Prostate Cancer and “the art of aging”


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As all of us septuagenarians (and probably octogenarians) know, and as Gilda Radner entitled her book, “It’s always something.” In it, she goes on to say, “I wanted a perfect ending. Now I’ve learned, the hard way, that some poems don’t rhyme, and some stories don’t have a clear beginning, middle, and end. Life is about not knowing, having to change, taking the moment and making the best of it, without knowing what’s going to happen next. Delicious Ambiguity.”

For most prostate cancer patients, the challenges presented by that diagnosis occur at a time of life when one is forced to admit that the sprained ankle doesn’t heal as fast, gray hairs are appearing, and/or your hairline is receding (or the bald patch growing), and there may indeed be as much life stretching out behind you in the rear view mirror as lies ahead. While one can choose to fight the cancer with every possible modern intervention, it is also true that there will be other challenges awaiting just around the corner, and it is impossible to handicap the inevitable threats to your health, of which prostate cancer is but one.

Recognizing this, and realizing that we spent two decades over-treating many patients, gave rise to the current option of “active surveillance” for men with low grade disease (Gleason 3+3, some 3+4). One of the most mature studies of this approach was published in the NEJM just last month. Peter Albertson, writing in F1000, nicely summarized the key findings from the article:

“First, the most powerful predictor of long-term outcome remains the Gleason score. Following surgery, men with Gleason 4+3 disease have an almost six times greater risk of dying from prostate cancer and men with Gleason 8 or 9 disease have an almost eleven times risk of dying from prostate cancer compared with men with lower grade Gleason 3+3 or 3+4 disease. Second, radical prostatectomy can provide improved outcomes, lowering the absolute risk of dying from prostate cancer by 11.7% and extending life by almost 3 years. Third, younger men less than 65 years of age at diagnosis are much more likely to benefit from surgery when compared to older men. Fourth, men with low grade cancer (Gleason 3+3 or 3+4) appear to have comparable outcomes and rarely died following surgery. The article was silent concerning the relative clinical outcomes of surgery and watchful waiting in this group of men. An important caveat to remember is that most men participating in this trial were diagnosed based upon clinical findings, not from testing for prostate-specific antigen. As suggested by data from the PROTECT trial, screen detected prostate cancer appears to introduce a lead time that could be as great as 10 years. This confounds estimates of the efficacy of surgical treatment especially among older men.”

I just submitted my own take on the active surveillance vs prostatectomy trial as follows:

“There is little to add to Dr. Albertsen’s excellent review although there are a few issues I would add as important perspectives in these kinds of long term followups. First, as a disease of aging, prostate cancer has many competitors in terms of cause of death. 261/347 (71.9%) men in the radical prostatectomy group and 292/348 (83.8%) men in the watchful waiting group have died from any cause. Of the 261 men in the prostatectomy group, 71(27.2%) died from prostate cancer while in the watchful waiting group, there were 110 deaths from prostate cancer (37.7%). From this perspective, prostate cancer is important, but far from the “most” important cause of death with ~2/3 of men dying from other causes regardless of what we do. Second, one needs to consider the quality of life (QOL), and this paper clearly indicates that many men develop metastases, requiring ADT with its side effects and this is reduced by prostatectomy, while the side effects of prostatectomy itself also take a very high toll on sexual function and a lesser, but significant risk of incontinence. If our goal is to “first do no harm”, the challenges of caring for men as they age remain with us, even as our technology for discovering earlier disease (in prostate cancer) and treating late disease (from any cause) advances.”

But there is something we can do to combat both prostate cancer and aging! Vigorous exercise. In a study performed at two hospitals in Canada and the UK, total and vigorous physical activity resulted in fewer men having worsening prostate cancer while on active surveillance. Further, retrospective studies demonstrate similar advantages even for men with metastatic disease. And if you don’t have prostate cancer, feel free to look at the 100’s of articles showing improved quality and length of life you can achieve with exercise (compared to minimal/no benefit from supplements). So the message is clear, even though “it’s always something” as we age or fight our cancers, we have it in our power to do something. Enjoy your time on the treadmill folks!!

 

 

 

 

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Ho, Ho, Hox


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Fruit flies are a fascinating scientific resource to consider if you can get beyond your annoyance when they appear in one of those lovely boxes of ripe fruit you receive from a relative this time of year. (Just be thankful it wasn’t fruitCAKE!). For some great reading on the topic, I highly recommend a book, “Time, Love, and Memory“, the story of Seymour Benzer and how his graduate students figured out how different genes are involved in these creatures’ sense of time, or how they do their mating dance or remember whether they shouldn’t put their little leg down into a beaker and get a shock.

As with their behavior, there are wonderfully complex genes that also control how they develop from a single fertilized egg into an adult fly. These are called homeobox or “Hox” genes and it turns out their analogues are conserved throughout the animal kingdom. In this nice review of their functions, the following picture shows how the gene family controls development in the anterior – posterior development of the fly AND the mouse embryo.

