COVID-19 and “the news”


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This won’t be a long blog, but since I anticipate lots of news this week regarding an article that was published a few days ago, I thought I would provide a “heads up” to my prostate cancer “groupies”. What makes the news and becomes “viral” is interesting and I haven’t had the opportunity to watch the sequence up close personally before. My wife is a pediatric infectious disease expert with specific interest in Kawasaki Disease. As you most likely have seen in the news over the past few days, SARS CoV2 now seems to trigger a KD type of illness in children. This became apparent a little over a week ago with calls flying back and forth from around the world among her friends, notably because Michael Levin, from London had seen some cases and sounded the alarm among the international colleagues. So, from “insider info” to public alarm seems to take about a week.

As you know from faithfully reading this blog, I predicted that men on androgen deprivation therapy might be protected from SARS CoV2 about 6 weeks ago and that physicians/scientists with access to large databases would be able to show this. And, true to the prediction, this past week an article appeared showing just that. I have summarized the data for you on this slide:

Screen Shot 2020-05-10 at 8.33.47 AM

It will be interesting to see this get picked up and “sensationalized” by the media over the coming days. And it is already underway. I am aware of a conference call with the CDC and another being hosted by the Prostate Cancer Foundation this coming week. So consider yourselves forewarned! CNN, FOX, ABC, etc. etc. will be all over it…

Now, as I also predicted, I would bet that there will be prospective studies looking at ADT as a form of therapy for COVID19 starting soon (if not already underway). My favorite design would be with the approved agent, remdesivir in a randomized prosepective trial. Male patients sick enough to be admitted to a hospital would all receive remdesivir, and 1/2 would receive ADT in the form of an anti-androgen (e.g. enzalutamide, apalutamide or darolutamide) or a single injection of a month of a GnRH analog like degarelix (Firmagon), or the androgen synthesis blocker abiraterone/prednisone (Zytiga). I would hope that this kind of approach could help men (and maybe even women) fight the virus by blocking TMPRSS2 as I previously showed you in the graphic on the original blog. Now YOU are the insiders!

PS, I think that another approach could be starting everyone in a nursing home “under attack” could be starting all the occupants on finasteride. Blocks DHT production from T and is very well tolerated in the  pcpt trial. Lower DHT -> lower TMPRSS2 -> lower viral replication.

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PSMA PET-CT scans for Prostate Cancer


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PSMA stands for Prostate Specific Membrane Antigen, which is a protein (enzyme) that is expressed on the surface of prostate cancer cells (and on a few other cell types). As with many cell surface proteins, you can find ligands that will bind to the protein, and then label these with radioactive isotopes that allow imaging. PET stands for Positron Emission Tomography, and of course, CT stands for Computerized Tomography. When you put these technologies together, you obtain a powerful way to look for prostate cancer that has spread outside the prostate gland. The physics of this (how a positron interacts with an electron, releasing gamma photons at 180 degrees) is very cool, but probably of interest only to the most nerdy. (I made a cloud chamber for my 7th grade science project and my hiking buddy is a nuclear medicine doc who wrote a definitive text on the math/science of his craft…so go figure).

Prior to developing PET agents for prostate cancer, we had standard CT scans and bone scans and we used these to determine whether someone with, for example, a very high PSA or high Gleason score had cancer deposits that had escaped (metastasized) from the prostate. If so, it was felt that putting them through surgery or radiation treatments in an attempt to cure was fruitless and exposed the patient to the unnecessary toxicity risks (impotence, incontinence, rectal damage, etc.) Especially if they had symptoms (e.g. bone pain), hormone treatment reducing testosterone was the best approach. If you had a rising PSA several years after local treatment, the question was always, “Where is the cancer?” but the sensitivity of routine bone and CT scans was quite limited not showing anything until the PSA reached 10 or so at which time ~1/2 of scans would be positive. Screen Shot 2020-04-26 at 7.26.14 AMThis figure illustrates the difference in sensitivity. A normal sized lymph node on CT scan (left) is revealed to  contain prostate cancer with the PET isotope technique (right). At present, the only approved PET scan in the U.S. is fluciclovine, the “Axumin” scan, which the FDA approved for detecting cancer in patients with rising PSA, but not in newly diagnosed patients. In several studies PSMA-PET CT scans are even more sensitive (about 3x) than Axumin. At the risk of calling up an overused phrase, “this changes everything”.

