ctDNA predicts resistance to AR-targeted therapy

Date Posted: 
2018-01-26

Drs. Wyatt, Chi and their teams have a new Cancer Discovery publication, "Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer,"  in which they identify novel genomic biomarkers that could ultimately help decide whether patients with advanced prostate cancer should receive abiraterone or enzalutamide. These biomarkers are available via a non-invasive technique, and therefore this analysis is highly suitable for integration into general clinical practice.
 
The standard of care therapies for metastatic castration-resistant prostate cancer, abiraterone and enzalutamide, are not effective in 10-30% of patients. We currently are unable to recognize this subset of patients up-front, which means they are treated with a drug that will not work and which gives them unnecessary treatment side-effects.

Our unique research team combines cancer bioinformatics expertise (Wyatt) with clinical oncology (Chi) to develop genomic-based strategies that better recognize patients with poor prognoses. Our prior work has shown that changes detected in ctDNA accurately reflect cancer itself and can therefore show the DNA changes occurring in a patient’s prostate cancer before, during, and after treatment.

In this paper we looked at changes occurring in the ctDNA of 202 Canadian men with prostate cancer enrolled on a phase II clinical trial comparing treatment with abiraterone to enzalutamide. We determined which changes can predict a patient’s subsequent response to treatment. In particular, alterations in DNA repair genes and the gene TP53 were strongly linked to poor outcomes with both therapies – and were independent of standard prognostic biomarkers (i.e. they provide prognostic information beyond what is currently available from clinical metrics). We also identified novel AR gene alterations (the AR is the central target of both therapies) in several patients who derived no benefit from therapy.

This work was supported by grants from the Canadian Cancer Society, Prostate Cancer Canada/Movember Canada, the Emil Aaltonen Foundation, the Prostate Cancer Foundation, and The Terry Fox Research Institute, as well as clinical trials funding from Janssen and Astellas.

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