Tag Archives: prostate cancer

Lu-177-PSMA-617 and “what’s next?”


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The presentation that received the most attention from readers of this blog and the press at this year’s ASCO meeting was the one about Lu-177-PSMA-617 for patients with advanced, metastatic castrate resistant prostate cancer (mCRPC). I have previously posted about PSMA and this approach to treatment as you may want to review here. Briefly, Prostate Specific Membrane Antigen, is a protein expressed on the surface of prostate cancer cells. There are molecules (ligands) that bind to this protein and can be tagged with radioactive isotopes. Thus, the tagged ligand, once injected, carries the isotope to the tumor cells. If the isotope is a positron emitter, a CT-PET scanner (Positron Emission Tomography) will light up the tumor’s location. Examples include Ga-68 and F-18. If the isotope releases stronger radiation, (for example Lu-177 releases strong beta particles that can kill cancer cells, just as the approved agent, Radium 223 -aka Xofigo™ -is a bone seeking agent that seeks out bone metastases and kills cancer cells by releasing strong alpha particles) then prostate cancer cells expressing PSMA will be killed.

The data presented at ASCO 2021 on Lu-177-PSMA-617 was from a large phase III trial comparing Lu-177-PSMA-617 with “standard of care” in patients who had progressed on most other therapies. The results are shown in the following figure:

Slide from presentation on Cancer.net, 6/16/2021.

These data will be evaluated by the FDA and it seems likely this new therapy will be approved. The answer to the question of “what’s next?” for a new drug is usually to study its use in earlier stages of disease. What if patients who have metastases but have not yet been treated with hormonal manipulation were to receive the drug at the same time they start hormonal treatment? What if used before prostatectomy? There are 9 such ongoing trials you can read about here. The hope is, that by using the drug earlier, even more benefit will result, and this is often the case in cancer medicine – for example using early “adjuvant” chemotherapy in high risk breast cancer, or using apalutamide (Erleda™) at the outset when initiating prostate cancer ADT in high risk patients.

As we progress in our understanding of when and in whom to use more aggressive therapies, it will also be helpful to identify the patients at greatest risk for failing one treatment or another. In an article appearing this month in Annals of Oncology, investigators evaluated tumor DNA levels after a single cycle of abiraterone (Zytiga™) and found that patients who didn’t have circulating tumor DNA at the start or converted from positive to negative had significantly better overall survival than patients who did not convert to negative. This means that as soon as 30 days after starting abiraterone, you could already pick out patients in whom you might want to change therapy or add other agents to treatment. They also showed that patients with alterations in specific genes like TP53, RB1 or PTEN either at pretreatment or after one cycle had significantly shorter overall survival. This kind of individualizing risk analysis will further enhance the ability to introduce new drugs like Lu-177-PSMA-617 earlier in patients who need it and avoid toxicities in those who don’t.

For those who helped support my mustache during Movember, these findings are tangible evidence of real progress we can all be proud of. You can share in the great feelings and read about your accomplishment here: https://au.movember.com/story/new-treatment-for-men-with-advanced-prostate-cancer-more-effective-than-chemotherapy?tag=prostate-cancer. Our donations DO make a difference and thanks for your help!

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Return to Estrogen?


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Remarkably, estrogen was discovered to be a cancer driver for breast cancer by surgeons in the late 1800’s but it was 5 decades before the relationship of hormones to prostate cancer was discovered. George Beatson had considered performing oophorectomy for women with breast cancer because the procedure was successful in prolonging lactation in cattle. His first patient experienced a complete remission from soft tissue breast ca metastases and lived another 4 years. He later said that he thought this treatment would induce “fatty degeneration” of malignant cells.

The relationship of testosterone as a driver of prostate cancer is credited to Huggins and Hodges, who found that either surgical castration or administration of estrogen to men with prostate cancer could reduce what was then the only known marker of prostate cancer, acid phosphatase. Additionally, if they administered testosterone to these patients, the acid phosphatase would increase. This built on observations that the enzyme was present in the prostate gland and would go up in patients as they developed metastases, usually in the bones. For this work, Huggins was awarded the Nobel prize in 1966. The use of surgical castration or estrogen administration remained the mainstay of treating metastatic prostate cancer until the introduction of leuprolide in the early 1980’s. I had the extraordinary opportunity to participate in those trials, which we published in 1984. We compared leuprolide to DES, an oral form of estrogen that works on the same endocrine axis as leuprolide, causing the pituitary gland signaling hormone, LH to drop, and subsequently the testicles stop making testosterone. Leuprolide worked as well as DES, but oral estrogen is dangerous – leading to blood clots and increased risk for heart attacks or strokes. Thus, leuprolide (and other GnRH analogs…including the recently approved oral GnRH antagonist, relugolix) became the standard for ADT therapy of prostate cancer.