First, it is clear that many high risk patients we would previously have treated with surgery or radiation to the prostate hoping to cure them might now be found to have prostate cancer deposits outside of the treatment target (prostate or prostate + pelvic lymph nodes). A superb study in this month’s Lancet found that PSMA PET-CT scans provided higher sensitivity (85% vs 38%) and specificity (98% vs 91%) than routine bone and CT scans in high risk patients (PSA >20, Gleason 4+3 or worse). Does this mean we shouldn’t treat the prostate in high risk patients with positive scans? In the study, conventional imaging changed the management in 15% of men, while PSMA PET-CT imaging changed the plans in 28% (p=0.008). Should all high risk patients have a PSMA PET-CT before deciding on treatment? Should the FDA approve this scan quickly? (It is currently available only in research centers and not covered by insurance…read my blog on how to search for such studies or click here).

Second, what about treating a small number of prostate metastases (oligometastatic prostate cancer) in a patient who was treated years ago and now has a rising PSA? Ongoing investigations suggest this might delay the need for hormone therapy in such patients or potentially even cure some of them. But the PSMA PET-CT isn’t perfect. How high do you let the PSA go up before ordering such a scan? – the farther it rises, the more likely the scan will show something, but that gives the cancer more time to spread. A negative scan is no guarantee there aren’t many more foci of a few prostate cancer cells that will eventually show up elsewhere in the body. Is this some version of Whack-a-mole? And how do we define “cure” anyway?? (My personal definition is that you die from something else, regardless of your PSA or scan results).

Finally, since even at research centers the PSMA PET-CT scan may cost you $3,000 or so, is it worth it? It is “free” in the European health care systems, but we all know nothing is free – even if Medicare pays for something it costs society and ultimately must be accounted for in terms of value. Medicare covered PSMA PET-CT’s vs fixing pot holes and bridges? How about finding a treatment for SARS Co-V2 instead? No easy answers, but if you are like me, homebound as a “high risk” senior citizen, plenty to think about. Wash your hands, wear your mask, and enjoy your grandkids on Zoom!

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COVID-19, ADT and Prostate Cancer


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Spoiler alert: As I start to write this, my intent is to delve into some basic science readers may find too detailed/complex and some speculation that has limited/no support and should NOT be taken as anything other than hypothesis generating. I fell in love with biology in about the 8th grade and with thinking about how to answer biology questions in medical school, so this is more self-indulgent writing rather than being written to inform.

Starting with the COVID-19 story, there have been so many excellent articles that if you haven’t read too many already, you can get a one minute overview from this video. Now for some more Screen Shot 2020-03-29 at 8.47.20 AMdetailed science. This figure from an excellent article in Science shows the real details of how the virus works and some of the drugs that might be useful in stopping or slowing it down at the cellular level. If you use your best “Where’s Waldo” approach, (and if you are an avid follower of prostate cancer biology) you may find a very familiar protein hiding in the membrane where the virus binds to the exterior of the cell, TMPRSS2. This protein is an enzyme in the family of serine proteases, proteins that can cut peptide bonds at the site of the amino acid serine. Trypsin is another example of this category of enzymes we use in the lab to release cells from petri dishes, and you use various enzymes every day in your dishwasher to digest proteins stuck to your dishes. As shown in the figure, TMPRSS2 plays a crucial role in the entry of the SARS-CoV-2 virus into the respiratory epithelial cells leading to COVID-19 disease.

