Tag Archives: prostate cancer

Changing States: Does a Blog Disappear?


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“Our patients lives and identities may be in our hands, yet death always wins. Even if you are perfect, the world isn’t. The secret is to know that the deck is stacked, that you will lose, that your hands or judgment will slip, and yet struggle to win for your patients. You can’t ever reach perfection, but you can believe in an asymptote toward which you are ceaselessly striving.” -Paul Kalanithi in “When Breath Becomes Air“.

This week, after considerable thought and with great ambivalence, I began saying goodbye to my patients. I have intentionally made my “retirement” a prolonged process, stretching back nearly 15 years and beginning with turning my research laboratory over to a wonderful trainee/fellow, Tom Flaig (now Vice Chancellor for Research at CU). I began to stop writing grants (for the most part), working more in the clinic on other people’s ideas, and continuing to write this blog while serving on various boards and IDMC panels (including with the two authors of that IDMC link). Eventually, I reduced my clinic time to one day/week, focusing entirely on prostate cancer and seeing patients only at our outreach site, the Shaw Cancer Center in Vail. But, as I anticipate turning 75 this summer, and as my wife has pointed out, “no one really wants an ‘over the hill’ physician” (even if that doctor is still doing well by his/her patients). It is time to leave the clinic. As Kalanithi points out, inevitably “your hands or judgment will slip”. And even if they haven’t or never do, I believe there is joy and elegance in stepping aside at the right time to provide opportunities for younger physicians to take your place and to the extent they wish, offer advice (wisdom?) if needed.

But what to do with a blog?? As an early adopter, I had great satisfaction helping ASCO develop its website, www.ASCO.org and wrote about what I envisioned as the evolution of internet oncology in this article. My colleagues and I assisted in moving much of the society’s print media online as well as hosting what I think may have been one of the first “virtual meetings” of a medical society in 1995. With the help of a contractor, we digitized 35mm slides, recorded audio, then merged them “by hand” and posted presentations on the internet (within hours of their live presentation) for viewing around the world. Shortly thereafter, I was invited to write medical blogs, and when that effort became commercialized with ads, I elected to start writing this blog “commercial free”. As the internet technology continued to evolve with the evolution of social media (twitter, instagram, tiktok, etc.) I opted out, and so this blog is all that remains of my “brief but spectacular” foray into content creation for the digital world.

The statistics on 733 subscribers to this blog suggest that relatively few visit the website, although I suspect more read the essays themselves which are sent out by the site as emails. Here are the stats for the last quarter:

The way you got this email (or link if you are reading on the wordpress site) is “push technology”. You opted in/subscribed to receive the emails. This led me to wonder what happens to an email or blog when you change pages or “delete”. We all know that they stay somewhere “forever”. I know this means bits and bytes on some server. But when I tried to think about it in Kalanithi terms to title this essay, I tried to imagine “When Pixels Become Electrons” or something similar. I failed. Here is how pixels work and this is how electrons control them. What happens to blogs is still mysterious to me, but I’m switching formats to “pull technology”: responding to queries/ideas rather than guessing what you might want.

There are now numerous online sources for prostate cancer information. If you want excellent push technology to keep you up, I recommend subscribing to “The Prostate Cancer Daily” written by and for experts in the field. If you want to look something up, like the latest clinical trials, please read this blog I previously posted.

Thus…I have decided to change states – just like the LCD crystals that change the polarization of the pixels that have turned black to provide you this text. Going forward, I will use this blog to try and help patients/families only IF they want, by responding to questions, but not by trying to guess what subjects may be of interest and creating a post. I am happy to do whatever research is necessary to explain advances and comment on the science behind them if you send a topic or question to me at prost8blog@gmail.com. I will post monthly answers here as essays on www.prost8blog.com so everyone can see them who is a subscriber. The person(s) who submit questions/ideas (if any) will remain anonymous and I will NOT provide case specific advice. I will also not send return emails from the gmail account except to indicate I have received your request/idea.

BOTTOM LINE: This will be the last post on this blog unless I receive a topic request or question at prost8blog@gmail.com. I will monitor that email site on a monthly basis and post here as needed. I have loved being a part of helping prostate cancer patients/families and wish the best to all of you who have subscribed. If the new approach works, great! And if not, I thank you (and your computer pixels) for sharing some of our lives together. Godspeed…

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Prostate cures…at any cost?


