Dr. Beltran on Using cfDNA to Detect Castration-Resistant Neuroendocrine Prostate Cancer

Himisha Beltran, MD, associate professor of medicine and physician in the Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology at the Dana-Farber Cancer Institute and Harvard Medical School, discusses the use of cell-free DNA (cfDNA) to detect castration-resistant neuroendocrine prostate cancer.

Investigators started to examine dynamic changes in the cfDNA that occur during the course of treatment resistance. In some cases, they saw that prostate cancer patients had multiple clones in the circulation that changed with time; others were dominated by a resistant clone that persists, says Beltran. These areas beg for further exploration, adds Beltran: understanding clonal evolution through serial cfDNA sampling can help understand how and when patients develop resistance during the course of their treatment, paving the way for strategies geared towards early intervention.

Investigators also looked at DNA methylation of cfDNA. Notably, neuroendocrine prostate cancer has common genomic alterations as prostate adenocarcinoma; however, the DNA methylation profile is very different and many of the genes that are differentially methylated and dysregulated are genes involved in differentiation and plasticity, explains Beltran. As such, the cfDNA methylation profiles were also compared with tumor biopsies and they were found to be fairly robust. The methylation profiles are going to be an important layer in trying to better identify this resistant subgroup, predicts Beltran.

The exploratory study initially examined highly selected patients doing extensive, in-depth analyses. Using this information, investigators developed a more targeted panel of genes, which is much more clinically applicable—especially in situations where there are not a lot of cfDNA due to lower tumor burden, explains Beltran. The next steps of this research are to apply the targeted panel to clinical trial cohorts to see how often neuroendocrine prostate cancer alterations arise after androgen receptor—directed therapies. Are they early or are they selected for? How do these cfDNA alterations correlate with expression of emerging therapeutic targets that are being developed for this subgroup? After validation, all of this will hopefully lead to the identification of a biomarker that could help identify patients developing neuroendocrine prostate cancer and help in treatment selection for clinical trials, concludes Beltran.