AR GENE AMPLIFICATION INCREASES PROSTATE CANCER MORTALITY RISK

May 22, 2012 (Barcelona, Spain) — Patients with prostate cancer who have extra copies of the androgen receptor (AR) gene face up to 10 times the mortality risk of patients without this gene amplification, according to research presented here at an oral poster session of ESTRO 31: European Society for Radiotherapy and Oncology 2012 Annual Conference.

"I suspect you could find some patients under surveillance who should have gone for active treatment if we had checked their androgen receptor amplification status at the outset," said Andrew Eichholz, MD, from the Male Urological Cancer Research Centre at the Institute of Cancer Research in Surrey, United Kingdom.

"The take-home message here is that any increase in AR gene [amplification] at diagnosis predicts a worse prostate cancer-specific survival, and in particular, those patients with locus-specific amplification do even worse and you can't necessarily detect them by other means."

The study included 596 patients with prostate cancer, all treated conservatively, for whom AR fluorescent in situ hybridization analysis was performed on prostate biopsy specimens.

Roughly 75% of the group had a single X chromosome with a single AR gene.

However, others had additional copies of the X chromosome, and therefore of the AR gene, with a small group showing locus-specific AR gene amplification. "So they had one copy of the X chromosome but on that single X chromosome there were lots and lots of copies of the AR gene, up to 50 copies of the AR gene on a single X chromosome," he said.

Patients with increased copies of the X chromosome and AR gene had statistically significantly worse prostate-specific survival, but this could have been predicted with more traditional prognostic markers, such as age, Gleason score, and prostate-specific antigen (PSA), said Dr. Eichholz.

However, patients with locus-specific AR gene amplification "did by far the worst of anybody — they did about 10 times worse, but we would have not been able to predict that from all the other factors," he said.

This final category with extremely poor prognosis was very small — just 6 out of about 600 patients, yet Dr. Eichholz believes the result is a reliable one.

"It is statistically significant and there is some robustness to it in that if you take out one or two patients and analyze it again it still remains statistically significant," he said.

"It's a novel and exciting piece of work because we are looking for biomarkers of whatever sort to help guide us on how to manage all forms of prostate cancer," said the chair of the session, David Paul Dearnaley, MD, from the Institute of Cancer Research, Royal Marsden Hospital in Sutton, United Kingdom.

"Having androgen receptor amplification may mean that what testosterone is there is is having a multiplied effect — and that may be why these cancers are particularly aggressive. That would be an important finding in a number of different ways," he told Medscape Medical News.

"For example, we now have a large group of prostate cancer patients that we don't want to treat because they have very early disease and most of that disease doesn't progress. Those patients will never need treatment during their lifetime, and you don't want to give them any side effects. But a third of them do progress to needing treatment, and if we could identify those patients at the beginning that would be a big, big plus."

Another possible benefit could be in the decision over whether or not to give hormone-suppressive therapy, he said.

"We use a lot of hormone-suppressive therapy when we use radiotherapy, and that therapy has side effects. If we could select patients who benefited more or less from hormone-suppressive therapy, we would certainly use that. It could be that patients who don't have androgen receptor amplifications do very well with radiotherapy alone and patients with the amplifications need the suppressive therapy. In other words, if you suppress their testosterone, then the adverse effect of their androgen receptor amplification disappears. But this is a hypothesis."

Dr. Eichholz and Dr. Dearnaley have disclosed no relevant financial relationships.

ESTRO 31: European Society for Radiotherapy and Oncology 2012 Annual Conference.. Abstract #PDO123. Presented May 10, 2012.