Category Archives: General Prostate Cancer Issues

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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.

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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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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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Thanksgiving for an oncologist


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First, I want to thank those readers who generously helped me reach my goal of fundraising for the annual Movember effort to increase awareness and support research into prostate cancer and men’s health. If you are so inclined and want to make a last minute contribution, you may do so here: https://mobro.co/michaelglode?mc=1 My itchy, scraggly moustache is destined to come off tomorrow!

Second, it has been an incredible journey since my internship to watch the evolution of our understanding of cancer. In 1972, when my mother called to tell me (a young medical intern) she “had a little lump in her breast” – it turned out to be not-so-little, and she fought the disease for another 4 years before succumbing – we had little we could do other than surgery and in some cases radiation. Even adjuvant chemotherapy (the CMF treatment) had not been published yet. During the next decade, remarkable strides were made in finding new drugs, most notably cisplatin, that allowed cures of previously lethal diseases – especially testis cancer.

Then, while on sabbatical in Helsinki in 1986, I found an article to present at our journal club that I thought would revolutionize medicine. The PCR reaction opened the door to rapid DNA sequencing. When I returned to my lab in Denver, my PhD colleague, Ian Maxwell had already started to use the technique with his own jury-rigged thermal cycler, but it would be 3 or 4 more years until a medical student in his/her 3rd year clinical rotation would be able to tell me what PCR stood for. Recognizing there would be a generation of physicians who “missed out” on what would be the revolution, I was able to help start a catch-up course in Aspen, Molecular Biology in Clinical Oncology, that is still ongoing. As a “fly on the wall” I was able to listen to the world leaders in molecular oncology (including this year’s Nobel Prize winner, Bill Kaelin) describe their research that unlocked the mysteries of how cancer works. Fly-fishing with some of them on the Frying Pan was a bonus to be cherished!

As the cancer story unfolded, I was able to participate in many clinical trials, bringing new treatments that emerged to my patients. Thanks to the brilliant writing of Siddhartha Mukherjee, author of “The Emperor of all Maladies“, it became possible for my patients to begin to understand the nagging question, “how did this happen to me?” And now, this week, a brilliant article summarizing all we know about the genes and mutations that cause cancer has appeared in the New England Journal. I invite you to read that (it’s free online) if you want to join me in peering over the horizon to the future of cancer medicine. It is both overwhelming and humbling.

The privilege of living through the last half of the 20th century and into the 21st is one of the most amazing journeys one could ask of a human lifetime. As I ponder it, looking out on the snow I will get to ski on next week and enjoying my grandchildren and family, I am truly thankful to have been here. Happy Thanksgiving to all!

 

 

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Immuno-Fighting Cancer Like Wildfires


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I live in what is now known as the urban wildland interface west of Denver, the kind of area prone to the devastating fires that have been scorching California. Our firewise community efforts have taught us a lot about how a single windblown ember from miles away can destroy your house, and many of us have done a lot of mitigation. But, if the “big one” comes, our best hope is to grab the family albums and head down the hill.

Cancer can be very similar. If someone walks in with widespread disease, unless it is one of the highly treatable ones like testis cancer, flying over the patient with flame retardant (chemotherapy) may delay things for a while, but often the home is lost. The earliest realization of how to do better may have come from breast cancer. William Halstead realized in 1894 that putting out the fire effectively might include getting the surrounding “embers” (lymph nodes) at the time of removing the primary breast tumor (campfire in this analogy). A century later, it had become clear that in many instances the embers had spread too far for more radical surgical approaches, but that in some cases the embers could be extinguished (adjuvant chemotherapy) before the fire got out of control.

But what if the fire could be self-extinguishing? What if there was a boy scout at the campfire with a fire extinguisher? Better yet, what if you had smoke jumpers who could parachute in and help the boy by putting out the small fires elsewhere started by the embers? Immunotherapy offers just such hope. In the 1980’s we learned that giving high dose IL-2 to some patients with particularly sensitive tumors (kidney, melanoma) could produce cures in some cases. I liken this to sending in a group of non-specialist firemen/women in huge numbers to fight the forest fire doing the best they can.

Sending these individuals to more specialized training resulted in Provenge (sipuleucel-T), the first “vaccine” approved for treating any cancer, prostate being the target, and I was fortunate to participate in some of the first trials of this approach. But what was needed was both more effective equipment (in this case the PD-1 inhibitors that can “extinguish” the cancer’s ability to turn off the immune response) and more highly trained firefighters (potentially think of CAR-T cells) who have advanced skills, graduate degrees from a university, and can be deployed to go in search of the embers.

Now to torture this analogy just a bit further, let’s imagine that rather than sending the firefighters to universities for advanced generalized training, we could send them to CIA camps where they would receive the most specialized training possible right at the site where the fire started. In cancer, this may be the idea of using cryotherapy or irreversible electroporation to kill the local tumor, then injecting some cocktail of immune stimulatory molecules that enhance the body’s ability to create very effective T-cells that can go out as smoke jumpers looking for the embers (metastases), without the need for the university training outside the body (Sip-T or CAR-T).

