the prostate genome to deal with. Such is the legacy of our good friend, Darwin.

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Sniffing out PCa – from dogs to the eNose

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It is always humbling to see how much you can miss in trying to keep up with medicine’s developments, even in an incredibly narrow area like prostate cancer. Fortunately, there are many crutches like Medscape that offer help (along with targeted ads of course). Reading through their recent post on the top stories in medicine in 2014, I was chagrined to learn that Medscape readers listed the eNose for detecting prostate cancer as the 3rd most innovative advance in 2014. Really?? I hadn’t heard a single presentation or comment on this at any of the cancer meetings I faithfully attend to keep up. Well, time to write a brief post, even if all of you didn’t bring this to my attention either!

The article in question appeared in July in the Journal of Urology. Researchers in Finland (my “second country”, having spent a delightful year on sabbatical there in the 1980’s – and no, I don’t speak the language…) utilized the “ChemPro® 100-eNose” to sniff the air over urine samples from men with BPH vs prostate cancer, and then determine whether the chemicals in that air could discriminate between the benign vs malignant condition. Although the study was very small, (50 prostate cancer patients compared to 15 BPH patients), “the eNose reached a sensitivity of 78%, a specificity of 67% and AUC 0.77″ according to the abstract.

There is a substantial literature on the ability of trained dogs to detect cancer in humans by sniffing either their exhaled breath or urine. In one review, reported sensitivity and specificity can be close to 100% for lung cancer. However, as with any system that relies on an animal focusing on a difficult task, there seems to be a wide range of issues regarding reproducibility. A good example of how this research goes is an attempt to detect bladder cancer by training dogs to sniff the urine of patients vs controls. Accuracy was clearly better than chance alone (41% vs 14% expected by chance alone), but far below what we need to adopt a procedure for routine use in medicine. For prostate cancer, the Europeans seem to be taking the lead in attempting to improve on the technology – in one case, using a single trained “Belgian Malinois shepherd”!

The eNose used in the Finnish study is an example of ongoing attempts to replace the dog by using electronic detectors to sample volatile chemicals in air. In their study, a thin layer of urine was pipetted into a plastic petri dish to allow evaporation of the chemicals, and the resultant gas was ported to the machine which is described in the article as follows: “The eNose used in this study is a commercially available model (ChemPro® 100, Environics Inc., Mikkeli, Finland) based on the ion mobility spectrometry principle. The device contains an ion mobility cell that consists of 8 electrode strips producing 2-channel output and a metal oxide based semiconductor cell. Together these sensors produce 18-channel measurement data. The sensors do not specify molecules but produce a characteristic smell print of the sample.” In accompanying editorials, there are concerns raised regarding the methodologies, how applicable this might be in the “real world”, and so forth, but in lung cancer there is even some evidence that different stages and types of lung cancer can be detected using this sort of technology. The holy grail in prostate cancer detection remains finding a way to non-invasively discriminate the “lethal phenotype” that needs treatment from the “background” of the >80% of men who will develop prostate cancer that will never bother them by the time they reach age 90. Perhaps this technology will evolve to contribute to that goal.


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The billionaire cancer researcher

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Several patients/friends told me this week about the 60 Minutes piece highlighting the ongoing efforts of Patrick Soon-Shiong, a surgeon who was involved in the development of abraxane and has become worth $11B as a result. So I did my duty and watched on the Internet tonight and will share my thoughts with you loyal followers. Let it first be said that the optimism in this video is compelling, and for the most part based on science that has been going on for the past decade or so in labs all over the country. The 60 Minutes team working with Dr. Soon-Shiong highlighted in a visually compelling, and mostly understandable way, the progress that is being made using the latest technology and understanding of cancer biology. I will highlight this as follows: 1) massive computer technology and sequencing advances allow “all” of the mutations that characterize a cancer cell to be displayed. 2) Drug development to attack vulnerable biologic pathways within cancer cells is accelerating. 3) The possibility of finding the gene mutations driving these cells by looking at circulating tumor cells portends a [mostly] promising way of sampling what is going on within a patient, yet not having to biopsy the tumors. 4) The recent breakthroughs in enhancing immune responses to tumors by shutting down the innate immune checkpoint controls appears to offer great promise for “wiping out” residual/resistant tumor cells.

