Here be Dragons


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There are times in everyone’s life when it is worth pausing to consider larger issues than the conditions you find yourself facing every day. Big issues like the meaning of life, how we got here, what happens after we leave…, have been the topics of philosophers and kings with far more eloquence than I have. Nevertheless, I am compelled to pay homage to one of the most influential philosopher-teachers in my own life today, because failing to do so would be an injustice to my feelings about him, and this blog is my sole “public forum”.

Donald Seldin was the Chief of Medicine at UT Southwestern Medical School, better known to most people as “Parkland Hospital”, the place they took Kennedy. I went there as an intern in 1972 and was privileged to be under his spell for the two years of my training that represent, for most physicians, the most intense interval in all of their preparation to become “a doctor”. Unless you have lived through your first night on call, wondering whether and how your medical school has prepared you to actually make decisions about another human being who has, by choice or by chance, placed their life in your hands, it is hard to put those feelings into words. “Here be Dragons” is a myth about maps relating to what early cartographers would put on maps when they reached the edge of the known world. I always found that phrase evocative when it comes to facing the unknown. For thousands of physicians who trained under Dr. Seldin, he became the pilot who helped you edge out onto that unknown sea called MEDICINE and gave you the confidence to succeed.

Dr. Seldin died at the age of 97 last week. His life and contributions have been extolled by many of his admirers. The shortest version I can find is this obituary from the New York Times. For a more extensive version, and to meet the man himself, you can watch this video. When I was in mid-career in the 1980’s, we took a sabbatical in Helsinki, Finland. It gave me time to think about the larger issues and to write to some of my mentors, thanking them for taking me on as a student and sharing their wisdom with me. Dr. Seldin was one of the men to whom I corresponded. As I recall, in the letter I referred to the pop song, “To Sir with Love” because at an emotional level, the phrase “How do you thank someone who has taken you from crayons to perfume?”  best captured how I felt about his tutelage. He wrote back to the effect that he “had no idea that he cast such a long shadow”, which was surely not true, but his modesty was just another facet of his remarkable personality.

So, if you are in any sort of a contemplative mood at some point this year, take a bit of time to write to one of your mentors or a family member. Thank them for what they mean to you. When they are gone (or when you are gone), that letter will be worth your time as an emotional bond as you sail on into the unknown. Godspeed Dr. Seldin!

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Improving our focus


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I have had two life changing experiences in focusing. The first was when my wife discovered the Myers-Briggs personality classification system and found I am a “strong P”. This meant I couldn’t help it when I was on my way to take out the garbage, noticed a light had burned out, put the garbage down and went to get a light bulb, but found that there was a spot on the carpet that needed cleaning and finally found the carpet cleaner but an hour later wondered why there was a garbage sack in the hall. Prior to her discovery, she just thought I was an idiot, but she became [somewhat] more tolerant of the foibles when she could “classify” me. The second was when I had my congenital cataracts removed and new lenses inserted in my eyes. It was a whole new world of color. I had been living in a fish tank with scum on the glass and “wow, the world is really pretty!” was my response when I took the patches off the next morning. “Trees have LEAVES!”

Focus in understanding prostate cancer is becoming clearer as well. For several decades we have known that the Gleason scoring system is pretty darn good at predicting the cancer’s behavior, adding a lot to what we knew when there was only the digital rectal exam… “Oh, oh, that feels like a really big tumor” or “Maybe I’m feeling something but I can’t be sure”.  Then came the number of biopsies positive, the percentage of each core, differentiating 3+4 vs 4+3, and now an avalanche of new molecular markers, briefly reviewed here. Combining the old standby risk categories with the newer methodologies has been challenging.

A recent paper in the JCO provides us with one way of integrating the old risk categories with the newer molecular classifications. Using the widely adopted risk categories of the NCCN, the authors added to this, one of the more mature molecular classifiers, the 22 gene Decipher™ scoring system to reclassify (focus) a new model to predict outcomes. As I explained previously, these genetic tests are typically developed looking at the level of gene expression in biopsies or in removed prostates in a group of patients for whom an outcome is known (examples include prostate cancer free survival at 10 years or freedom from metastases at 5 years). The investigators (or companies) then go to a different institution or collection of biopsy material and see if their gene expression model developed from the first group accurately predicts the outcome in the second group. This is called “validation” of the test. Decipher has done all of this. The question is how it might change the risk classification of the “old” system.