I first heard of TMPRSS2 several years ago in a lecture at the PCF annual scientific meeting. Investigators at the University of Michigan found that in a large percentage of prostate cancer, the androgen response elements in DNA that control the expression of TMPRSS2 have become fused to an oncogene, ERG. Every gene in our DNA is controlled by “upstream” segments of DNA called promoters or enhancers that regulate the expression of the gene. In the case of prostate cancer the androgen receptor, AR, binds to testosterone (or DHT) and then the is translocated to the nucleus where it binds to DNA at the sites of androgen response elements, leading to transcription and expression of the “downstream” genes. A reasonable analogy is to think of testosterone flipping a light switch to “on” and the AR being the wire going to the light bulb, TMPRSS2, in our case. You are familiar with this if you know about drugs like Lupron, Zytiga, or Xtandi that block testosterone signaling in various ways. Although taking any of these drugs turns off many genes related to prostate cancer development and progression, one of these genes is clearly ERG (if you have the TMPRSS2:ERG fusion), and of course you probably turn down expression of TMPRSS2 in normal cells.

So what does this have to do with COVID-19? As you may have seen, men have approximately twice the mortality of women from infection with SARS-CoV-2. There are no doubt many possible reasons. Men smoke more. Men may not practice social distancing as much. Men have more heart disease. But what if one reason is that they express higher levels of TMPRSS2 in their respiratory epithelium? The exact mechanism of TMPRSS2 in the infection can be found in this article.  A cartoon from the article illustrates the several points in the viral infection cycle where TMPRSS2 (and other serine proteases) acts to facilitate the entry, replication and budding of the virion from a cell.

Screen Shot 2020-03-29 at 10.19.32 AM

The article discusses several drugs that are being investigated to inhibit TMPRSS2 that could hopefully be effective in fighting COVID-19. One of them, camostat (seen in the first figure in this post), is already scheduled to begin clinical trial at the end of this month.

However, there is already a very interesting global “clinical trial” underway if you have followed the above (and necessarily complex …sorry!) story about TMPRSS2. If ADT, familiar to all men with metastatic or high risk prostate cancer, turns down the expression not only of ERG and other oncogenic pathways, but also the expression of TMPRSS2, it might reduce the infection rate or morbidity/mortality from COVID-19. Looking at large global databases, it may be possible to see whether men with a diagnosis of both “prostate cancer” and “COVID-19”  can be extracted from the data, and then whether within this grouping, those men on ADT have a better outcome than those not on ADT. It would be complex, of course, since some of the men not on ADT might be on chemotherapy, or more sick in general, and thus more susceptible to dying from the infection. It might also be possible to see what the expression levels of TMPRSS2 in the pulmonary epithelium of men versus women are as a potential partial explanation of the differences in mortality. Finally, and this would be the most intriguing possibility of all, a clinical trial that combined some partially effective “drug X” from the list of drugs in the first figure with or without ADT could determine whether short term use of ADT could enhance the treatment. Proof that no one ever has a “unique” idea (and of the speed with which you can share ideas in today’s internet environment), in doing a minimal amount of literature research on this topic, I came across a preprint of a beautiful article looking at exactly the hypotheses I laid out above. It was submitted only 5 days ago! The authors have found very significant differences in the levels of expression of TMPRSS2 among adults using published databases and hypothesize that this could explain why some individuals may be more susceptible to bad outcomes. They also evaluate the potential of down regulation of the gene with ADT drugs like enzalutamide or estrogens and they conclude, “Together, these results identify existing drug compounds that can potentially be repurposed to transcriptionally inhibit TMPRSS2 expression, and suggest that the activation of estrogen pathways or inhibition of androgen pathways can be a promising modality for clinical intervention in SARS-CoV-2 infection.”