But estrogen still works. In fact, it may have some significant advantages over surgical castration or GnRH therapy. Our team found that DES could still produce meaningful responses in patients with rising PSA’s who had failed GnRH even though we did see blood clots. But, you can also give estrogen via transdermal patches which avoids many of the problems of oral DES. This week, the PATCH trial program in the UK reported the safety results of using estradiol patches (E) to treat prostate cancer patients compared to GnRH agonists. The ability to produce therapeutic (castrate level) testosterone was the same, but the E treated patients had lower cholesterols, lower blood pressure, less diabetic tendencies, and far fewer hot flushes. Previous study analyses have shown that E is better for bone health with no calcium loss. The only thing that was worse was breast enlargement (gynecomastia) which was seen in 86% of E patients compared to 38% in the GnRH agonist patients. To some extent, gynecomastia can be treated by radiating the breast tissue. The efficacy of E in treating the prostate cancer in these patients will be reported in 2023 and 2024. The cost of E treatment (4x .025mg/24h patches every 3.5 days) is about $62/week ($750/3 months) which is definitely less than any of the GnRH agonists or antagonists. It will be terrific if this “old fashioned” treatment can again join the treatment options for men with advanced prostate cancer. I think it would also be reasonable to try in patients who are failing the newer second generation agents before trying the more expensive/complicated/toxic alternatives like taxane chemotherapy or radionuclide agents (Radium 223, Lu177-PSMA, etc.) With PSA monitoring, it should be relatively easy to find patients who benefit from such treatment.

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Epigenetics


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One of our faithful readers suggested this topic. My first introduction to the concept of epigenetics may have been in a lecture that the late Don Coffey gave at a course I helped organize at the Given Institute in Aspen which still goes on today. Don was a pied piper to hundreds of students at all levels at Johns Hopkins, and on his first visit to the course told them about arriving late at the Denver airport, driving his rental car too fast over Vail pass, then exiting and hiding under a bridge while a State Patrol car zoomed over him, and getting back on the road to make it to Aspen just in time. Not a bad way to endear yourself to some younger physicians in training!

His signature illustrative story was that of the fertilized hen’s egg. There it sits, with all the information needed to make a full chicken encoded in the DNA, but nothing happens until it is put in an incubator and the temperature rises. Only then does the machinery kick in to go from a single cell to billions of cells with everything from feathers to an intestinal tract. “How does that happen?”, he would ask, and then proceed to talk about how the DNA is wrapped around histones as shown in the following illustration:

Dr. Coffey would then show pictures of DNA in prostate cancer cells, some of which was compactly wound around the histone proteins (and therefore inactive) and some of which was “open for business” with long loops of DNA strands sticking out from a chromosome. I love the simplicity of this illustration, because it demonstrates how not only temperature can influence the long string of base pairs that otherwise are the deceptively simple ATCGTCCATA… code, but also begins to explain how environmental factors, drugs, aging, and diet can change gene expression. My hiking friend, who is somewhat of a eugenics devotee, thinks mankind will evolve to [his view of] perfection by using CRISPR to modify just the DNA sequence and change everything from physiognomy to behavior. I, of course, disagree based on epigenetics. A woman in her first trimester who eats too much broccoli one evening might well affect her child’s math score by 1/10 of a point…

But back to prostate cancer! As shown in the above figure, one of the common ways genes and their expression is modified is through methylation. The chemistry is shown in this figure and a complete article on DNA methylation from Wikipedia is here.

This image shows a DNA molecule that is methylated on both strands on the center cytosine. DNA methylation plays an important role for epigenetic gene regulation in development and cancer. [Details: The picture shows the crystal structure of a short DNA helix with sequence “accgcCGgcgcc”, which is methylated on both strands at the center cytosine. 