This figure illustrates how it plays out when a large number of institutions collaborate to study the information gained and develop a new model.Screen Shot 2018-04-28 at 10.16.05 AM

As an example of how this can be used in the “real life” clinic, we are often faced with a patient who has a “favorable intermediate” prostate cancer. Let’s say this is a 75 year old man with excellent health. Should we advise that he adopt a “watchful waiting” strategy, given his age and the relatively low risk? By adding the genomic test, you can see that 27% of the time, this might be a bad recommendation. Similarly, in the unfavorable intermediate group, 40% of patients are moved into a high risk category. Such a patient might be well advised to “do more” (example: more prolonged ADT with radiation, or use of brachytherapy in addition to external beam radiation if they had chosen radiation therapy as their preferred treatment modality).

These kinds of improved focus will allow investigators to do better studies prospectively as well. In breast cancer it is already a standard of care to do molecular classification of certain stages and types of tumors, allowing women to make far better decisions on whether (for example) to take chemotherapy in addition to surgery/radiation. In prostate cancer, where I have been concerned that we aren’t “racing for the cure“, rather we are “crawling for the cure”, it looks like we may be catching up. Research is the answer – sign up and contribute!

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Are we any closer to cure? (yes and no)


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I have at least three thoughts on the issue of curing advanced prostate cancer. First, the number of new treatments that are life prolonging has been incredibly gratifying. See my posts on abiraterone, enzalutamide, apalutamide, Sipuleucel-T, and Radium 223, to say nothing of cabazitaxel and docetaxel. That said, my second comment (and yes, I DO say this in the clinic to try and keep some perspective on a deadly, but often slow disease) is that “if you die of a heart attack or a stroke, we call that a CURE!” Many patients have very slow moving prostate cancer that just grows old with them, and some of the drugs listed above can slow it down still further, even though the side effects (particularly of ADT itself) are definitely unpleasant. The third thought is an old saw: “For every complex problem, there is a simple answer, and it is often wrong.” I looked it up, and it is attributed to H.L. Mencken, who actually said, “Explanations exist; they have existed for all time; there is always a well-known solution to every human problem — neat, plausible, and wrong.”  I found he also said, “We are here and it is now: further than that, all human knowledge is moonshine”. Pretty cynical, but we digress…

Thus, the article that made me think about how complex a problem prostate cancer actually presents us was this one. The authors are very much the Who’s Who of prostate cancer research, and what they did was sequence the exomes from 1,013 prostate cancers. They were looking for so called, “driver mutations”, that is, mutations in a gene(s) that are the underlying cause, or at least the accelerators of prostate cancer. Their abstract conclusion states, “We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer…”

Screen Shot 2018-04-04 at 9.41.57 PM

The list of mutations found

This means that although we might see some drugs developed for the most common mutated driver genes, there lurks a host of others for which developing a drug for the very small number of patients (even if that is possible – not all mutated genes are “druggable”) with a given driver may not be economically attractive. And then there is the issue that if one of the common driver pathways (for example the androgen receptor) is effectively knocked out, as has been done with the second generation inhibitors, it is likely there are other mutated drivers in the wings. 

On the other hand, the study of metastatic prostate cancer has uncovered a wealth of new genomic classifiers that may be of real utility in further separating the “bad” cancers from the more indolent variety. As they state, “this analysis, which includes more advanced cases, has identified new and biologically and clinically relevant events and creates an opportunity to prospectively assess a metastasis-associated genomic marker for clinical stratification in localized prostate cancer.” All well and good, but don’t forget the issue of tissue heterogeneity. If you biopsy one metastatic site, or even one site within the primary tumor, you might get a different answer from a site only a few millimeters away or from a different metastasis, as I previously pointed out in another very sophisticated article by some of the same authors.

Nevertheless, be of good cheer. To have so many outstanding biologists and physician scientists uncovering the underlying mechanisms of prostate cancer is a good thing. The more we learn, the more opportunities we have to slow the disease down, even if there may never be a “cure” other than a heart attack. Immortality may be elusive, but your friends and family are not…carpe diem!

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Delaying metastatic disease – ASCO GU18


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Previously, we have discussed the conundrum of the rising PSA and when to start therapy. I also opined that for some men with a very slowly rising PSA, it might be best to just forget about it and enjoy life, comparing it to watching a clock, an opinion that understandably garnered negative comments from some. Of course the nuances surrounding PSA kinetics and their meaning are myriad. However, one graphic that helps understand this better is shown here.

Screen Shot 2018-02-12 at 2.49.27 PM

Smith, JCO 2013

This figure illustrates the fact that individuals with relatively long doubling times (>8-10 months) have a much lower risk of developing metastases or dying from prostate cancer than those with shorter doubling times. In a classic study published almost 2 decades ago, Pound et. al. followed a large number of patients who had rising PSAs following prostatectomy at Johns Hopkins. On average, men with rising PSA’s  who received no additional treatment, did not develop metastases for ~8 years. “In survival analysis, time to biochemical progression (P<.001), [i.e. the time from prostatectomy until PSA rise was detected] Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease.”

