Early identification of androgen receptor gene amplification and prostate cancer risk

Historically, it has generally been assumed that androgen receptor gene amplification was a result of androgen deprivation therapy (ADT) and occurred in some 20 to 30 percent of men with castration-resistant prostate cancer (CRPC). However, in a new paper in the British Journal of Cancer, Merson et al. have demonstrated that androgen receptor gene amplification can actually be identified much earlier in prostate cancer development and may be a key indicator of very high risk for prostate cancer-specific death much earlier in the development of this disorder. The implications of this finding could be very important, and they are also discussed in an article on the Medscape Oncology web site.

Merson et al. used a series of tissue microarrays of samples of tissue from 596 hormone-naive prostate cancer patients to identify so-called “copy number alterations” for the X chromosome and for the androgen receptor gene.

Through the application of a technique known as “four-colour fluorescence in situ hybridization” (four-color FISH), they were able to:

  • Detect copy number alterations for the X chromosome of ≥ 4-fold in 0.7 percent of the microarray samples
  • Detect copy number alterations for the androgen receptor gene ≥ 6-fold in 1 percent of the microarray samples
  • Demonstrate the presence of androgen receptor gene amplifications in very small foci of prostate cancer cells (≤ 600 nm, or ≤ 1 percent of tumor volume)
  • Show that men with high androgen receptor gene copy number gains had poorer prostate cancer-specific survival than their peers with normal numbers of androgen receptor gene copies

The authors go on to hypothesize that

  • A significant proportion of androgen receptor-amplified CRPC could exist in  some men prior to the application of ADT
  • Patients with such pre-existing androgen receptor-amplified CRPC might, perhaps, benefit from very early and very aggressive forms of total androgen ablation therapy (using drugs like abiraterone acetate and enzalutamide).

Now it does need to be understood that the techniques described in this paper are a long way from being efficient methods for the detection of small amounts of androgen receptor gene amplification. Thus, we are going to need to find better ways to identify such small amounts of androgen receptor gene amplification early in the process of diagnosis and treatment of prostate cancer if we are to be able to better explore this hypothesis and test men early on for such androgen receptor gene amplification.

Having said that, this concept does help us to understand why excessive and overly early use of less aggressive forms of  ADT may actually stimulate the early onset of CRPC in a subset of patients (which is clearly something that we want to be able to avoid).

One Response


    I’m looking at these very interesting observations as a 14.5-year survivor, doing very well, of a challenging, once life-threatening case that was treated solely by IADT3 (intermittent triple androgen deprivation therapy — for me exclusively Lupron as the LHRH agonist and mostly Casodex/bicalutamide as the antiandrogen, with mostly finasteride as the 5-alpha-reductase inhibitor) plus supporting drugs (such as simvastatin and Fosamax and aggressive diet and other life-style practices) until last year’s shot at a cure with 39 sessions of (image-guided) TomoTherapy IMRT with pelvic coverage.

    We can expect this paper to have quite a favorable and needed impact. It gives us a novel insight into the role of AR in lethal prostate cancer, and this strikes me as a big step forward.

    However, I have long been puzzled by the lack of appreciation of the role of DHT in prostate cancer and the role of advanced hormonal blockade — a.k.a. androgen deprivation therapy (ADT) — in effectively fighting it, as it has for me. We already have this technology, but my impression is that it is under-used.

    While we have known for a long time now that behavior of androgen receptor (AR) protein is key to survival and growth of prostate cancer, doctors who use a lot of advanced ADT in their practices have also known for many years about the enormous importance of dihydrotestosterone (DHT). DHT is made from testosterone, and it is the real key that fits the AR lock, thereby fueling the cancer. It is also important for us to realize that DHT can remain high even when testosterone has been sharply reduced. (Dr. Charles “Snuffy” Myers, MD, a prominent medical oncologist specializing in prostate cancer and known to many of us, has remarked that he was one of these patients: excellent control of testosterone but poor initial control of DHT.) DHT is considered from five to ten times more potent as a fuel for prostate cancer than testosterone, so controlling it, which should involve monitoring it, is vital. In my own case, during my third round of ADT, I was unable to get my DHT below 5, and my PSA was not declining quite as well as desired, so we switched from finasteride to dutasteride (Avodart) — known to be more effective in this role; that did the trick.

    I am curious how use of ADT will evolve now that the new drugs abiraterone acetate (Zytiga) and enzalutamide (Xtandi) have been approved for later stage disease. The rap on Casodex/bicalutamide has always been that it has not been very good at binding to AR in competition with DHT. In fact, one of the theories why adding the third drug finasteride or Avodart (dutasteride) — both 5-alpha-reductase inhibitors (5-ARIs) — makes two-drug ADT (or orchiectomy plus an antiandrogen) much more effective is that the 5-ARI drugs severely curtail conversion of testosterone into DHT, thereby resulting in far less DHT to compete with Casodex/bicalutamide to occupy (and block) the ARs of cancer cells. It also is consistent with the observation by some doctors using these drugs a lot that increasing doses of Casodex/bicalutamide from 50 to 100, or 150, or even higher sometimes achieves much better cancer control. Xtandi is known to bind much more effectively to AR than Casodex/bicalutamide. I’m curious whether it binds well enough that reducing the amount of DHT may no longer be as important as it has been in the past. Theoretically, if Xtandi were 100% effective in blocking AR, there could be an abundance of DHT in the blood but it would not be able to connect with AR to fuel the cancer because it would have been blocked. On the other hand, use of Zytiga may fulfill this DHT reduction role as Zytiga is known to sharply reduce testosterone produced from all significant sources of production — from the testes, from indirect adrenal production, and from within the cancer itself; that reduces the material needed for production of DHT so there should be much less DHT.

    The issue whether early use of ADT is counterproductive is given some illumination in research by the team involving Drs. Mark Scholz, Stephen Strum, Richard Lam, and colleagues, who represent a practice that has been in the forefront of ADT technology since the 1990s. Some of their published papers indicate that two-drug and triple intermittent ADT seems not to increase early onset CRPC. This observation is echoed in informal observations by other experts, such as Charles “Snuffy” Myers, MD, and it is my understanding and belief, as a now savvy veteran of ADT. Unfortunately, while there are some other papers relevant to this issue, there has been no definitive research, and the counter-argument cannot yet be dismissed as I see it. (I do hope to find some time to comment on the earlier article on primary ADT, which I believe has a role to play for some lower-risk men; the Scholz and colleagues team has published some interesting research on this.) I am convinced that early use of poorly done ADT — something that seems to be almost the standard of care — is not wise and leads to problems, including less effective control of the cancer, but unfortunately neither the patients nor the doctors providing such ADT are aware that it is being done poorly. I suspect Sitemaster’s thought is right that ineffective ADT may stimulate earlier onset of CRPC.

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