BIOLOGY OF PROSTATE CANCER

New clues as to which prostate cancers are the ones that kill come from research conducted in the United Kingdom, which has found evidence of amplification of the androgen-receptor (AR) gene in men with prostate cancer even before treatment with hormone-deprivation therapy.

This AR gene amplification is seen in about 20% to 30% of men with castration-resistant prostate cancer. It is thought to develop as a consequence of hormone-deprivation therapy and is a prime cause of failure, the UK researchers explain. But they found evidence of this AR gene amplification in men who had not been treated with hormone-deprivation therapy, and say this is the first time the finding has been reported from a large comprehensive study.

The finding was published online January 30 in the British Journal of Cancer.

"Our research has shown that an early form of this hormone-gene amplification is present in a number of prostate cancers that have never been treated with hormone-reduction therapy," said lead researcher Jeremy Clark, PhD, from the Department of Cancer Genetics at the University of East Anglia in Norwich, United Kingdom.

"We think that it is these cancers that will grow and kill the patient," he added, speculating that in the future "this discovery could be used to identify these killer cancers in patients much earlier than is currently possible."

These patients, who show AR gene amplification even before therapy, could be candidates for more aggressive treatments, such as the new "super androgen blockers" such as abiraterone ( Zytiga) and enzalutamide ( Xtandi), the researchers suggest.

However, in an interview with Medscape Medical News, Dr. Clark said, "we are not there yet." The detection methods used in this research are labor intensive, a problem that will need to be solved before this finding can be implemented clinically, he said.

One issue is that the gene amplification was seen in small clonal foci within the tumor, but they accounted for only about 1% of the total tumor volume, so it would be unlikely that these would be found on biopsy, he said.

Tissue Obtained During Debulking Procedure

The study was conducted in 596 men with hormone-naive prostate cancer who were diagnosed after having undergone transurethral resection of the prostate (TURP). This is a debulking procedure, usually carried out after men develop problems with urinating because of prostate hyperplasia, and it removes quite large pieces of tissue, Dr. Clark explained. In their initial study, up to 6 cores per patient were taken for analysis by tissue microarray.

AR gene amplification (determined by fluorescence in situ hybridization [FISH]) was found in 6 of the 596 patients. Three patients had gained more than 5 copies of AR, 1 patient had 3 copies, and 2 patients exhibited duplications.

On intensive follow-up FISH examination of whole sections of TURP block tissues, these tumor clones were always less than 1% of the tumor bulk, Dr. Clark noted.

Correlations with clinical variables demonstrated an association between AR category and increased Gleason score, increased baseline prostate-specific antigen (PSA), and percentage of cancer in the original diagnostic biopsy ( P < .001 for each of these factors), and also were associated with a more advanced clinical stage of prostate cancer ( P = .025).

This cohort of patients had 10-year follow-up survival data. When the researchers analyzed the outcomes for the 6 patients who had been found to have AR gene amplification prior to hormone therapy, the results "demonstrated a consistent correlation between AR copy number and poorer-specific survival," they report. However, because of the small number of patients (n = 6) in this analysis, they comment that these results should be "considered to be anecdotal only."

The results led the researchers to hypothesize that small subclones of cancer cells with AR amplification could be a driving force in the progression of prostate cancer, similar to the way in which HER2overexpression drives some breast cancers.

"In principle, clones of cells containing AR amplification could exhibit a growth advantage and gradually become the predominant cancer clone, even in the absence of treatment by castration," they write.

At present, their research has implications for men such as those in the study who were found to have prostate cancer after undergoing TURP. For such men, AR FISH mapping "could, in principle, provide a method for identifying men who should immediately receive more aggressive therapy," they suggest.

However, for the research to be applied more broadly, a simpler way of finding these AR-amplified clonal foci in prostate tissue would need to be developed, Dr. Clark suggested. Working together with Colin Cooper, PhD, from the University of East Anglia, and other colleagues, the team is now looking at different methods to sample the whole prostate, including investigating tissue exosomes in urine voided after a prostate massage.

Approached for comments about this new research, Marc Garnick, MD, clinical professor of medicine at Harvard Medical School (HMS) and Beth Israel Deaconess Medical Center in Boston, said: "The authors have provided a greater level of precision, often suspected clinically, of defining yet another alteration in androgen-receptor biology that may predict adverse outcomes of men with prostate cancer."

Dr. Garnick, who is also editor-in-chief of the HMS Annual Report on Prostate Diseases, said "the data provided seem to again support the known adverse clinical parameters of patients who are likely to suffer worse outcomes. Indeed, the higher categories of androgen-receptor gene copy number seem to comigrate with clinical parameters readily available at the bedside, such as Gleason score, high PSA, and more advanced primary tumor size."

"This type of work is important in helping provide a sound scientific rationale for the design of next-generation treatment strategies that could potentially include agents (earlier on in the course of the disease) with differing mechanisms of interfering with androgen/androgen-receptor biology," he added.

This work was supported by the Association for International Cancer Research, as well as several UK cancer charities.

Br J Cancer. Published online January 30, 2014. Abstract