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Already there are clinical trials underway with this technique that show promise. Gary Onik has demonstrated some remarkable responses in metastatic prostate cancer patients. Diwakar Davar just presented similarly exciting data in high risk melanoma patients who received intratumoral CMP-001 and systemic nivolumab before resection of the primary tumors. 62% of the patients had no tumor left in their surgical specimens! So  the cancer/firefighters are out there and although there will always be wildfires we simply can’t extinguish, the prospects for controlling them before or soon after they have spread have never looked better.

 

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Movember has arrived!


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In an era where every single topic seems to divide along political lines, I am so happy and proud to be able to support Movember – no politics, just good vibes. So far as I know, it is the single best organization bringing attention to prostate cancer and supporting research worldwide, much like Koman has done for breast cancer. I hope you will agree, sign up to grow a mustache and challenge your friends to donate!

If you don’t want to do that, I invite you to donate to my goal, and THANK YOU for your consideration.

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[How to] Choose Your Own Adventure


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Back when Al Gore and I invented the internet (just kidding…but it does seem like a long time ago – before twitter, instagram, and all the rest), I had the privilege of helping my professional society create its first website, ASCO Online. As part of that effort, I wrote an introductory article to assist my colleagues in understanding what I felt lay in the future. In addition to trying to explain how browsers and the internet worked (as an amateur early adopter), I stated, “Oncologists will increasingly act as information guides rather than information resources for patients and their families with cancer.”

Herein, I will attempt to make that easier for you if you have a personal interest in prostate cancer. There are now more than 103 million “hits” in a google search for “prostate cancer”. Therefore, first understand your condition. If you are thinking about screening, put that in your search term, or read this article I selected for you.

Next, be familiar with the myriad of terms that have evolved to describe different situations (“states”, “stages”, “conditions” etc.) to describe the disease. “Localized” means you have prostate cancer that is felt to be (or even proven to be after surgery) confined to the prostate. If localized, is it high risk, intermediate risk, or low risk? Your physician should be able to help you understand this based on the Gleason score, pathology findings, and PSA, but there are now multiple molecular tests that can be done to help further characterize what has been found. There is an excellent article to help you understand these here. If you haven’t had surgery or radiation, and are just deciding what to do, some of these tests can be done on your biopsy. I once wrote a blog about the challenging decision of choosing a method of primary treatment that is still relevant here.

However to be really up to date, you may wish to look at the research going on for any of the more advanced prostate cancer conditions. For this, you should become familiar with and use the NIH website, Clinicaltrials.gov. To help you with this, I have done some preliminary searches for different conditions, but recognize that the terms you enter change what you see, so regard this as just a start. Pick your condition, and click on it and you will find some trials that are ongoing (I preselected “recruiting”) for some common situations. If you don’t see your situation, play with the search terms yourself.

High risk after surgery based on pathology
Rising PSA (biochemical failure) after surgery or radiation
Known metastatic disease (spread to bones or nodes on scans) never previously treated
Rising PSA or new metastases on scans while on hormone therapy

Now, taking the last example which gave links to 160 studies, you can narrow the search results by using the pull down menu on the search screen, starting with country. Note that limiting to the U.S. drops the available trials from 160 to 93. Adding the state, Colorado, drops it to 14 studies, etc. Maybe you have a relative in a certain city or state you could visit if a trial fits your situation. If you would like to look only at immunotherapy trials, try entering the term, “immunotherapy”.

Next, let’s go further into one trial. Let’s say we are interested in the NIH immunotherapy trial being conducted at the NCI. If you scroll down, you can see what will be involved:

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Next, since the devil is in the details, you need to know if you are eligible for this trial. Continue to scroll down to the Eligibility Criteria section. Here you find what clinical conditions you MUST have (Inclusion Criteria) or MUST NOT have (Exclusion Criteria).

At this point, you should understand how it would be almost impossible for your physician to stay up on all of the trials. YOU are now the “information guide” and if you are interested in whether a certain trial (or even an approach you have found that might be something you could do outside of a trial) could be useful in your case, you should make an appointment to speak with your doctor about the trial/approach. Recognize that this will probably take more time than your “usual visit” and notify the clinic you will want extra time to discuss this. Print out the relative parts of the trial so you can show it to her/him, and ideally have your meeting in an exam room with an internet-connected computer so you can search through details together. If there are questions, each trial has the phone number for a contact person (typically a research nurse), and since your physician may be able to answer questions you would have trouble finding in your record, this phone call is best made together from the exam room.

In our fast-moving, internet-enabled era of medicine, this is how I think medicine should be practiced. The shared burden of “keeping up” means the patient has to do his (no women have prostate cancer) or her (if you are a supportive spouse or similar) own research, help the doctor, and work on approaches as a team. Being respectful of the time involved is critical, but it CAN work. And it is much more rewarding than keeping up with tweet storms!! And if this is “not for you”, find a grandchild and choose some different adventures here. (disclaimer: I have never done this, but looks like it could be fun)

 

 

 

 

 

 

 

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