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This week brought excellent and exciting news from the ASCO GU Meeting about management of high risk prostate cancer using “triple therapy” for metastatic disease. Adding further evidence for the “kitchen sink” approach, Matt Smith from MGH presented data from the ARASENS trial. The study involved 1306 patients with metastatic prostate cancer (86% of whom presented with metastases and the remainder of whom developed mets while being followed after primary treatment). The trial evaluated whether adding the potent anti-androgen, darolutamide aka Nubeqa® (similar to enzalutamide and apalutamide) to standard ADT (e.g. orchiectomy, leuprolide, or other GnRH analog) plus docetaxel (Taxotere®) could improve survival. We already knew that 6 cycles of docetaxel added to ADT in this situation improved survival from the CHAARTED trial I wrote a blog about several years ago. This was the trial design:

The results of the trial were very positive and represent a new “standard of care” for patients with metastatic prostate cancer:

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2119115?articleTools=true

Although it is too early to say whether some of the patients in this or similar trials, such as PEACE 1, have been cured, it is clear that throwing the “kitchen sink” at prostate cancer can offer real improvement in survival. Now the questions become: Who are the patients most likely to benefit? What kind of toxicities do these patients have to put up with? How much does this kind of treatment cost? What if we added other known effective treatments like Lu-177-PSMA or PARP inhibitors to appropriately selected patients? Would adding this kind of treatment cure some patients with oligometastatic disease? And perhaps most intriguing, could we imagine applying this kind of treatment to patients with newly diagnosed, localized (but high risk …e.g. Gleason 8,9,10, or node positive) disease as part of a plan that involved prostate surgery or radiation?

The answer to all of these questions will come only from appropriately designed clinical trials. I am reminded, too, of the famous quote from one of the pioneers in prostate cancer treatment, Dr. Willit Whitmore who said, “Is cure possible? Is cure necessary? Is cure possible only when it is not necessary?” There are obvious differences between the 52 year old man who presents with high risk prostate cancer and is otherwise healthy versus a 79 year old gentleman who had prostate surgery 15 years ago, a pacemaker, and now has a rising PSA with only one or two metastases showing up on a PSMA-PET scan.

The progress in prostate cancer research has accelerated dramatically during my career. As well, the costs of oncologic care are rising at a faster rate than can be maintained, “National costs for cancer care were estimated to be $190.2 billion in 2015 and $208.9 billion in 2020 (2020 U.S. dollars), an increase of 10 percent that is only due to the aging and growth of the U.S. population… National oral prescription drug costs were highest for female breast, leukemia, lung, and prostate cancers” (See this reference) As an aging (rapidly…) man myself, I can only hope we are able to fall back on the precepts taught in Sir William Osler’s essay, “Aequanimitas“, combining the qualities of “imperturbability” and “equanimity” to achieve “”coolness and presence of mind under all circumstances”. If so, we should be able to navigate the avalanche of medical knowledge and associated costs with compassion, empathy, and wisdom. Meanwhile, hats off to the researchers and men who participated in clinical trials and brought this advance and many others you can see here to fruition.

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Molecule of the year: PSMA


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We made it around the sun another time, and in spite of Covid 19, are still here to thank you for your interest in this blog and most especially for your support of prostate cancer research via my annual efforts to grow a moustache and help Movember raise funds for prostate cancer research. A heartfelt thankyou!!

With all of the “Ten best” and “top songs” lists that appear this time of the year, I thought I would expand a bit on PSMA as a real game-changer that is coming on strong to change our management of prostate cancer. So what is Prostate Specific Membrane Antigen?? Well, first of all, I think you know what an antigen is, or if not, here’s a timely clue: Spike protein. When you received your vaccination with Moderna, Pfizer or J&J vaccine, you were exposed for the first time to a foreign protein that the SARS CoV2 virus (COVID-19 disease causing) uses for entering the cells that line your airways. Your body responded to this antigen (foreign protein) by developing antibodies – the levels (titers) of which prevented you from getting COVID, or at least prevented you from getting very sick. Antibodies are very specific proteins made by the B-cells of your immune system that bind to foreign antigens and are the first line of defense against invaders.