In summary, if you have prostate cancer and are on ADT, the well known side effects you put up with are unpleasant to say the least. But there is a “not-zero” possibility that your ADT is also protecting you. The best advice is still to practice social distancing, wash your hands, and be vigilant regarding your health, but maybe there is a silver lining in this story. I hope so, and there are already clinical and basic scientists exploring the hypotheses discussed above. Be well and my best wishes during these trying times!

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(Love) Advice in the time of (Cholera) Coronavirus


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I wanted the title to look like this, but the software wouldn’t let me: Love Advice in the time of Cholera Coronavirus. In any case, if you are a patient or in the patient age range of prostate cancer you are automatically at some increased risk. There isn’t much evidence that cancer patients in general who aren’t on chemotherapy or an immunosuppressive agent have much increased risk. In fact, patients on ADT may actually do a little better based on reactivation of thymic function. Here is a quote from this complex article by James Gulley and colleagues:

Analyses of these data suggest that AR expressed by thymic epithelium play an important role in thymocyte development, and could explain why androgens induce apoptosis of thymocytes in vivo but not in vitro (31). In subsequent studies, androgen withdrawal led to increased thymopoiesis and reversal of thymic atrophy in post-pubertal male mice (32) and even in aged mice (33, 34). Furthermore, thymopoiesis decreased with the administration of testosterone (35, 36). Castration also results in increased T- cell export in aged mice and increased naive splenic T cells compared to aged controls (34).

Although persistent thymic function is evident in older individuals, it is decreased, as demonstrated by lower TREC [T-cell receptor rearrangement excision circles] levels (37). However, studies show that ADT can induce thymic renewal in older individuals (38). In one study, elderly prostate cancer patients given GnRH-A experienced a notable increase in TRECs in 6 out of 10 cases, indicating renewed thymopoiesis (34). These studies suggest that the effects of androgen ablation are not limited to the young, as evidenced by restoration of thymic function and export of naïve T cells after surgical (orchiectomy) or medical (GnRH-A) castration.

 

The enhanced thymopoiesis associated with ADT has important clinical implications for the treatment of immunocompromised patients and for immunotherapy for prostate cancer (see Figure 3 for a summary of ADT’s effects on the T-cell compartment). Thymic renewal in these patients may increase the diversity of the T-cell repertoire, increasing the pool of antigens recognized by the immune system. In the setting of vaccine therapy, an increased naïve T-cell compartment may enhance the response to immunotherapy.

 A few patients have asked me about whether to postpone surgery. In general, for patients with “average” (Gleason 3+4) tumors, this would probably be OK. It is a harder decision for those with Gleason 4+3, or any component of Gleason 5. It will have to be an individual decision (as are all decisions of this sort) with your doctor. The same would apply to radiation therapy treatment which can have some immunosuppressive effects, but certainly has never been studied in this situation.

In general, I would also recommend that you put aside your political biases and listen to the scientific experts. I was disturbed by a poll presented this morning on Face the Nation that indicated a significant difference in the perceptions of risk between Republicans and Democrats. This virus does not know or care about your party or politics. Practice the social isolation being recommended by Fauci and the other experts: “We should be over-reacting to this…” It would be just fine to look back and say we did that.

If you want to delve further into the science of this (which also dispels a lot of misinformation about where the virus comes from and how it arose), you should certainly look at this presentation: http://www.croiconference.org/

And in case you haven’t been thoroughly inundated with advice or just came out from under a rock, here is the succinct list of expert recommendations:

  • Social Distancing to flatten the curve of the pandemic (reduce infectivity rate from >2 to <1):
    • Wash/sanitize hands frequently
    • If sick, do not go to work
    • Work from home if at all possible
    • Maintain your personal space when around others
    • Eliminate travel (don’t be fooled by cheap flights or hotels)
    • Reduce exposure to groups of people
    • COVID-19 can persist on hard surfaces for several days so wipe down frequent contact surfaces repeatedly
    • Recognize that social distancing will have some mental health implications so be especially compassionate

Stay home. Stay well. Here is a list of things to do:  Fun Free Time Activities_

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New findings from clinical trials 2020


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There are a number of ongoing trials or completed trials that represent attempts to develop new approaches to prostate cancer. I am sometimes asked what I know or think about them (often not as much as I would like) from various investment consultants, so I thought rather than respond to a recent list, I would just use it to explain the trials for readers of this blog. Perhaps when your friends ask you whether there is “anything new out there”, you can point them to some of these.