With these findings as a background, two studies were presented at the ASCO GU18 meeting, both involving use of improved analogues of bicalutamide (Casodex): enzalutamide (Xtandi) or apalutamide (Erleada). These drugs block the androgen receptor, thus preventing stimulation of prostate cancer growth, but are more potent than bicalutamide. Patients with rising PSA’s in spite of having low levels of testosterone from surgical (orchiectomy) or medical (GnRH agonists/antatgonists) castration, short doubling times (<10 months), but no metastases were treated either with apalutamide/placebo (SPARTAN trial) or enzalutamide/placebo (PROSPER trial). The trials were both remarkably positive in delaying the time to development of metastatic disease.

Screen Shot 2018-02-19 at 8.44.28 AM

SPARTAN TRIAL (Apalutamide)

Screen Shot 2018-02-12 at 2.42.37 PM

PROSPER TRIAL (Enzalutamide)

These are remarkable findings and great news for patients with the most aggressive forms of prostate cancer. However, there are (as usual) numerous questions raised by the trials, as was nicely discussed by Dr. Kantoff after the data were presented. These included a more careful analysis of the side effects and clinical benefits. Obviously patients are psychologically better off when they don’t have a rising PSA or metastases, but neither study reached statistical significance when it came to improved survival (both are trending in this direction). What are the side effects of being on such drugs for longer periods of time? In the enzalutamide study, there were more deaths from “other causes” – not pca within 3 months of progression. Why? In the apalutamide study there were more falls and fractures compared to placebo. Why? To these, I would add the issue of “pay me now or pay me later” – how much time/quality of life do you really lose by waiting until the first metastasis shows up, never mind the extraordinary costs (to patients, insurers, medicare, etc.) of remaining on these drugs for years. Further, neither study compared the outcome to using bicalutamide, the generic and much cheaper alternative anti-androgen, instead of placebo. And what about using the newer scans? All of the patients have metastatic disease, we just can’t see it until there are enough cells in one spot to turn a scan (e.g. fluciclovine or PSMA PET) positive. We can possibly gain advantages in staying off ADT of any sort in some patients by radiating oligometastatic disease. Nevertheless, these studies are great progress and landmarks in the fight against prostate cancer. Apalutamide became the first drug to be approved by the FDA for use in this setting with a “snap approval“. And I need to disclose that I am a paid advisor to J&J, although I have no personal stock in their company, and did not treat patients on either trial.

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Of Prostates and Teslas


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If you thought this might be an article about how your urologist shops for his/her newest fancy car, you are mistaken (sadly…). Nikola Tesla was a fascinating inventor and ultimately “mad scientist” at the turn of the last century. Every time you plug your cuisinart into the wall to chop something up, you are the beneficiary of his contributions to the alternating current coming to your kitchen and the motor driving the chopper. My favorite story (because of the local connection) was his laboratory in Colorado Springs, where he attempted to develop a method of transmitting power without wires. By creating YUUUGE electromagnetic fields, he could make lots of electrical things happen at considerable distances, including knocking out the power station for the city. Here’s a quote from the Wikipedia article:

He produced artificial lightning, with discharges consisting of millions of volts and up to 135 feet (41 m) long.[11] Thunder from the released energy was heard 15 miles (24 km) away in Cripple Creek, Colorado. People walking along the street observed sparks jumping between their feet and the ground. Sparks sprang from water line taps when touched. Light bulbs within 100 feet (30 m) of the lab glowed even when turned off. Horses in a livery stable bolted from their stalls after receiving shocks through their metal shoes. Butterflies were electrified, swirling in circles with blue halos of St. Elmo’s fire around their wings.[12]

Of course, for purposes of this blog, the key thing is that the strength of magnetic fields was named after him. When you get an MRI of your prostate, brain, or anything else, you are put into a machine with a superconducting magnet that produces 1.5 or 3 “T” of strength. At the risk of being completely wrong and oversimplifying, what happens in the MRI machine is that a strong magnetic field temporarily lines up the hydrogen atoms in the water that is 70% of “you”, and when these atoms “relax” they give off radio signals that can be converted to images. Details and images are here. Early on, my colleagues and I were fascinated by the possibility of using MR to investigate the prostate gland and published an article (completely ignored – cited only 3 times, so must not have been that important…) showing changes in MR that occurred after testosterone administration to castrated rats.