Now, if you inject a mouse with human prostate cells, the mouse will recognize all sorts of the proteins as “foreign” and make antibodies against them. In such an experiment, Wright and colleagues in the early 1990’s found that one such antibody could be useful in detecting prostate cancer. It turned out that the antibody was detecting a protein expressed on prostate cells, but also tumor blood vessels and the salivary gland that became known as PSMA. Unlike PSA, this protein is bound to the membrane of the cancer cells and doesn’t circulate in the blood stream. PSMA is actually an enzyme involved in the normal absorption of folate (a vitamin) from the intestine, but for unclear reasons, it is dramatically over expressed by prostate cancer cells. Over the next 25 years, numerous researchers worked on tagging radioactive isotopes to antibodies that would bind to PSMA and therefore could be used to detect prostate cancer or if the radioisotope was powerful enough, kill prostate cancer cells. One of the challenges, however, in using radio labeled antibodies is their size, resulting in a lot of non-specific “sticking” in the liver, spleen and elsewhere. A better approach evolved by finding small molecules that would stick to the PSMA enzyme activity site as illustrated in this figure:

As a result of this research, it became possible to develop highly sensitive PET scans that can detect much smaller metastases of prostate cancer than any previous bone or CT scans were able to do. Gallium and Fluorine isotopes hooked to the peptide (617) are rapidly becoming available in PET scan centers across the United States (and have been available for the past 3-5 years in Europe, Australia and elsewhere) and will likely become approved as the new standard for staging newly diagnosed and PSA recurrent metastatic prostate cancer. Moreover, the isotope Lu177, that emits strong beta radiation (electrons) can be attached to peptide 617 and kill cells that express PSMA.

In the VISION trial, published this year in NEJM, the use of Lu177 PSMA to treat advanced prostate cancer patients who had progressive disease after previous treatment with a second generation hormone agent (such as Zytiga or Xtandi) plus chemotherapy with a taxane (Taxotere or Jevtana) were scanned with Gallium labeled PSMA then treated with Lu177 PSMA. The treated men were compared to alternative “standard of care” which might have included other forms of chemotherapy for example. The results were extraordinary as shown in these curves.

So for this year, I’m nominating PSMA as the molecule of the year. PSMA PET scans will likely be the only scans needed to follow prostate cancer metastases, and are already being used in newly diagnosed patients with high risk disease to make sure we don’t miss something. Further, if there are only a few metastases, we can treat these at the same time we treat the prostate with hopes that some of the patients with metastatic disease can still be cured. And ongoing research is underway to evaluate the use of Lu177 PSMA in earlier patients without resistant disease. Great progress and I leave you with fond wishes to you and your family for a healthy (VACCINATED) 2022!

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Join me fighting prostate cancer in the “Hairiest month of the Year!”


It’s that time again. A scraggly moustache may be better than none at all, and this is the organization that has done the most, along with PCF, to make prostate cancer history. Start your own fund raiser here.

Or if you don’t want to fund raise on your own, feel free to join my campaign by visiting my Movember Website.

Movember has made a HUGE difference in prostate cancer awareness globally by sponsoring research at every level -from clinical to basic science and the creation of data bases like the GAP3 project. Many of the posts I have written this last year like the ones on PSMA PET scans and Lu177-PSMA therapy are the direct result of Movember funding. Let’s keep the progress rolling!

Thanks for your consideration,
Michael Glode

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Here’s what you should “eat” to fight prostate cancer…


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OK, I will admit right up front to bait and switch. In the last month I have seen two of my patients who are what the public health aficionados call “positive deviants“. One man is a professional who still goes to work every day. I have been seeing him for about 5 years; he has metastatic cancer in many bones and lymph nodes, a PSA in the 100’s, yet other than being a bit too thin, carries on with his life helping other people in his chosen profession. The second gentleman looks like an olympic athlete – great muscle preservation, a military posture, and also continues to work at his regular job in spite of having “mCRPC” which most readers will know as metastatic castrate resistant prostate cancer. What is it they do far more than most of my other patients? What is their secret diet? …EXERCISE

In this piece from the New York Times on heart health, Dr. Emery, a cardiologist, refers to exercise as a magic pill. “It’s just that you can’t swallow it, you have to earn it,” he notes. You need to click on that hyperlink and read the whole article. These are the benefits for heart health:

  • It enhances the cardiorespiratory system.
  • It increases HDL cholesterol.
  • It lowers triglycerides, a type of fat that circulates in the blood.     
  • It reduces blood pressure and heart rate.      
  • It lowers inflammation and improves blood sugar control.

