CRPC, “personalized” medicine, and the science of whack a mole

We have known for decades that prostate cancer is an “evolutionary” cancer. In other words, clinically significant prostate cancer and prostate cancer-specific mortality are the consequence of a series of events over time (probably both genetic and epigenetic) that lead to progressive and then to metastatic disease of variable levels of aggression.

What we do not know yet is exactly how and why prostate cancers are initiated; what events are necessary to make a prostate cancer tumor sufficiently aggressive to start to spread through and outside of the prostate; exactly why some prostate cancers are more aggressive than others; etc.; etc. On the other hand, what we have been discovering over the past decade is that literally hundreds of mutations to cancer cells may be associated with the progression of prostate cancer over time. Some of these are common and are probably “necessary” to the development of clinically significant disease. Others are much less common and we have no real idea yet just how important they may be in the development of clinically significant prostate cancer — indeed, they may be an effect of the disease progression as opposed to a cause.

At the same time, we have all started to think about the treatment of prostate cancer in terms of “personalized” medical care. The simplest way to think about this is that, at least in theory, if we have a complete picture of the molecular biology of the individual prostate cancer in the individual patient at a specific point in time, we may be able to treat that specific cancer with much greater efficacy (and much less risk) in that individual patient. It’s a nice idea … but we aren’t there yet, and we may never really be able to get there! (Just being able to process all of the relevant data may well need the cognitive capacity of IBM’s Watson computer.)

Let’s look at some recent developments in the management of late stage disease that have become more apparent since the development of drugs like abiraterone acetate (Zytiga) and enzalutamide (Xtandi):

  • We have been able to identify a specific subtype of androgen receptor called the AR-V7 receptor. Men with advanced prostate cancer who carry the genes for and express this receptor do not (generally) respond well to either abiraterone or enzalutamide (click here for more).
  • We know that, at least in the Chinese population, the degree of expression of the AR-V7 receptor increases significantly with the progression of prostate cancer over time (see Figure 1 in this paper by Qu et al.).
  • On the other hand, we know that men with metastatic castration-resistant prostate cancer (CRPC) who are AR-V7 positive and are treated with docetaxel-based chemotherapy still respond respond nearly as well to treatment as do comparable men who are AR-V7 negative (see this news report based on a presentation by Antonarakis et al. at the recent ASCO meeting in Chicago).
  • In addition, in the same presentation, Antonarakis et al. showed that 7 of the 12 men with AR-V7-positive disease at the start of their chemotherapy were converted to AR-V7–negative status after chemotherapy (see this report on the same study).
  • What we do not know (yet) is whether the men who were converted from AR-V7-positive to AR-V7-negative status on chemotherapy also regained sensitivity to drugs like abiraterone or enzalutamide.

It is clear that the positive or negative status of patients in terms of expression of the AR-V7 receptor is critical to when to give a man abiraterone or enzalutamide once he is castration-resistant. What is less clear is whether what we are really doing here is attempting to manage a life and death version of whack a mole.

If how we treat patients based on their expression of genetically controlled proteins, enzymes, receptors, etc., can actually be used to turn the genetic controls for these biochemicals on and off (but not in a totally predictable manner), then arguably each time we use a specific treatment to address a particular “individualized” form of prostate cancer, we are actually increasing the risk that we may turn “on” other expression systems that need to be “off” or we may turn “off” other expression systems that need to be “on”.

That’s going to become a real problem very fast, and it may have something to do with why we are simultaneously seeing an expansion in risk for development of neuroendocrine forms of prostate cancer — as also discussed at ASCO by Small.

While The “New” Prostate Cancer InfoLink is all in favor of finding better ways to treat castration-resistant forms of prostate cancer, we are also in little doubt that what is really needed is for us to find ways to stop the progression of prostate cancer much earlier in its development, so that the need for androgen deprivation therapy is massively reduced and the consequent need for treatments for CRPC and metastatic CRPC can be minimized.

By contrast, what we have been doing over the past 20 years — to a large extent — is finding ways to extend the survival of men with progressive prostate cancer so that they live longer with hormone-sensitive and then castration-resistant and chemotherapy-resistant prostate cancer. Progress based on that management strategy is inevitably limited over time. There is a strong argument that greater research focus needs to be placed on how to prevent or at least significantly delay the initiation of the metastatic process — and that applies as much to many other cancers as it does to prostate cancer too.

5 Responses

  1. As a metastatic, castration-resistant prostate cancer victim I’m not sure whether to be heartened or disheartened by the sitemaster’s very well written thesis.

    I have just completed a course of PROSTVAC as a volunteer trialist. But as it was a double-blind trial I’m very much in the dark which arm I was on. Certainly my PSA is now well and truly out of control (doubIing time approx 4 weeks) and I will need to consider my options.

    I would be interested to know whether there is a test for AR-V7 receptor as I have seen a few other articles on the subject, all saying the same thing, of course.

  2. Wonderful presentation and approach to a multifaceted problem.

    Refreshing synthesis.

  3. Dear Graham:

    As I understand the situation the only laboratory capable of testing accurately for the AR-V7 receptor at present is the one at Johns Hopkins. They are working on a test that could be carried out by others too, but that will take time.

  4. Dear Graham,

    In response to my recent inquiry, Dr. Emmanuel Antonarakis of Johns Hopkins advised the following:

    “In about three months, patients will be able to have AR–V7 testing either by QIAGEN or the Johns Hopkins CLIA lab. I will send more information once the test is ready for prime time.”

  5. Thanks for that information. Unfortunately, in my case 3 months is probably too long to wait so I thought to have enzalutamide immediately (keeping fingers crossed I am AR-V7 negative) and then chemotherapy.

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