A very different way to project risk for clinically significant prostate cancer?

We don’t want to suggest that the recent paper by a Japanese research team in the journal Andrology is necessarily going to revolutionize the diagnosis of clinically significant prostate cancer. A great deal more work would be required to justify the hypothesis that they put forward. On the other hand, their hypothesis is definitely interesting.

Shibata et al. set out to investigate whether there might be a predictive correlation between pre-treatment levels of androgens in prostate biopsy specimens (as opposed to in serum) and future risk for castration-resistant prostate cancer (CRPC).

To test this idea, they enrolled 165 men diagnosed with prostate cancer. All patients received multi-core prostate biopsies at diagnosis as well as one additional biopsy core to provide tissue for determination of tissue androgen levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). All 165 patients then went on to receive androgen deprivation therapy (ADT) as their first-line treatment.

After initiation of first-line ADT, the researchers monitored the patients’ PSA levels to determine: (a) how fast the PSA to dropped half of its initial value (the PSA halving time); (b) the patients’ nadir (lowest) PSA levels, and (c) when patients became castration-resistant (defined as when their PSA levels increased to 25 percent above their nadir PSA level and reached a minimum of 2.0 ng/ml).

Here are the key findings from this study:

  • There was a significant correlation between the PSA halving-time after ADT and the pre-ADT tissue androgen content.
  • 23/165 patients (13.9 percent) became castration resistant during the follow-up period (but the length of the follow-up period is not reported in the study’s abstract).
  • Compared to the patients who did not become castration resistant, at diagnosis the 23 CRPC patients had
    • A significantly higher concentration of prostate tissue testosterone (T) (p < 0.01)
    • A significantly lower concentration of tissue 5α-dihydrotestosterone (DHT) (p < 0.01)
    • A significantly higher tissue T/DHT ratio (p < 0.001).
  • The patients’ pre-ADT tissue T/DHT ratios and their Gleason scores were both independent predictors for development of CRPC.
  • The patients’ pre-ADT tissue T/DHT ratio could be used to project relative risk of development of CRPC.

Shibata et al. conclude that their data “suggest that the evaluation of prostate androgen content in a single needle biopsy specimen may be useful to predict future CRPC development after primary ADT.”

It is relatively simple today for a pathology laboratory to conduct liquid chromatography-tandem mass spectrometry (LC-MS/MS) on small tissue samples. If further studies were to confirm that LC-SM/MS can, in fact, accurately project risk for CRPC, then this may be extremely helpful in knowing which patients are at really serious risk for CRPC at the time of diagnosis. On the other hand, the androgen levels of tissue may only be relevant to such a projection in men who already have evident metastatic or micrometastatic disease at the time of initial biopsy. That is just one reason why further study will be needed before we can evaluate the practical application of this hypothesis.

9 Responses

  1. ” The patients’ pre-ADT tissue T/DHT ratios and their Gleason scores were both independent predictors for development of CRPC.”

    Makes me wonder if the pre-ADT tissue T/DHT ratio is less of an “art” than Gleason scoring. If different Gleason scores can be read on the same specimen by different readers would the same differing results come from different labs? Time may tell.

  2. Another reason not to take 5-ARIs?

  3. Hi Doug and fellow participants.

    No. I hope to have some more information regarding your prior questions, but I have been side-tracked by my current course of radiation therapy.

    I have now been taking a 5-ARI continuously since September 2000. In fact, that’s the only class of drug I have been on continuously to combat my challenging case of prostate cancer.


  4. The DHT finding seems counter-intuitive given it is characterized as supercharged T. Wouldn’t a higher concentration of DHT be expected along with the concentration of T? What am I missing?

  5. Rick:

    I have seen studies which show higher DHT levels associated with less serious cancer (not 5-ARI studies).


  6. Hi Doug.

    Please mention the specific study (or studies) and what it/they said so we can look at the relevance, if any.

  7. Rick and Doug,

    I hope to respond again, in favor of 5-ARI drugs and the importance of countering DHT in prostate cancer, but here’s a link to a just-published study by Schröder et al. (epub late last year) that supports these points.

    The relative risk reduction in time to PSA doubling found for dutasteride use over 2 years was two-thirds!

    This is just one more piece of evidence supporting the role of 5-ARI drugs.

  8. Jim,

    Here is one such study by Murtola et al. Do search for the rest.


  9. I do not doubt the efficacy of 5-alpha-reductase drugs — the big question for the UCSF docs is whether they accelerate the time to castrate resistance. … They think it does, thus are reluctant to prescribe double blockade but will do so when pushed.

    I am looking for an explanation as to why men who become castrate resistant have a lower level of DHT in their prostate at diagnosis. Logically, we would expect them to have a higher level.

    Maybe they were secretly taking Proscar or Avodart before diagnosis. … Just kidding!

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