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Predicting the effectiveness of prostate cancer treatment from a blood test.

PCFA Staff
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What if a simple blood test could predict the effectiveness of a treatment for metastatic castration-resistant prostate cancer (mCRPC)? A recent Australian study suggests this is a possibility. Using a blood test, researchers were able to detect circulating cell free DNA and RNA for altered androgen receptors in the blood of men with mCRPC. Men who had altered androgen receptor DNA or RNA in their blood had a poor response to treatment.

Cell free DNA (cfDNA) and RNA (cfRNA) can often be found in the blood of people with cancer. As a tumour grows, new cells are made, and old cells die. The dying cells release their genetic material, DNA and RNA, into the bloodstream. This genetic material could be used as a biomarker for the cancer as they provide information about the types of gene abnormalities that are present in the tumour they were released from. To be useful as a test for cancer, researchers need to identify which cfDNA and/or cfRNA molecules will provide specific information that doctors can use to understand the type of cancer present and how to treat it. In addition, a sensitive, reliable and accurate test for finding the cfDNA and/or cfRNA of interest needs to be developed. Blood tests like this are sometimes called liquid biopsies.

In a study recently published in the well-respected journal European Urology, researchers report the outcome of their study that used a novel, highly sensitive, next- generation sequencing test that could detect both cfDNA and cfRNA in blood samples at the same time. The research was carried out by a team of Australian researchers from the School of Clinical Sciences at Monash Health (SCS) and Peter MacCallum Cancer Centre, in collaboration with Chris O’Brien Lifehouse and a California-based biotechnology company, Predicine.  

The researchers wanted to know if they could detect altered cfDNA and cfRNA for the androgen receptor (AR) in the blood of men with mCRPC and if these changes would provide information on how a man might respond to different treatments. To do this, the researchers recruited 67 men with mCRPC who were about to begin treatment with an AR pathway inhibitor (ARPI; 41 men) or taxane chemotherapy (26 men). The men on ARPIs received either Enzalutamide (Xtandi) or Abiraterone (Zytiga).  Before starting the treatment, a small 10ml sample of blood equivalent to about half a tablespoon of blood was collected from each man. This sample was used to test for altered cfDNA and cfRNA for the androgen receptor gene (AR).

The researchers were able to detect cfDNA for the AR gene in all 67 blood samples and cfRNA for the AR gene in 59 (88%) of the blood samples. Sequence analysis of the AR cfDNA and cfRNA revealed that more than half (36, 54%) of the men tested had one or more AR abnormalities. These abnormalities included sequence mutations, changes in gene copy number and rearrangements of the genetic material.

The research team then compared the AR cfDNA and cfRNA data to the clinical outcome for the men tested. These men all had advanced prostate cancer, the median time from starting treatment (when the blood sample was first taken) to disease progression was 10.4 months and the median overall survival time was 17.1 months. The researchers found that men whose blood test results showed an increase in AR copy number (AR gain) or multiple AR alterations had a worse clinical outcome then men whose AR was unchanged. For men with AR alterations the median time to disease progression was 3.8 months (vs 12 months for the rest of the group) and the median survival time was 10.4 months (vs 17.1 months for the rest of the group). Disease progression was determined by changes seen in PSA levels and in radiological imaging.

Interestingly, patients treated with Enzalutamide or Abiraterone who had both AR gain and AR rearrangements had shorter median disease-free progression time of 2.1 months and an overall survival time of 11 months.

To verify the data, the team analysed blood samples collected from 40 mCRPC patients for a study conducted at the Mayo Clinic in the USA. The results from this group supported the Australian observations. AR gains or an AR gain in combination with another AR alteration correlated significantly with poor outcome and reduced overall survival.   

In summary, the authors state “In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer”. Importantly, the technique they use is “a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA” meaning that in a single test they can determine both the AR gene changes (in the DNA) and gene expression changes (in the RNA).

The paper’s lead author Heidi Fettke said, "Historically, it has been very difficult to profile metastatic prostate cancer due to difficulties with accessing up-to-date tumour tissue. With this research we hope to make the analysis of blood-based biomarkers a suitable alternative to conventional biopsies, and to better guide therapy in aggressive prostate cancer."    

During treatment for prostate cancer, blood samples are more easily obtained and less invasive then the procedure for obtaining tissue biopsy samples. A/Prof Arun Azad, senior author on the study and medical oncologist at Peter MacCallum Cancer Centre said, “Liquid biopsies have demonstrated strong congruence with tumour biopsies, whilst simultaneously encapsulating the genomic complexity often seen in mCRPC.”

This study demonstrates a simple way to analyse tumour specific changes using blood samples. It brings us closer to treatments for prostate cancer that are tailored to each man’s individual needs. However, before blood biopsies can be made available for the clinical management of prostate cancer, large scale clinical trials are required with much longer patient follow-up times to identify and validate clinically useful biomarkers.

PCFA is proud to support Australian-based clinical trials like these – thank you for enabling our work. 

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