Tag Archives: research

Black holes and genetic laws


To read this on my blog site, see previous essays and sign up for future posts, please click here. (Also, please note that all of the hypertext links I put in these articles are hopefully enticements to help you expand on the ideas – try a few)

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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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

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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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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Filed under General Prostate Cancer Issues