These methylation changes are frequently found in what are known as CpG islands, or areas of the genome that are rich in Cytosine Guanine base pairs, and particularly in the so called “promoter regions” upstream from the gene itself that control whether the gene is “active” or not. In prostate cancer, methylation of an enzyme called GSTP1 was one of the first methylation markers that became useful in detecting prostate cancer. If a man with a highly suspicious rise in PSA was biopsied and there was no cancer found, if the biopsy of the “normal” tissue next to true cancer was analyzed and methylation of GSTP1 was found, it was highly predictive that real cancer was present but just missed. As time went on, many other genes with hypermethylation changes were found, and panels of such genes could be used to detect prostate cancer cells in the urine, potentially replacing invasive biopsies. More recently, utilizing advanced techniques to search for methylation patterns in the whole genome, it has been possible to find markers (probes) for genes (see this article) which are differentially methylated in prostate cancer and have dramatic prognostic significance. Here is one such example showing that depending on which form (allele) of a gene called ATP2A3 (that can be methylated or not) you inherit, it can affect your survival.

The homozygous alternative genotype of a haplotype on chromosome 17, associated with methylation of ATP2A3, gives a survival advantage. HR and P values are from the CoxPH model.

Although much of the article from which I copied that figure is way (WAY) over my head, the point of understanding epigenetics is that prostate cancer is much more complicated than just a mutation or two in some cancer causing genes. The expression of a myriad of other genes that can be controlled by methylation or other epigenetic processes can play a major role in what happens to us. As it turns out, this week’s NEJM has an article specifically related to the epigenetics of prostate cancer as it evolves from localized to metastatic. Here is the key illustrative figure and accompanying explanation.

Figure 2. Epigenetic Regression with Clinical Progression of Prostate Cancer. Pomerantz and colleagues4 describe epigenomic patterns that occur in the transitions from the normal human prostate gland to organ-confined prostate cancer to metastatic castration-resistant prostate cancer, with their findings regarding metastasis relying largely on patient-derived tumor xenograft models. Sites of androgen-receptor binding in the genome have been associated with this transition from normal prostate gland to metastatic disease. Such binding sites are “premarked” by the transcription factors HOXB13 and FOXA1. Also, the researchers found that sites that are specific to metastatic castration-resistant prostate cancer correspond with sites in the open chromatin state in the normal prostate gland and in organ-confined prostate cancer, which indicates a lower barrier to reprogramming to a metastatic state. The epigenome (H3K27 acetylation) pattern in prostate cancer metastasis was similar to that in fetal (but not adult) prostate cells. A limitation of the study is that it does not include an analysis of circulating tumor cells or metastatic castration-sensitive prostate cancers.

As this story unfolds, “precision medicine” will become a way to individualize prostate cancer treatment. However… the heterogeneity of prostate cancer metastases will remain a major challenge in the practical application of such knowledge. Meanwhile, if you haven’t already supported prostate cancer research through my Movember effort, feel free to wander over to my website and make a contribution – and THANKS to all of you who helped me reach my goal!

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Yay – Voting is over and it’s Movember y’all


Every year, in honor of the guys I care for and the progress Movember has made in supporting research for prostate cancer, I join in the effort to raise funds from my faithful readers. This year is no exception. 2020 has been such a downer, we all need to do something positive to make ourselves feel better. So, if you can spare some change, I humbly ask you to support my annual scraggly moustache, and I can assure you the funds are well spent. For example, new tests are coming out of labs Movember supports. They constantly update the priorities as you can see in this article, and support ongoing clinical trials like this one. And for men isolated in our COVID times, there is the kind of support you need when facing tough questions at “Men Like Me“. In short, I hope you will help me with a donation to my Movember effort by clicking here:

Mike’s Movember Website

  • Then click the DONATE BAR under my picture: (not the one at top right)

For donors of >$50, I have ordered some Movember Moustache masks and will send you one. And for all participants, let’s plan on a zoom celebration in December – maybe I can answer questions sent in on chat or similar. If you are more savvy than me, scan the following image on your smart phone to be taken to my Movember webpage. And THANKS for your consideration and help!!!