The PROFOUND, TALAPRO-1, TRITON-2 studies are all designed to evaluate the efficacy of small molecule drugs that inhibit “PARP” which stands for an enzyme (Poly ADP-ribose polymerase) that is involved in DNA repair. It turns out that patients who inherit a damaged/mutated version of any of several enzymes that help cells maintain their DNA integrity (BRCA1/2 being an example you may have heard of – when mutated it leads to the development of breast and ovarian cancers as well) are more likely to get prostate cancer, and often it is of the more aggressive variety. It is also a frequent condition of prostate cancer metastases in patients who no longer respond to hormone therapies (leuprolide, abiraterone, enzalutamide, etc). These patients appear to be uniquely sensitive to PARP inhibitors and several pharmaceutical companies are developing them. Olaparib and rucaparib received breakthrough designation from the FDA for accelerated development. In the PROfound trial, patients who had progressed on either enzalutamide (Xtandi) or abiraterone (Zytiga) were randomized to receive the “other” new hormonal agent or the PARP targeted drug olaparib (Lynparza). As reported by my friend/colleague Maha Hussain, the olaparib treated patients fared significantly better than the patients who received the “other hormone”. The take-home message from these trials is that we now have ways to look at the molecular underpinnings of resistant prostate cancer. If you have metastatic prostate cancer, ask your physician about the genomic tests that can be done to see if you might benefit from one of these new drugs.

In a somewhat similar design, the CARD trial evaluated treating patients who had had been treated with docetaxel (Taxotere) and then progressed while on enzalutamide or abiraterone with cabazitaxel (Jevtana) rather than the alternate hormone targeted drug. Chemotherapy with cabazitaxel was the better approach. This was similar to a previous trial called FIRSTANA that looked at alternatives of mitoxantrone or cabazitaxel in progressing docetaxel treated patients. The take-home message here is that chemotherapy with cabazitaxel may be a good choice if you don’t fit the PARP profile above, and studies have shown that cabazitaxel is preferred in terms of side effects compared to docetaxel.

Finally, I will comment on the VISION trial. PSMA stands for prostate specific membrane antigen and it is expressed on prostate cancer cells. It can be used to direct pet-scanning agents to metastatic cancer deposits and these scans are currently the most sensitive ones we have for detecting prostate cancer. These scans are available at several centers in the U.S. and are now routinely used in Europe. By linking a more radioactive isotope, Lu177 to the PSMA, you can also treat prostate cancer and early results in patients with progressive hormone refractory disease have been encouraging with more than half of patients responding. The VISION trial compares this approach with cabazitaxel to see which might be the best, but in the long run, it may be possible to use both agents, and potentially to use them even earlier before resistant disease has developed.

We have entered an era when there are numerous promising options for treatment, and the key is to get as many men  as possible to participate so we can finish the trials and get these new agents approved. We also have drugs like cabazitaxel that have been approved for some time and a better idea of when to use them. Working with a team that has the expertise to guide a patient and offer the right choices at the right time is essential for the best outcomes.

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Tools for planning ahead


I am currently at the ASCO GU 2020 meeting (abstracts here ) with lots of great information being presented. (Actually drowning in great info, but that is an aging thing…). I promise to post something in the next week or so from the notes I’m taking.

Meanwhile, before I forget it (yes, another aging issue), I wanted to make available to subscribers a remarkable website that I recommend for planning. If you follow this blog, you may remember I was surprised and concerned regarding data that showed an increase in Alzheimer’s and dementia from ADT therapy. The most surprising issue was that among 74 year old men with prostate cancer diagnosis and NO ADT, the incidence of Alzheimer’s was 9% at 10 years and rose to 13% if they had been treated with ADT.