Best of all, exercise is the type of medicine that appears to produce benefits no matter how small the dose.

But what about prostate cancer you might ask? The studies there are compelling. In a recent article from Taiwan, 125 patients who were treated with ADT and radiation for high risk prostate cancer were studied for changes in body composition. The patients experienced a 5.5% loss in skeletal muscle over 180 days, and each 1% loss of the skeletal muscle index resulted in a 9% increase in non-cancer mortality! Although it is a small study and it is shocking, but it illustrates the problem of taking testosterone away from older men. You don’t need to rely on small studies however. In the Health Professions Follow-Up Study, 2705 men diagnosed with prostate cancer were followed from 1990-2008. “Men with ≥ 3 hours per week of vigorous activity had a 61% lower risk of PCa death (HR, 0.39, 95% CI, 0.18 to 0.84; P = .03) compared with men with less than 1 hour per week of vigorous activity. Men exercising vigorously before and after diagnosis had the lowest risk.”

So, the message is clear. Compared to any “diet changes” you can make, or supplements you might take, exercise is definitely more important to enhance your chances of surviving prostate cancer. Ideally, you should work with a trainer who can help you develop an individualized program that takes into account your current physical fitness. From the NYT article, here is a place to start if you don’t have access to a trainer:

“Anything is better than nothing. But the ideal dose of exercise for adults, according to the Centers for Disease Control and Prevention, is as follows:  

  • 150 minutes of moderate-intensity aerobic exercise a week.      
  • 2 sessions of about 30 minutes each of resistance training a week.

You can spread the aerobic activity throughout the week however you like, such as 30 minutes five days a week, or 50 minutes three days a week. Examples include running, swimming, brisk walking, riding a bike, playing basketball or tennis, and doing yard work. As for strength-building activities, ideally, you should set aside at least two days a week for 30 minutes of exercise that works the major muscle groups, such as the legs, back, shoulders and arms. What counts as strength training? Lifting weights, using resistance bands, doing bodyweight exercises like yoga, push ups and sit ups, and even heavy gardening with a lot of digging and shoveling. Vigorous exercise should get your heart rate up to 70 to 85 percent of your maximum heart rate. Not sure what that is? Here’s how to calculate it.” I also recommend your resistance training should utilize weights that cause your muscle group to “fail” on the second or third set of repetitions.

So there you have it – how to change your “diet” to beat prostate cancer. Definitely not as easy as just avoiding red meat and increasing soy products, but almost certainly the most effective thing you can do. Movember is coming up. Time to MOVE!

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The Future of [Prostate] Cancer Screening


As I’m sure most of you know, this has been a controversial topic for more than 2 decades. The problem is fairly simple: Screening can pick up earlier disease, save some lives, but treatment has side effects for virtually 100% of men who get treated, and “active surveillance” is not a picnic with repeat biopsies every 2-3 years. We may have to treat as many as ten men to save one life. On the other hand, if they live long enough, more than half of men probably develop prostate cancer, usually of the low grade (Gleason 6 or less) type that will never bother them. Here is a nice article that shows how autopsy series over time have found prostate cancer in up to half of men, dependent on age, race, etc. but notably pointing out how seldom autopsies are now performed compared to earlier eras. The reality is that we have no idea these days how many 90 year old men would have a small cancer if we really looked hard for it. What we understand is that they didn’t need to know they had a prostate cancer if they were never treated and died from something else.

Now, add to these challenges the revolution in cancer detection provided by molecular testing. This field is moving so fast that the “old idea” of PSA screening is becoming passé. For example, Illumina, the company that makes automated next generation sequencing machines spun off a startup, GRAIL that developed a “pan-cancer” test that looks for fragments of DNA circulating in the blood, the fingerprints for most of the common cancers. This test, called “Galleri” is undergoing real world testing in the UK, but is not covered or approved in the U.S. Proponents (some of whom are consultants for biotech companies) suggest that it could save “millions of lives”. The test, because we live in a free, capitalistic society is already marketed on the internet for an out-of-pocket price of only $949 with payment plans available. But…and the prostate cancer community knows this perhaps better than any other…the challenge of knowing whom to test, when to test, and what to do with a positive test may take decades to figure out. Here’s an article covering some of those promises and challenges (false positives, lead time bias, costs for treatment, etc.)