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Nex Gen Diagnostics and Treatment


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When I was a fellow in Dr. David Livingston’s lab 40+ years ago, DNA sequencing had just become “widely” available, developed by Maxam and Gilbert. There was a brilliant MIT student, 16 years old as I recall, who visited the lab that summer and brought his TI calculator to the lab, assigning a number (1,2,3,4) to each of the bases and would go into David’s office with a string of numbers to look at. The evolution of that technology to what goes on today when you send in a saliva sample to 23 and Me is shown in the following video:

This video explains next generation DNA sequencing

With what seems (to an old guy like me) shocking speed, the human genome was unraveled and with it, all (most?) of the genes that control cellular processes including cancer. As I have recommended before in this blog, for a fabulous review of the story, I recommend you read “The Emperor of All Maladies” by Siddhartha Mukherjee.

Due to the power of DNA sequencing it is now possible to obtain DNA that originates in tumors and do sequencing of cancer causing genes directly from the blood stream or from the urine or other body fluids. This is a so-called “liquid biopsy“.

The entry of this technology into caring for cancer patients has also been incredibly rapid. At the present time, for prostate cancer, the NCCN patient guidelines are a great place to start learning about pca in general if you are new to the topic, but the physician NCCN guidelines are much more specific regarding what you need to know about your genetics. Here are the recommendations for “germline” testing, i.e. what you have inherited that may have pre-disposed you to develop prostate cancer and what might affect other members of your family including children or siblings:

The guidelines are also very informative about this testing being done with the help of professional genetic counsellors:

Genetic testing in the absence of family history or clinical features (eg, high- or very-high-risk prostate cancer) may be of low yield.
• The prevalence of inherited (germline) DNA repair gene mutations in men with metastatic prostate cancer, unselected for family history (n = 692), was found to be 11.8% (BRCA2 5.3%, ATM 1.6%, CHEK2 1.9%, BRCA1 0.9%, RAD51D 0.4%, and PALB2 0.4%). The prevalence was 6% in the localized high-risk population in the TCGA cohort (Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011-1025; Pritchard CC,Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443- 453).

• Genetic counseling resources and support is critical and pre-test counseling is preferred when feasible, especially if family history is positive.

• Post-test genetic counseling is recommended if a germline mutation (pathogenic variant) is identified. Cascade testing for relatives is critical to inform the risk for familial cancers in male and female relatives.

https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

However, as noted above, we can also sequence the tumor itself or look for mutations in tumor DNA that is circulating. The most important thing that may show up in these analyses is a mutation that can be specifically targeted with one of the newer drugs. Examples include the finding of a DNA repair gene mutation such as BRCA1 or BRCA2 in which case the use of a category of drugs called PARP inhibitors or platinum based chemotherapy might be an important consideration for patients who have failed hormone therapy. Thus, we now utilize DNA sequencing both in patients who have family histories for certain cancers, patients with metastatic disease, high risk disease, and again when there is progression of the cancer after hormone treatment stops working. Beyond these impacts of DNA sequencing are the many gene-based tests that have evolved that can help determine risk for finding prostate cancer on a biopsy, or predicting whether someone is at high or low risk for metastatic disease after a positive biopsy and Gleason score is known.

I tried to help understand the complexities of integrating all of these new tests and therapies in this blog. Although it may be difficult to keep up with this rapidly evolving landscape for both patients and physicians, there is no doubt that we have entered the “next gen” era of prostate cancer management. Finding an expert who focuses on pca and discussing some of the issues raised in this blog is key to taking advantage of what is being learned. Hopefully this blog will help you become a better informed member of your team in terms of the underlying technology. For a more erudite discussion of cancer precision medicine, you might read this newly posted discussion.

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Why can’t we cure this???


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A frustration for patients and physicians alike is the incurability of metastatic prostate cancer in spite of the great response that many/most patients have to initial hormonal treatment. As most readers of this blog know, almost all prostate cancer cells depend on stimulation from testosterone to grow and to get outside the prostate, moving to lymph nodes or bones (the most common place for metastases in pca). Testosterone is normally made by the testes and adrenal gland, circulates in the blood stream, and enters the cancer cells where it binds to the AR (androgen receptor). The AR then translocates to the nucleus where it binds to specific locations “upstream” from various genes (including PSA, and interestingly TMPRSS2 which has implications for COVID-19) leading to the gene being “activated”. Many of the activated genes lead to cell division and invasion that characterize/lead to metastases we detect with bone, CT, or PET scans.

