Black holes and genetic laws


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I just finished reading Stephen Hawking’s last book, Brief Answers to the Big Questions, which I found more accessible than A Brief History of Time, written more than 30 years ago. Hawking’s abilities to explain the very (for me) abstract concepts of how no information can flow out of black holes and that the amount in there is somehow directly related to the cross sectional area of the hole was satisfying. As a very math challenged individual, I’m also a fan of Heisenberg and the perplexing issue that in the quantum/wave world of particle physics, you just can’t be certain about position and momentum. Yet, there are certain laws, like the speed of light, that are never violated, at least in the universe we live in.

So what does this have to do with genetics and prostate (or other) cancers? Here is a law: A always pairs with T, and C always pairs with G. In our biologic universe, without this law, no life as we know it could exist (prions may be an exception, but that gets too far into the definition of “life”). Yet, just as with the uncertainty of Heisenberg, the base pairing in DNA/RNA is not completely inviolable. Mistakes are made…and this can result in cancer. Cancer is a genetic disease and for anyone who hasn’t read it, I still recommend you avail yourself of the incredibly well written book, The Emperor of All Maladies. In the short time since that book was written, the explosion in our understanding of how genetic errors and cancer are related has been difficult to keep up with. The Cancer Genome Atlas (clever name, eh?) is but one example, and its use by scientists skilled in math (ugh) continues to help classify cancers based on how their mutations drive them rather than just how they look under the microscope or which organ they started in. Here is the math and the results one such analysis has on predicting survival for stomach cancer:

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As you can see, the prognosis and potentially the treatment for one subtype of “stomach cancer” might be very different for one patient than for another. Bringing this technology to prostate cancer, we already know the mutational landscape is vast. For example, this article looked at 1,013 different prostate cancers and found 97 significantly mutated genes, including 70 not previously recognized, and many present in <3% of cases. There is hidden good news in this story, in that the same mutational uncertainties that can give rise to cancer (breaking the law of AT-CG) also allows our immune systems to react to the novel mutated proteins that cancers now display. For an interview from this week’s NEJM on gene editing, click here.

Keeping up with this world of laws, broken laws, and “black holes” will be a remarkable challenge for patients and oncologists alike. My final recommendation for reading about this is a terrific article you can find here by George Sledge, one of the outstanding leaders in our field. He notes that even the most skilled oncologist, paired with the smartest of patients, will be unable to keep up. But remember this, you can’t go faster than the speed of light. That’s the law!

 

 

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Tweet Storm from ASCO GU


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The American Society of Clinical Oncology (ASCO) along with other professional societies sponsors an annual symposium focused on GU cancers, with a day and a half devoted to prostate cancer. You can view all of the abstracts on screening, detection, and management of localized disease here. If you have an area of specific interest (for example, the use of MRI in detection) you can use the search function on your browser to find articles of interest. On the mac, it is “command+f” keys for both safari and chrome. You then type “MRI” into the box and use “command+g” to scroll through all of the abstracts. You come up with very interesting new information like an abstract on page 108, “MRI targeted biopsy dramatically increases detection of clinically significant prostate cancer while reducing the risk of indolent cancer detection.”

If your interest is more on the newest studies for advanced prostate cancer, you can go here, and do the same thing. What you will find, of course, is that the avalanche of information is pretty hard to digest. When we started ASCO OnLine in the early 90’s, the technology was limited, but now it overwhelms. We are left to hope that the experts who select the most important abstracts to be presented will have done a good job, but that presumes they know our individual interests, which of course they can’t. When tweeting became available, I decided I was too old. I did sign up for a handle, @ascotwit, that I used in a couple of meetings but in general, I haven’t found twitter to be very helpful, even though some of my younger colleagues tried to help me and we even wrote an an article about it. (…I certainly don’t think it is a good way to run a country…but I digress).

So to you, my loyal followers, and with no attempt to correct spelling (why should I if the leader of the free world doesn’t do it?), here are the tweets from the oral abstract presentations that I would have sent out if I was a twitter user:

Ipi + novolumab – “checkmate 650) therapy duration  only 2.1 or 1.4 months. Only 1/3 reached maintenance phase with ~1/2 of patients dropping out for toxicity. compared to patients in melanoma trial getting about 4 doses.“if you can’t get the drug in, you can’t see a response” 25% of patients had a response in cohort 1. They tend to respond early The subsets are those who had PD-1 positivity or high tumor mutation burden.

