Gene mutations can predict prostate cancer drug resistance

Researchers have identified the genetic mutations that drive resistance to the hormone therapy abiraterone in patients with advanced prostate cancer.

As these mutations were detected prior to treatment, they say the findings could be used to identify men who would be more suited to alternative therapies, such as chemotherapy or radiotherapy.

The researchers used blood samples taken from 97 patients with advanced prostate cancer to detect circulating tumour DNA (ctDNA). These patients all had a form of prostate cancer known as 'castration resistant', which has stopped responding to first-line treatment with androgen-deprivation therapy. Using the blood test meant that the researchers were able to detect DNA from metastases, which are challenging to obtain traditional biopses from.

They found that men who had particular point mutations or additional copies of the androgen receptor (AR) gene had poorer responses to abiraterone than men without these variants. They were 4.9 and 7.8 times less likely to have a decline of at least 50 or 90 percent, respectively, in prostate-specific antigen — a key marker of disease progression. These patients also had significantly poorer progression-free and overall survival.

Overall, 45 percent of the men tested had one of these mutations before treatment, and 13 percent also developed a point mutation during treatment.

Additionally, patients with higher levels of ctDNA detected tended to have poorer outcomes than patients with lower ctDNA concentrations.

The researchers, who report their findings in Science Translational Medicine, say that they are now planning a clinical trial to explore whether men who test positive for AR mutations fare better on chemotherapy than abiraterone or other drugs.

'Critically, we believe that this sort of technology would be relatively straightforward to implement in NHS hospitals, making it accessible to a large number of patients,' said lead researcher Dr Gerhardt Attard from the Institute of Cancer Research.

'Additionally, looking at tumour DNA in the blood of patients could potentially give us an overall picture of why the cancer is progressing all over the body, unlike a biopsy that only tells us about the area sampled,' he added.

Last year, NICE, National Institute for Health and Care Excellence, rejected abiraterone for prostate cancer, outside of end-of-life care, due to concerns over data presented by the manufacturer Janssen and over costs. Therefore, campaigners hope that the test, by identifying patients most likely to respond, could help increase the availability of the drug.

'We know that a one-size-fits-all approach to treating prostate cancer doesn't work,' said Dr Iain Frame, Director of Research at Prostate Cancer UK.

'When the clock is ticking for a man with advanced prostate cancer, finding out early that his treatment needs changing can not only save precious time, but can also help avoid unpleasant side effects from a treatment that no longer works for him.'