With that summary, let me urge anyone who watches/watched the video to pay close attention to my good friend, Derek Raghavan’s commentary. Derek is one of the most insightful and honest translational medical scientists I know. In essence, he points out that although Dr Soon-Shhiong is applying an “all of the above” approach to the attack on cancer, there will still be enormous amounts of work to be done and thereby hints at the problem I have  with the video – overselling hype/hope is a specialty of the media. Presenting the single patient with pancreatic cancer who is doing well is an example of this focus on the “sizzle and not the steak” approach. I take nothing away from what a billion dollars can do to pull the existing technologies together and applaud Dr. Soon-Shiong’s efforts. As a matter of fact, one of the techniques he touches on, using low continuous doses of chemotherapy, is something we may have been the first to try in prostate cancer several years ago and published here.

So what are the cautionary issues? 1) The sheer number of mutations found in most cancers (and perhaps especially prostate cancer where the term “shredding of the genome” has been used, make attacking ALL of the pathways at once nearly impossible.  If even one cell can further mutate in the face of having, say 6 or 7 drugs being given to shut down the mutations, it will survive to become the dominant and lethal metastatic problem. This is layered onto the challenge of using “all 6 drugs” together, which will more than likely compound the toxicities to the host when compared to using one of them at the optimal dose. 2) Tumor heterogeneity. In an incredible tour-de-force, a team of scientists at the Cancer Research UK London Research Institute  did whole genome analysis of the original kidney cancer in four patients as well as in their metastases. The graphic of how the research was done is shown here:

Screen Shot 2014-12-10 at 10.23.28 PM

Each spot in the original tumor as well as each metastasis had a somewhat unique set of mutations. Thus “personalized medicine”, the favorite buzzword of the moment in medicine, has a huge challenge in cancer, since there might be different combinations of drugs required for each metastatic site in some patients. The same might apply even for the evaluation of individual circulating tumor cells of course, which is now possible. A cell coming into the research syringe at one time might reflect a tumor deposit in one area, while the next cell isolated could be coming from somewhere else. 3) The excitement over using the most clever of the immune approaches, including the checkpoint inhibitors and the CART cell approach have significant challenges, either because of unleashing autoimmunity, or the very high costs of manipulating each individual patient’s T-cells in order to come up with the autologous cancer-fighting cell treatment.

So, here’s to the optimism and billionaire strategies, and we all hope it moves forward quickly and successfully. And here’s to 60 Minutes for highlighting the amazing biology and progress that is being made. Hope is one of the keystones of human progress, whether it is landing on Mars or repairing a broken relationship. Love and hope are what make life worth living. May your holiday celebrations be filled with both!


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Deep in the weeds. “Doc, is there anything new?”

How to answer this VERY common question is a pretty daunting task. Last week I was at the PCF Foundation annual scientific retreat. This is the ultimate place to hear about new science in prostate cancer, and the incredible progress being made. That said, distilling even one of the many lectures given by leaders in the field is challenging. If I were writing for the National Enquirer, I would have enough notes to write at least a year’s worth of “CANCER BREAKTHROUGH PROMISES PROSTATE CANCER CURE” articles.

So let me just wander into the weeds a bit from only two such lectures . Karen Knudson is one of the best prostate cancer researchers on the planet at this point. She works effectively with clinicians and basic scientists alike on a variety of projects that ultimately yield insights into what controls prostate cancer cell biology. Her lecture this year was on DNA repair targets. (Disclaimer: It is very much beyond my area of expertise to try and cover DNA repair at a sophisticated level, but there is an excellent article dealing with this in the New England Journal this week.) So here we go, weed hunters.

