Blood Test Identifies Mutations Behind Drug Resistance in Patients Taking Antiandrogen for Prostate Cancer

Scientists developed a blood test that can identify key mutations driving resistance to a widely used prostate cancer drug and which patients will not respond to the treatment in advance. This study may allow a blood test to inform prostate cancer treatment in the future so only patients whose tumors are free of resistance mutations will take abiraterone.

The study is also a proof of principle that testing for cancer DNA in the bloodstream can detect drug resistance mutations. This allows patients who will not benefit from one drug to receive an alternative treatment instead.

Researchers at The Institute of Cancer Research, London, the Royal Marsden NHS Foundation Trust, and the University of Trento, Italy, analyzed 274 blood samples from 97 patients using state-of-the-art DNA sequencing techniques. They found that mutations in the androgen receptor (AR) predicted resistance to the prostate cancer drug abiraterone, and that patients with these mutations had poorer survival.

The new study was published in Science Translational Medicine (doi:10.1126/scitranslmed.aac9511), and it was funded by Cancer Research UK, Prostate Cancer UK, the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR), and the University of Trento.

Abiraterone, which was discovered at the ICR, is now standard treatment for men with advanced prostate cancer, but although it is highly effective in many patients, 30% to 60% do not respond.

Investigators have been searching for a marker that will help predict in advance which men will benefit from the drug, and who should be given a different treatment.

They discovered that men who harbor either 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 prostate-specific antigen (PSA) levels.

In 13% of the tumors that progressed on abiraterone, 1 of 2 point mutations was acquired as the drug stopped working. These occurred in men who did not have either mutation before starting treatment, and the mutations appeared in the bloodstream several months before patients developed any symptoms.

Blood tests are particularly valuable in cancer patients because biopsies are often difficult to perform and can carry risks. Even when biopsies are possible, they only give a snapshot of cancer genetics in a small specific area, whereas blood tests can give information that is more representative of multiple different tumors around the body.

 “We're 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,” said Gerhardt Attard, MD, PhD, clinician scientist at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust in the United Kingdom.

"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. … 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."

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