But for prostate cancer, the same DNA technology is making real progress. What we want are tests that not only tell us who has prostate cancer, but who has the kind of cancer that NEEDS to be treated or followed closely, and lowers the detection of clinically insignificant cancers. An example of this kind of testing sophistication appeared in NEJM this month from a group in Stockholm. This group has developed a test called Stockholm3 that is “a risk-prediction model that is based on clinical variables (age, first-degree family history of prostate cancer, and previous biopsy), blood biomarkers (total PSA, free PSA, ratio of free PSA to total PSA, human kallikrein 2, macrophage inhibitory cytokine-1, and MSMB), and a polygenic risk score (a genetic score based on 254 single-nucleotide polymorphisms [SNPs] and an explicit variable for the HOXB13 SNP) for predicting the risk of prostate cancer with a Gleason score of 7 or higher.” They then took men at risk of having prostate cancer (PSA>3 and Stockholm3 >11%) and either did “blind” 12 core biopsies or did an MRI first and included targeted biopsies of high risk lesions only if seen on the MRI.

Outcome for Stockholm3 high risk screened men with PSA > 3 who did or did not have MRI targeted biopsy in addition or instead of standard biopsy.

Note that the number of biopsies needed went down, as did the number of benign or clinically insignificant cancers. This is the sort of effort that will eventually reduce the number of men having unnecessary biopsies or treatment by combining all of the great new molecular and radiology technologies (dynamic contrast enhanced MRI’s). We now routinely use some of the molecular tests to help us in screening and deciding about treatments as I reviewed in this blog.

While we are still a long way from applying this kind of technology to “every man over 50”, the future for the next generation (our sons and grandsons) will be much better – fewer unnecessary biopsies and treatments. Hopefully this type of approach can be applied to the pan-cancer type of “Galleri” screening being proposed, and make such testing cost effective as well. Congratulations to the prostate cancer researchers and their patients for leading the way!

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Cancer Camp and Survivorship


A cancer diagnosis affects every patient in a different way. However, regardless of what type of cancer is involved, it is a cold water “slap in the face” that we all share the same fate: “our days are numbered” – something everyone knows but we generally find it more convenient to simply not think about.

Prostate cancer, in my opinion, is somewhat different in this regard for most men. First, like all cancers, it is clearly a disease of aging, but even more so. The median age at the time of diagnosis is 66 years. This means the majority of newly diagnosed men have lived a reasonably long (and hopefully healthy) life. There has been time to deal with other health threats, watch children grow, and usually face the deaths of parents or close family members. However, the good news is that the vast majority of men will still have the opportunity for enjoying many more years of living.

Taken from the US SEER database: https://seer.cancer.gov/statfacts/html/prost.html

In fact, regardless of race or ethnicity, over 90% of men newly diagnosed with prostate cancer will be alive in 10 years. These data hold true even for men with regional disease, but fall off rapidly if metastatic disease develops. And there is continued improvement in treatment for the metastatic patients as well. In a recent article looking at three large studies for the benefit of second generation androgen receptor antagonists (enzalutamide, apalutamide, darolutamide) to delay metastases and improve survival, even men >80 years of age clearly did better than before.

From Lancet Oncology, July 23, 2021 https://doi.org/10.1016/S1470-2045(21)00334-X

So the question becomes, “what will you do with the time you have left?” regardless of how long that is. My thought, having just returned from volunteering at the Epic Experience cancer camp, is that it always good to take some time and reflect on how you want to spend that time. Write another paper? Start another company? Make even more money? Grasp for the latest treatment option? Or potentially reconsider family and friends and what really matters to you. The Epic organization has had trouble recruiting men to their camps, but for the men who have come, their perspectives have been altered in very positive ways as you will see in this video. Many more women come to the camps, just as women have led the way in advocating for breast cancer research, and in general reaching out via support groups. We have a lot to learn from them!

There are many support groups out there for prostate cancer survivors of all stages. Prostate Cancer Foundation has put a nice list together here. And if you would like online support for specific issues, Movember’s True North initiative has great articles to help you here.

The bottom line for me, having had a chance to “get back to camp”, is that we can all use a little encouragement to get out there and live again as we come out of our COVID isolation. I hope you will do just that this summer!

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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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