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Screen Shot 2018-12-15 at 3.39.27 PMWhen things go wrong in the fruit fly (Drosophila), you can get a fascinating mutation that makes the fly look like this, with legs appearing where there should be antennae. In humans, analogous mutations can result in having extra fingers or malformations. You can read in more depth about how the Hox (a subset of the master homeotic regulator) genes are regulated at the Kahn academy in this article.

OK, you say, but what could this possibly have to do with prostate cancer? Ah, that’s what I find fascinating. Cancer is a superb example of dysregulation of the genetic programs that make cells behave. By the time you get to an animal developing a prostate gland, there are countless regulatory genes that must each turn on or off at the right time in embryogenesis. And just as “ontogeny recapitulates phylogeny“, oncology recapitulates ontogeny. One of these homeobox genes, HOXB13 was discovered to be mutated in studies of families with hereditary risk for prostate cancer by Johns Hopkins investigators several years ago. This gene interacts with the androgen receptor, so it makes some sense that the prostate gland would be affected by mutations. Further studies of families with this mutation indicate that if you inherit one copy of the G48E mutation, your risk of developing prostate cancer is 2.6 fold increased.

Whereas testing for such genetic mutations (and many others) used to be the provenance  of research labs, we are entering a time in medicine when genetic testing is becoming “mandatory” for best practice care. The following criteria are now used to help discern who might benefit from such testing:

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This table comes from a company, Myriad, that is now advertising for its own cancer risk gene panel, but there are several such companies and panels of genes. Although we (I) still don’t send off a genetic panel test to Myriad, Foundation Medicine, Invitae or the other companies in all patients, we are rapidly approaching the time when that will be standard. The challenges (as outlined in this article) are which genes should be tested, and what to do with the results. Some mutations such as those involving DNA damage repair, are already recognized as useful in directing therapy. For now, it is a topic best discussed with a genetics counsellor, and I fear, even more importantly one with an interest in prostate cancer if you can find one. Most of us physicians are struggling to keep up with which panel (if any) to order and when to order it.

So just remember when you see that little fly emerge from your fruit box this season, he/she/it has made immeasurable contributions to cancer research, and be thankful for all the science that is helping us to understand our amazing world.

 

 

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We did it!!


half moustacheHey everyone, your outpouring of support for my crazy moustache was incredible. I can’t thank you enough! Not only did you help me reach my $2500 goal, you blew the top off and raised over $5K. Today I share with you readers an “exclusive” – my Half Mast Mo in memory of the guys I have cared for and all the others who died fighting prostate cancer. It’s also a tributeto the goal Movember has set for cutting deaths from prostate cancer in half by 2030. Have a great December and know your generosity is truly humbling.

 

 

 

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Buddy, can you spare a …


Sorry for the intrusion, and I promise to write another blog after December 1 (my commitment for one/month). I’m thinking about discussing the HOX gene system which is fascinating – stay tuned. But for today, I’m shamelessly begging for 9 folks to contribute $25 to help me reach my Movember goal. If you can “spare the change”, please head on over to my website <https://mobro.co/michaelglode?mc=1&gt; and join in.

Many thanks to all of you who contributed this year and even encouraged your friends and family. Know that it makes a difference and we are on our way to beating prostate cancer!

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Lest we forget…


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Screen Shot 2018-11-12 at 11.28.18 AMOn this Veteran’s Day, we would be remiss not to thank the thousands of men and women who serve and remember those who have died in the cause of freedom. My parents used to take me to our local cemetery where the American Legion guys would solemnly fire a 21 gun salute at exactly 11AM and we would lay some flowers on the graves. Those were simpler times, before Viet Nam and all that has followed, but we still need them and I honor their service.

That said, I have wondered over the years how many thousands of men (and women) might have died from cancer caused by smoking that started when they joined the military. In searching for some information on this, I came across this article, actually from a “pro-smoking” magazine, that is a reasonably balanced history of tobacco in the military and admits to the relationship.

Focusing on prostate cancer, there is NO doubt that smoking increases your risk for developing the disease, and if you have prostate cancer, you definitely reduce your length of survival by smoking. I doubt there are many smokers who read this blog, but if you know someone who is fighting prostate cancer be sure to make them aware of this. It is probably one thing they could do (besides EXERCISE, EXERCISE, EXERCISE…) that could increase their survival… more than any supplement which we all continue to put false hopes in. In one (of many) articles evaluating the risk of biochemical relapse (rising PSA) after radical prostatectomy (N=6538) former (N=2086) and current smokers  (N=2214) were 1.5 times more likely to have relapse than never smokers (N=2238). If the men had quit > 10 years, their risk returned to the same as the never smokers.

So, if you know a vet (or non-vet) who is still smoking, thank them for their service, but give them a hug to encourage their smoking cessation.

 

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It’s MO time – please help!


To view this post on my blog site, sign up for future posts, and read more info relevant to prostate cancer, please click here. Donate to my moustache here. Even better, grow your own and get your friends to help out here. The more of us who join in, the wider the recognition of men’s health issues.

