01 December 2015

By Dr Wendy Winnall - PCFA Research Team

Abiraterone and enzalutamide can be effective treatments for patients with metastatic castration resistant prostate cancers (CRPC). These are patients who have relapsed after hormone therapy. Unfortunately some CRPC patients don't respond to these drugs because their tumours are resistant. It would be really useful if we could predict who will respond well to these drugs before treatment. A new study by a team of scientists from the UK and Italy has invented a blood test that can accurately predict resistance to abiraterone.

Cancers can evolve to changes in their environment, in a similar way to the evolution of species. As cancer cells multiply, they can accumulate changes in their cellular DNA. When a drug is used to stop the cancer cells from multiplying, some of these cells have DNA mutations that allows them to avoid the effects of the drug. These cells will then be the only ones growing, and the cancer will subsequently become resistant to the drug. Drug resistance is usually reliant on the existence of the DNA changes before exposure to the drug. Fortunately this gives us the ability to ask whether a drug will work or not before it is used.

In the case of prostate cancer, this strategy has been complicated by the need for repeated tumour biopsies to detect changes to the tumour DNA. Another issue is that metastatic prostate cancers consist of multiple tumours in different regions, and these tumours often have different DNA profiles; it’s difficult to get an overall picture without a biopsy of all the tumours. A new method for analysing tumour DNA has been developed by the UK/Italian team that has an elegant solution to both problems. They are able to analyse DNA present in the blood that has been shed by these tumours, allowing an overall snapshot of tumour DNA from a non-invasive sample (a liquid biopsy).

Changes to the androgen receptor gene are commonly seen in patients with CRPC. These are either mutations at specific points in the gene, or an increase in the AR gene copies. In this study, the researchers showed that CRPC patients whose tumour DNA carried either of two specific mutations, were much more likely to have tumours resistant to abiraterone. They also showed that an increase in the number of AR gene copies was also associated with tumour resistance. Patients with either risk factor were considerably less likely to show the lower PSA levels and disease-free survival time period that are normally seen with abiraterone treatment.

The next step is to validate this test in a clinical trial to see if we can predict, ahead of time, which patients will benefit from abiraterone treatment. If successful, a test for AR-gene status could become an important part of a precision medicine-based approach to treating prostate cancer. Precision medicine is a treatment model in which medical decisions are tailor-made for individual patients. Avoiding treatments that have little chance of success reduces side effects and cost, and allows alternative treatment pathways to be followed.