The DNA in each cell is not the long strand of double helix you are used to seeing. Rather, it is intimately wound up with proteins that give it structures looking like a thread wound around a protein ball, then these are further formed into bundles that aggregate and ultimately form the chromosome pictures you find in biology textbooks. The nuclear proteins that are part of this process, in turn, are not only structural, but also contribute to how the Androgen Receptor (AR) binds to specific locations on the DNA and leads to cell growth, turning on the gene that makes PSA and so forth. As you know, AR biology insights led to abiraterone (Zytiga™) and enzalutamide (Xtandi™)

OK, if you have followed this far, get ready for more complexity. The nuclear proteins can all be modified in their functions (helping to initiate the replication of DNA, peeling off the RNA that will go to the cytoplasm to code for proteins, changing the structure of the chromosomes, etc) by enzymes that change the proteins themselves (their shape, charge, function). There are several such modifications, but common ones consist of adding CH3 (methyl) molecules to specific spots on the proteins, or COCH3 (acetyl) molecules. These changes can have dramatic effects on which genes are expressed in which tissues and there is an easy to read overview called the histone code in Wikipedia. (please, please click on that link and read the paragraph on its complexity to get a feel for the research described below)

Honestly, Glode, get to the point….(and I sincerely hope you took a look at some of the links I put in above to make the structures and details more available)

OK, so to make it more relevant to Pca, an important modifier that has explicit functions in cancer is a protein called PARP1. This is an enzyme that modifies the nuclear proteins by a process called ADP ribosylation and adds simple molecules called ADP-ribose to various proteins (including itself) for modifying function. It turns out that PARP1 binds at sites similar to the place where the Androgen Receptor binds in the DNA and also changes other other proteins called DNAPKs that help to repair DNA. The DNAPKs are dramatically over expressed in castrate resistant prostate cancer, and if you inhibit them, you can suppress metastases from forming. Inhibitors of PARP1 and inhibitors of DNAPKs are under intense study as possible therapeutics for prostate (and other) cancers. One such example is cc-115 that is being studied by Celgene, but there are others.


So if you got this far, you have successfully navigated exactly 35 minutes of notes from Karen and another colleague from Celgene, Kristen Hege. And remember, the program went on for a day and a half with me furiously writing notes. It was like drinking from a fire hose, but the net result is this answer to the question, “Anything new?” OMG, “YES” and thanks to the science community for working so hard on unraveling what we need to know about how cancer operates!


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Yay…Movember is here. Let’s kick Pca

Hi friends and relatives (those who will admit it…),

This Movember, I’ve committed my upper lip to help change the face of men’s health by growing a moustache, now I need your support at Movember Foundation is the leading global organization committed to changing the face of men’s health. I’m passionate about this cause because too many men are dying unnecessarily from prostate cancer. In 2014, more than 233,000 men will be diagnosed with prostate cancer. Even better, join our team and donate to yourself and invite your friends/family to the cause! Our team is here:

 The Movember Foundation is working tirelessly with an urgent goal in mind: accelerating breakthroughs in prostate cancer research that will benefit patients and their families. Movember is achieving this with the formation of the largest, global alliance of prostate cancer researchers and clinical specialists, who are tackling the toughest prostate cancer challenges. I had the privilege of hearing the updates on the research they have been sponsoring last week at the PCF retreat. More progress in the last 5 years than in the previous 25. Take a look there for updates/posts yourself!

I need your support to fund this important work. Together, we can create a world where no man dies of prostate cancer.

You can donate by:

- Donating online at (and follow the pathetic growth of my not-so-manly moustache…)

- Writing a check to ‘Movember’, referencing my registration ID: 5798901 and mailing it to:  Movember, P.O. Box 1595, Culver City, CA 90232

You can learn more about the important work and impact Movember is having at:’s a lot riding on this moustache, thank you for your support!

 Mo Bro Michael Glode

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The robot vs the surgeon.

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I have previously blogged on the issues surrounding robotic prostatectomy. Recently I was asked by my professional society, ASCO (the American Society of Clinical Oncology) to provide commentary on two experts “debating” the pros and cons of open (tradiational) prostatectomy vs. the robotically assisted laproscopic approach. Rather than give a long, repetitive blog to you, I am just going to have you click on THIS LINK to read the post.

The issue is largely going away because of the dominance of the robot in clinical practice, but I thought that the experts did a great job explaining their positions.


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