Genomic cfDNA profiling feasible in metastatic CRPC

By Shreeya Nanda, Senior medwireNews Reporter

Comprehensive genomic profiling of cell-free DNA (cfDNA) can provide clinically useful information in men with castration-resistant prostate cancer (CRPC) treated with enzalutamide, research indicates.

In this study, plasma samples were collected from 65 participants with metastatic disease before the initiation of enzalutamide 160 mg/day treatment, and from a subset of 30 after 12 weeks' treatment and also at progression, when treatment ended.

cfDNA was extracted successfully from 122 samples, and 119 were of sufficient quality to undergo targeted sequencing of exons 2-8 of the androgen receptor (AR) gene. cfDNA samples also underwent array comparative genomic hybridisation to detect copy number alterations.

In all, genomic changes - either AR mutations or copy number aberrations - were identified in 48% of participants at baseline, with the most common being the AR L702H, H875Y and T878A mutations.

The presence of certain genomic alterations at baseline was associated with poor response to enzalutamide - for instance, MET gain and/or amplification and RB1 loss predicted worse progression-free survival even after adjustment for the presence of tumour-derived cfDNA.

Of the post-baseline samples, 60% had genomic alterations, which the researchers say is indicative of "tumor clonal population changes and consistent with complex and dynamic intrapatient heterogeneity".

There were some differences relative to the baseline samples - for example, the AR W742L/C mutation regressed completely in the later samples, while the L702H mutation emerged in an additional five patients.

The team also performed targeted sequencing of 19 prostate cancer-associated genes in samples from 14 patients at the end of treatment. All samples were found to harbour either somatic mutations, copy number alterations or both. Observed aberrations included clinically actionable mutations in PI3K pathway genes and activating mutations in the CTNNB1 gene.

Thus, cfDNA analysis could be "a simple and practical method" for identifying patients most likely to respond to an appropriate agent, Kim Chi (University of British Columbia, Vancouver, Canada) and co-authors write in JAMA Oncology.

They continue: "Beyond the molecular landscape and clinical associations reported herein in the context of enzalutamide treatment, cfDNA therefore holds remarkable promise for the practical implementation of precision medicine programs in advanced prostate cancer."

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