Now there are complex MRI protocols to image the prostate using techniques I don’t fully understand (multiparametric imaging) that give us remarkable pictures of the prostate gland. Here is one:

Screen Shot 2018-01-10 at 1.53.20 PM

Prostate gland with red arrow indicating a suspicious lesion that could be biopsied or followed closely.

As with any radiologic imaging technique, the skill of the radiologist as well as the equipment being used determine the accuracy of the MRI to diagnose a cancer.

While most of us learned how to “read X-rays” in medical school, it is beyond most clinicians to read MRI’s of the prostate. Fortunately, the radiologists have developed a system that helps us think about “how abnormal” some area of the gland is, called PI-RADS.  This can be very useful in thinking about what area to concentrate on when biopsying a patient, or in trying to determine whether surgery or radiation therapy should be altered if there is concern that the cancer is outside of the gland. An interesting question that is still controversial is whether the MRI could replace repetitive biopsies in a man who has chosen active surveillance. Particularly when combined with molecular techniques (see my previous blog here) to characterize biopsies, it may be that Tesla will be helping to do more than get you from one place to another or run your electric shaver. (Rock on, Elon Musk) To me, that is a pretty interesting outcome from knocking out all of the lights in Colorado Springs!

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PCa Immunotherapy (for people in a hurry)


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I just finished reading Niel deGrasse Tyson’s book on astrophysics that was pretty understandable. Although I am no immunology expert, and certainly not at the academic achievement level of Dr. Tyson, I have made monoclonal antibodies in my lab and participated in several prostate cancer immunotherapy trials, so I’ll give this a try. My inspiration comes from a truly excellent and comprehensive review on the topic by Laccetti and Subudhi that appeared in Current Opinion in Urology. I will follow their outline with my own “layman’s view” and comments.

Provenge (Sipuleucel-T) was the first immunotherapy ever approved for treating Pca, and has been available since 2010. To be eligible, you have to have failed standard androgen deprivation therapy (though not necessarily the newer agents) and have metastases that can be detected on bone or CT scans. While the treatment works, has been shown to slow the rate of PSA increase and prolong survival, it is complex to administer. You need to donate your own immune cells for “activation” in a treatment facility, following which you receive them back as a transfusion. The process is repeated 3 times and costs in the range of $100K. Many of us wish it was even more effective given the costs and inconvenience, and of course all patients want to see their PSA go down with ANY treatment, which doesn’t happen often with this treatment. Efforts to improve the efficacy have included earlier use when patients are still hormone sensitive and combining SipT with ipilimumab, an antibody that enhances immune responses.

A number of [somewhat] more traditional vaccines are in trials. In a phase II trial, Prostvac, utilized a pox virus approach to deliver PSA (as the antigen) along with co-stimulatory molecules to help the immune system recognize and kill PSA producing cells. Although the phase II data looked very promising, the phase III trial was closed in September when the data did not support continuing to treat patients. Given this disappointment, it is not surprising that the immunologists/clinicians pursuing the goal of a successful prostate cancer vaccine would turn to the “checkpoint therapies” as a possible way to induce the body to fight prostate cancer.

Perhaps the best known of these approaches (due in part to intense advertising on the evening news channels) are nivolumab (Opdivo™) and pembrolizumab (Keytruda). The general idea here is that the immune system would potentially constantly be fighting our own body parts if there wasn’t a way to turn it off. Examples include diabetes (immune system attacks the insulin secreting cells of the pancreas) or rheumatoid arthritis (immune system attacks your joints). The checkpoint system, known as PD-1 (programmed cell death protein 1) is a shutdown system whereby the attacking T-cells are turned off by the PD-l1 ligand, a protein that can also be secreted (unfortunately) by the cancer cells. Thus the cancer cells can turn off our own immune system which is trying to attack and kill the cancer. The checkpoint antibodies effectively throw a monkey wrench into this system, allowing the immune cells to do their thing (and of course, as you would predict, the side effects can include attack of other “self” organs like the lung or colon or pituitary gland). This approach has shown real promise in melanoma, lung cancer, head and neck cancer, bladder cancer, and in some patients with colorectal cancer. Another checkpoint player is ipilimumab, which was first approved for melanoma and also releases “blunted” T-cells to go on the attack. Unfortunately, none of these checkpoint inhibitors have been promising by themselves in early tests in advanced prostate cancer, but there is optimism that by combining them with some of the vaccines in trial, or, perhaps by timing their use with androgen deprivation or radiation therapy when lots of pca cells are dying we will see improved responses. There are 19 actively recruiting studies at clinicaltrials.gov with the terms “vaccine, prostate cancer, recruiting”.  As with many of the challenges in prostate cancer, the best time to use an immune approach is likely early on, when the disease burden is low (for example, a Gleason 9 patient with NO evident metastases). These trials are challenging because such patients are fortunately uncommon, and because these men also can live for many years with current treatments, making the evaluation of a new treatment modality difficult.

