AR gene amplification and risk for CRPC

An article just published in the British Journal of Cancer, has proposed that androgen receptor (AR) gene amplification may be a prime cause of treatment failure in a subset of men with progressive prostate cancer. This paper by Merson et al. (on behalf of the Transatlantic Prostate Group) is also discussed in some detail in a report on the Medscape web site.

Basically, what Merson et al. have been able to show is that AR gene amplification (the presence of higher than normal numbers of copies of the AR gene) in hormone-naive patients can be associated with heightened risk for onset of castration-resistant prostate cancer (CRPC) in at least some patients with progressive disease, leading to questions of whether (a) we can identify such men early and (b) whether they should be treated more aggressively early on.

Merson et al. used a technique known as tissue microarray analysis to look at the “copy number alterations” for the X chromosome and the AR gene locus in a series of tissue from 596 men with hormone-naive prostate cancer (HNPC).

They found that

  • High level gain numbers of the X chromosome were detected at low frequencies in the tissue microarrays of men with HNPC (≥ 4-fold; n = 4, 0.7 percent).
  • Locus-specific amplification of the AR gene could also be detected at low frequencies in the tissue microarrays of men with HNPC (n = 6, 1 percent) .
  • Mapping of whole sections taken from the original HNPC specimen blocks showed that AR gene amplifications exist in small foci of cells (≤ 600nm, ≤ 1 percent of tumor volume).
  • Men with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival.

The study’s lead researcher has been very clear in interviews that although the research team believes that “it is these cancers that will grow and kill the patient,” it is not yet possible to use this type of tissue microarray analysis to clinically identify individual patients prospectively. He noted that, “The detection methods used in this research are labor intensive”, which would make it extremely difficult to use these methods to accurately identify the patients who might be appropriate for early aggressive treatment with (perhaps) drugs like abiraterone acetate or enzalutamide.

It should be noted that we already know that this type of AR gene amplification occurs in some 20 to 30 percent of all the men who are found to have CRPC, which suggests that accurate assessment of AR gene amplification in men with HNPC may actually be able to identify heightened risk for CRPC in as many as 20 to 30 percent of all men with high-risk  or progressive forms of prostate cancer. But we’d need a better test method to be able to demonstrate this and to apply it in clinical practice.

Perhaps one of the most important aspects of this paper is that, once again, it helps us to better understand (a) why there is such diversity in the ways men have responded over time to traditional forms of androgen deprivation therapy and (b) that advanced prostate cancer comes in many “flavors” that — to date — we are still just beginning to be able to identify with accuracy.

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