  • Scher assay. Getting to CTC 0 was useful in predicting better survival and was better than looking at a drop of 50% in PSA. The development of a show term outcome marker remains elusive. 46% of the patients who lived 13 weeks were not included because of not enough CTC’s
  • #140 ARAMIS study – efficacy and safety of darolutamide in nmcrpc.  Different structure than end and app and does not cross blood/brain barrier. men with no mets and psa dt <10 months. ADT + placebo vs dark. met free survival 18 months vs 40 months . overall survival 83% vs 73% placebo at 36 months. also improved time to pain, time to skeletal, time to cytotoxic chemo. Tolerance was excellent with no difference in AE rates. Fatigue 15.8% vs 11.4% (see nejm this week)
  • Final analysis of Phase III Latitude study. High risk met castrate naive pca newly diagnosed
    • High risk gleason >/= 8
    • Abi vs placebo + ADT. 
    • Final analysis showed hazard ratio of 0.66. OS 36.5 months vs 53.3 months. Time to pain progression was much longer (see slide). High volume patients clearly benefited most
  • #687 ARCHES trial ADT +/- Enz
    • included both low and high volume CHAARTED criteria, as well as could have had prior docetaxel or not. 2/3 had gleason 8-10; 18% had prior doce in the hormone sensitive setting
    • Primary endpoint was rPFS or death. secondary: time to spa progression, new rx, spa undetectable rate objective response rate
    • rPFS HR =0.39 across all subgroups including those who had previous doce Time to spa progression was 91% at 12 mo vs 63%. 68% got 0 psa vs 18%. 
    • Fatigue and hot flashes were worse but mostly grade 1/2. 93% of patients still alive. at 14.4 months
    • DISCUSSION
    • Is M0 crpc really important? New imaging techniques – does it even exist??. Inflection point of doubling time <6mo is important predictor (matt smith curve). Cost: for Enz 220k/year of life saved. PFS2 is the time to progression or death on the theft therapy. The Latitude trial suggests delay in time to next endpoint.  
    • Cost for abi/p is still 10k/mo but generic is now approved
    • discussion of which one to use. not strictly comparable patient populations. need cost effectiveness randomized trial?
  • # 2 Choline scan can replace conventional imaging, but has poor negative predictive value – identifies mets earlier but no way to say that the earlier management changes makes any difference.
  • #144 – small. initiation of apalutamide early may result in prolonged effect looking at psa2 See screen shot. Earlier treatment for non-metastatic disease is likely better than waiting for mets. There are 3 potential agents (enz, apa, dur). Delaying time to symptoms is also very important. Suggests that anything you add later still does not make up for starting early.
  • #365 – yu. Pembro + olaparib in doce pretreated patients with mCRPC. Needed disease progression after doce, randomized to cohort A Pembro + olap 68% had measurable disease. 41% with visceral disease. None of the patients had DDR mutations by biopsy or circ. dna. 12% response rate. 39% had some measurable disease response. they will expand from 42 to 100 patients. Continue randomizing to other cohorts.
  • #146 Chen Genetic drivers of poor prognosis and enz resistance in mcrpc. 86% patients had ar gain. Complete biallelic loss of RB1 median OS 14.1 months vs 42 months (not looked at in association with enz resistance -they didn’t look). WNT btea catenin pathway was highest abn asso with resistance. CTNNB1 mutation found only in enz resistant patients and was also associated with  poor prognosis similar to the RB1 
  • #147 – compared 3 arms. MDT upfront with SBRT. vs abi/ADT up front vs ADT up front. Assumed 10 years. Markov model. Looked at  cost effectiveness. ADT upfront low cost/low effective. Abi/ADT is not cost effective compared to MDT. Willingness to pay threshold of $100,000/qaly. Costs would need to decline by 90% to be the dominant strategy. MDT is a cost effective treatment. Did not look at MDT + upfront ADT with or without abi. Model assumed 1-3 extracranial metastases using data from STOMP and M1 Stampede.
  • #148 Doce +/- enz CHEIRON study. N=246. Combo arm more toxic with neutropenia. disease control 89% combo vs 73%. But no difference in overall survival but most patients did go on to receive 2nd gen adt.

Reading through them, with misspellings, poor wording, and probably containing some real errors (don’t rely on this “tweet” – go to the abstract to verify anything above) I realize how challenging it is to keep up these days. My best suggestion to ALL cancer patients is that they find a physician who is focused on their particular disease if at all possible. I fear the era of being a general medical oncologist is over (and certainly over for a 71-year-old like me). While any of us could use the NCCN guidelines (or other practice guidelines from organizations like ASCO or AUA) to care for patients, there is little that can replace the actual experience one gains by participating in the development of new agents that are rapidly coming into clinical use these days. If you can think of a solution, don’t tweet to me because I have no idea how to use it and don’t “follow” many people. However, I welcome your comments on this old fashioned blog, and can even throw in an emoji (of sorts):   😉  Have a great February and remember, the prostate is our only heart shaped organ.

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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). I’m also a fan of Fred Bartlit’s book, “Choosing the Strong Path” and his crusade to age gracefully by pumping iron. 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.

Screen Shot 2018-12-15 at 3.29.21 PM

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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