2017 was a year when we lost one of the most inspiring teacher/researchers in prostate cancer, Dr. Donald Coffey. The good news is that his legacy lives on in the large number of researchers who continue to push the frontiers of prostate cancer diagnosis and treatment. We owe him a great debt of gratitude for his tireless efforts to advance this field of medicine. I predict it won’t be long until we have the kinds of exciting pca immunotherapies that have made such a remarkable difference in melanoma and other cancers.

 

 

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23 & You – Genetic tests for pca


The genetics of prostate cancer are daunting, but there are now a range of tests available that could be used at almost every stage of the disease IF you can deal with the answers you are likely to receive. Generally these tests are the product of science that goes something like this: A complete molecular picture is taken of all the mutations or all the genes expressed in a series of prostate cancer patients diagnosed years ago. For these patients “all you need to do” is go back to the paraffin blocks that were saved for each patient, extract the DNA/RNA and quantify gene expression and any mutations that can be detected. A decade ago, the technology for doing this was daunting, but now it is relatively easy. Once you have the gene expression profile, you can ask a computer to look for gene expressions that correlate with a certain outcome. For example, you take 500 patients from one center for whom the outcome is known…50 patients are dead, 32 from prostate cancer…70 patients developed metastases by 5 years…these 315 patients are alive and well with no evidence of recurrence…etc. Let’s say there are 50 genes that show changes in expression or mutation. Do we need all 50 to forecast what happened to the patients in that group? No. A computer algorithm can keep testing combinations and permutations of genes and reduce the 50 to a smaller number. We can either let the computer pick the final genes, or we could start with genes we think are related to tumor progression and then do the reduction. In the end, we have a small number of genes with characteristics that accurately separate the patients into “good” and “bad” groups and everything in between. We now take our gene panel, reduced to something like a computer chip and apply the test to 500 patients at another institution blinded from what actually happened to those patients. If our algorithm works, we should be able to accurately predict what happened to those patients in the next 5 or 10 years. If it works, our testing system has been validated, and we can begin offering the test to newly diagnosed patients at some stage of illness. For example, a Gleason 3+4=7 patient might fall into a group where surgery produced a 90% chance of being cured at 10 years, or a 40% chance depending on the gene expression. BUT…and this is key…what to do about the result is still a complex decision for both patient and physician. If you are a Gleason 3+3=6 patient and with no treatment at all you have an 85% chance of “cure” at ten years, is that good enough? What if it is a 95% chance? Will that make you more comfortable choosing no treatment, or do you want to be cured at any cost (impotence, incontinence, other side effects of radiation or surgery)?

As none of these tests has been proven in a prospective study – that is, using the tests to do something like even more aggressive therapy in a group of high risk patients, we are still in the early stages of understanding how and when to use them. Fortunately, my colleague, Dave Crawford and some colleagues have put together an excellent website to help patients/doctors understand the tests. http://www.pcmarkers.com has a list of most of the available tests and you can see what results might look like before you and your physician decide to send one off. This is a rapidly evolving field however, and not every test that is being commercialized is listed, and at big centers, there are always new tests being developed.

Finally, as with all of medicine, the payment systems/insurance coverage is crazily complex. Only today, I received an email with the “news” that a cardiologist/congressman, Rep. Buchson has introduced a bill called the “Prostate Cancer Misdiagnosis Elimination Act of 2017” that uses DNA profiling to make sure the tissue being tested is yours. You could theoretically apply this test to ANY cancer biopsy of course, so why prostate cancer? Then there is the motivation…call me cynical, but I suspected that the good congressman, meddling in medicine, might have a local connection, and sure enough, the company that markets the test is from his home state, Indiana. Not to say it isn’t important to know that tissue being tested comes from the correct patient or that the test isn’t a nice application of the kind of technology that identified OJ’s blood, just that we live in interesting times where medical technology is rapidly consuming more and more of our tax/insurance/personal dollars. Personalized medicine will depend totally on this type of technology and can be incredibly expensive. Whether it saves money or consumes it may depend on how many “worthless” (for that patient…and is a treatment with only a 5% chance of working really worthless??…not if you are in the 5% group) treatments are avoided and at what cost. I don’t have the answers. Hopefully this blog at least helps you begin to understand the current molecular diagnostic landscape.

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