In my career fighting for the cure of prostate cancer, two organizations (besides the National Cancer Institute) have been outstanding partners. Movember was started by a couple of friends in a bar in Australia. This became the answer to a long standing jealousy of mine for something as popular and effective as the Susan G. Koman Foundation and Race for the Cure. I often refer to our prostate cancer journey when I lecture by noting how we “crawl for the cure” while our sisters are racing. In 2016, the NCI budget for breast cancer research was $519.9 million, more than twice as much as that for prostate cancer at $241 million. This, in spite of the fact that prostate cancer deaths this year are 3/4 as common (29,430) as breast cancer deaths (40,920). It’s not a contest really, since all cancer research is moving the field forward rapidly, but Movember has been incredibly helpful in sponsoring research and advocating for us.

The other organization, Prostate Cancer Foundation, shows how much a single individual with great connections and personal motivation can do. Michael Milken deserves enormous credit for his vision and leadership. I personally benefited from grants given out by the foundation, and even more from their amazing annual meeting that draws together prostate cancer researchers from around the world to share data and ideas. Dr. Howard Soule is a key factor in PCF’s incredible success and his name should be as well known as Susan G. Koman in my view.

I hope you will join with all of us in fighting for the cure in prostate cancer. Grow one, or support someone who is growing, and tell your friends. The progress and future has never been brighter, and our hairy upper lips should show it!

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Rorshach and biomarkers


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Psychology, or for that matter being able to read others’ personalities, has never been a strong suit for me. Neither was art – I still am at the stick figure stage when drawing. It turns out that Hermann Rorshach was probably good at both. The question of what you see when looking at an ink blot seems relevant to the current status of biomarkers in prostate (and others) cancer. On the one hand, some biomarkers are fabulous – for example the Philadelphia chromosome, described in 1959, was the first unique cancer marker that ultimately resulted in a specific targeted treatment, imatinib (Gleevec), dramatically improving survival for patients with chronic myelogenous leukemia. PSA, on the other hand (our “favorite”) is not so great, and as I previously noted, may give rise to the “PSA Clock” effect in which patients ruin their lives by clock watching. But, as we know, it is remarkably useful as a weather vane. When a prostate cancer patient is being followed on any sort of therapy, going down is good and going up is bad.

Thus, there have been thousands of articles attempting to either make PSA interpretation  better, or to replace it with more sensitive or more accurate predictors of prostate cancer behavior. I reviewed some of these, and the challenges here. Today, yet another article on a rather “simple” biomarker, PTEN loss, showed up among the >20 prostate related emails I receive each day. Writing in European Urology, a group of well-known prostate cancer investigators looked at immunohistochemistry (using special stains to highlight a protein in cells under a microscope slide) to evaluate loss of PTEN, a tumor suppressor gene, in prostatectomy specimens. This simple test (in this particular experiment) was as good as the commercial Prolaris test that evaluates a panel of genes related to how fast cells are dividing in predicting biochemical recurrence (PSA relapse) or prostate cancer specific mortality. With PTEN loss, the chances of having a biochemical relapse (rising PSA) or developing metastases or dying in a 10 year followup period were significantly greater than if you did not have PTEN loss. A simple, inexpensive test might replace a more complicated one.

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Here’s where Dr. Rorshach’s psychological construct comes into play at so many levels. If you are the scientist looking through the microscope, do you score a loss when there is only faint staining? Are you sure you are looking at a cancer cell and not a normal cell or  a stromal cell, or maybe even an immune cell? If you decide on giving a score to each cell, say “1+, 2+, or 3+” staining, how do you add all those up?  How many cells should you examine? All parts of the tumor, or only the most aggressive (Gleason pattern ≥ 4) And if you can figure all that out, can you teach your colleagues to look at the same specimen(s) and come up with the same answer? These are the challenges we face when we move a lab experiment into the clinic (and they are well recognized by the authors).

But…there is more! Look at the graphs. Obviously you would rather be on the upper curve with PTEN present, but how bad is it really? At 10 years, only ~10% of the men had developed metastases or died in this study. Recognize that these men were a cross section of patients, median age 59, median PSA 5.9, 64% Gleason 3+3 and another 23% Gleason 3+4 with pretty low a priori risk (did we need the PTEN test to tell us?). So the real issue is whether you would want anything different done to you if you were one of the few patients with Gleason 3+3 and PTEN loss, just because you have this new information? And what would that be?? Radiation? Hormone therapy? How much and how long? -all in the psychology of looking at those curves. Some men might want nothing more done, while others would want “the kitchen sink” thrown at them, even if they had relatively little (and unproven) to gain.

So, medicine remains as much an art as it is a science (with no offense to my mathematical statistical colleagues). As the father of American Internal Medicine, William Osler, told his students, “Common sense in matters medical is rare, and is usually in inverse ratio to the degree of education.”

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