Normally, the way we detect that cancer cells are “turned off” or dying is by the PSA falling. PSA in general is far more sensitive than scans, but it really tells us about the “big picture”, not what is going on with individual collections of metastatic cancer cells. Measuring PSA every 3 months is a very common way to monitor the response to drugs that stop testosterone synthesis (abiraterone – Zytiga) or block testosterone from binding to the AR (bicalutamide-Casodex, enzalutamide-Xtandi, apalutamide-Erleda, darolutamide-Nubeqa)

Although much more expensive, monitoring response by repeating scans can begin to answer the question posed for the title of this blog. Why doesn’t hormone therapy lead to cures? The reason lies in a single word, heterogeneity. As I reviewed previously, when we look at different sites of cancer metastases, the tumor deposits in one area may have a very different genetic mutation profile than those in a different area. I was very struck by how well this is illustrated in a recent article using quantitative PET scans. In patients treated with enzalutamide, the different sensitivity is graphic as shown in this figure from the article:

Compare PET1 taken at the start of treatment with enzalutamide to PET3 when disease was progressing indicated by a rising PSA. Green spots indicate partial or complete response to the antiandrogen while red ones are new or progressive locations. This is a graphic example of the result of tumors having genetic changes that make them more or less sensitive to the drug. Finding a combination of chemotherapy or hormone therapy that can attack all of the genetically different deposits is impossible at this time. However, the immune system may be able to keep up with all the changes in some patients, and this provides hope for the expanding trials of immunotherapy in prostate cancer you can find here. Glass half full or half empty? You choose!

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Prostate Theranostics


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Sometimes a great new word evokes curiosity, so I have used it to title this post and see if a few of you thought it would be worth looking at rather than sending to your “junk” email. You can’t find it in the dictionary, interestingly enough, but it’s related in derivation to Theranos, the bizarre company started by Elizabeth Holmes and if you haven’t read “Bad Blood” or seen the video you can find that story here:

For us prostate cancer followers, however, theranostics represent a “new” field in which the same/similar drugs can potentially be used for both diagnosis and therapy. There is a nice review of an ASCO educational presentation on the topic here. The main idea is that a radioisotope can be specifically directed to a target for either diagnosis or therapy. One of the oldest examples of this is radioiodine which is taken up by the thyroid gland. If you have thyroid cancer, the metastases will also take up the radioactive iodine and with nuclear medicine detectors you can see them, or if you inject even more, it will be “hot” enough to kill them.

223Ra is an isotope that seeks bone, just like calcium, and where there is more bone turnover/remodeling, more of it accumulates. As a drug, it was given the name Xofigo, and was approved for treating prostate cancer in men with bone dominant disease in 2013. It emits alpha particles, which are known as “high Linear Energy Transfer” radiation because they go only a very short distance before interacting with cancer cells and killing them. This is important since you would not want the radiation to kill the normal bone marrow cells that live in the same neighborhood. In the study leading to approval of 223Ra, men with symptomatic bone metastases and no visceral (e.g. liver or lung) metastases who received the isotope as a monthly injection for 6 months lived 14.9 months as compared to 11.3 months for placebo (P<0.001) and had fewer skeletal events and less bone pain. I always loved alpha emitters because I had the fun of making a cloud chamber for a science fair when I was in 6th grade. You might want to help a grandchild do that!

177Lutetium (177Lu) is an isotope that allows both diagnosis and therapy because it emits gamma radiation for detection, and high energy beta radiation that can kill cancer cells. When bound to PSMA (see these posts)

177Lu becomes a theranostic that shows considerable promise for treating prostate cancer. There are a number of completed trials of 177Lu-PSMA that have been summarized in this table:

For more details on 177Lu-PSMA treatment, this is an excellent recent review from the European Society of Radiology:

https://epos.myesr.org/poster/esr/ecr2020/C-00307

There are a number of ongoing trials of 177Lu-PSMA that you can find here.

Keep wearing your masks to protect your fellow prostate cancer groupies, be patriotic, and if you want to pay homage to one of the great scientists whose research led to these advances, look no farther than Radioactive, the recent Amazon Prime movie about Marie Curie. As one of the commentators on the trailer posted, “In a world full of Kardashian’s… be Madam Curie.”

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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.

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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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Filed under General Prostate Cancer Issues, Prostate cancer therapy

(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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Filed under General Prostate Cancer Issues, Prostate cancer therapy