So here’s the thing. There is something you can do about planning in advance. Compassion and Choices has put together a great tool that takes you through a number of scenarios and lets you decide what you would want done in advance of you becoming impaired. I strongly recommend you take a look and consider this important issue:

Click here.

There are other tools you may also find useful, but I think we all owe it to our families to go through the dementia tool given the challenges we seem to face as we age. Best wishes for a Happy Valentine’s Day with your loved ones.

 

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Dear Abby, my PSA…


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If you are a reader of this blog, it is likely that you or a close friend/relative has dealt with or are dealing with prostate cancer. Hence, you have become the “expert” in your family or book club or similar for people who know your story. One of the most frequent questions I encounter in such circumstances is a question about someone’s recent PSA. As an example, an 86 year old otherwise healthy cardiologist recently called me asking what to do about his  PSA that had gone from 4-ish to 6-ish during the last 2 years.

There are a few generalizations that seem to apply to most of these queries. First, the PSA increases at a fairly predictable rate with age. As a crude rule of thumb, I tell patients/friends that it should be less than 2 when you are 50, less than 3 when you are 60, and less than 4 when you are 70. A recent article in JAMA illustrates this point nicely. In the PLCO cancer screening trial, 10,968 men aged 55-60 had a baseline PSA drawn and were then followed with various screening strategies for prostate, colon, or lung cancer. Among the men with baseline PSA of <0.99, the incidence of developing clinically significant prostate cancer in the next 13 years was only 1.5%, whereas if their baseline PSA was 2-2.99, the chances increased to 10.6%. The authors concluded that ” These findings suggest that repeated screening can be less frequent among men aged 55 to 60 years with a low baseline PSA level (ie, <2.00 ng/mL) and possibly discontinued among those with baseline PSA levels of less than 1.00 ng/mL.” What to do for my octogenarian cardiologist friend is more complicated, of course.

A second generalization is that if someone has chosen to follow his PSA more closely, say on an annual basis, because they have read enough about screening to feel that regardless of the controversy, they wish to do so, they should plot their data. A column of numbers is much harder to interpret than a visual graph. There is an easy way to do this by entering the data on a website like this one: Doubling-Time.  It is also important to realize that different labs may give slightly different values on the same patient – particularly challenging if one is trying to torture the data in the lowest ranges of detectability (<0.2).

Thirdly, and related to the plotting approach, for any given patient with known metastatic prostate cancer, the absolute value of PSA may be less important than the rate of change (doubling time). A rising PSA that goes from 3 to 6 in 6 months is of greater concern than someone with a PSA going from 150 to 160. Of course having a lower value generally means a lower cancer burden, but I once had a patient enjoy elk hunting during the later stages of his disease with a PSA over 2000. He had relatively few symptoms in spite of his advanced disease.

Lastly, and related to my aging cardiologist friend, there’s a lot more to know than the PSA in most cases. When I asked him what his urinary habits were (unchanged) and what his rectal exam revealed (he hadn’t had one), I suggested he should visit a urologist for a more complete picture. If you biopsied his prostate, there is probably >50% chance of finding cancer at his age, but the key question is whether it would be a “clinically significant” cancer (Gleason score >3+3=6, or multiple cores positive etc.) In addition, one now has the opportunity to do pre-biopsy tests such as Select MDx, PHI, or ExoDx with newer tests being developed all the time to try and NOT find patients with low risk disease who might never need any sort of treatment.

So, at your next cocktail party when a friend asks about PSA, you can gently explain the complexities you are all too familiar with, and hopefully guide them in the right direction. And if you are interested in more blogs, I recently discovered Snuffy Myers’ blog site, Prostapedia, that has numerous blogs from highly respected prostate experts with great ongoing updates. Happy New Year and most importantly EXERCISE!

 

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