Analysis of Circulating DNA Predicts Prostate Cancer's Development of Drug Resistance

Analysis of prostate cancer DNA circulating in the bloodstream identifies a mutation that indicates whether the tumor will become resistant to the drug-of-choice abiraterone, and enables the physician to choose an alternative treatment.

Androgen receptor (AR) gene aberrations are rare in prostate cancer before primary hormone treatment but emerge with castration resistance; therefore, determination of AR gene status using a minimally invasive assay would have broad clinical utility.

Towards this end, investigators at the Institute of Cancer Research (London, United Kingdom) developed a targeted next-generation sequencing approach amenable to plasma DNA, which covered all AR coding bases and genomic regions that have been linked to prostate cancer.

The investigators sequenced 274 plasma samples from 97 castration-resistant prostate cancer patients treated with abiraterone at two institutions. They controlled for normal DNA in patients’ circulation and detected a sufficiently high tumor DNA fraction to quantify AR copy number state in 217 samples (80 patients).

Results revealed that patients with a specific mutation or an increase in the number of copies of the AR gene were 7.8 times less likely to have a reduction of more than 90% in their PSA (prostate specific antigen) levels, a widely used test to monitor the response of prostate cancer to treatment. The study also found that in about 15% of men given abiraterone who did not have either genetic aberration before starting treatment, it was acquired as resistance appeared and the drug stopped working. The mutation was detectable in the bloodstream several months before patients developed any physical symptoms.

Senior author Dr. Gerhardt Attard, clinician scientist at the Institute of Cancer Research, said, "The discovery of abiraterone was an important step forward for patients with advanced prostate cancer, but we know it does not work for all men, and we have been searching for a marker that will tell us in advance which men will benefit. We are delighted to have developed a test that appears to predict very accurately whether a patient will respond to abiraterone, and that it can be performed on blood samples—removing the need to take a biopsy. We are now planning a clinical trial involving up to 600 men in which we aim to prospectively show that men who are positive with our test have significantly greater benefit from chemotherapy in preference to abiraterone or similar drugs. Additionally, looking at tumor 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."

The study was published in the November 4, 2015, online edition of the journal Science Translational Medicine.

Related Links:
The Institute of Cancer Research