By Diagnostics World Staff
December 17, 2024 | A study led by the University of Minnesota Medical School and Duke University found that a cell free DNA sequencing assay for advanced prostate cancer patients can distinguish between patients with poor and favorable prognoses. The study was published last week in Nature Communications (DOI: 10.1038/s41467-024-54847-1).
The assay, AR-ctDETECT, detects low volumes of circulating tumor DNA (ctDNA) among cell free DNA (cfDNA) circulating in plasma in the blood of certain patients with advanced, metastatic prostate cancer. The test was validated with blood samples from a phase 3 clinical trial of advanced prostate cancer patients. The test identified ctDNA in 59% of patients with metastatic prostate cancer. Patients with detectable circulating tumor DNA had significantly worse overall survival compared to those without.
“Our AR-ctDETECT test, designed for prostate cancer, shows how valuable these blood tests could be in helping doctors better understand a patient's cancer and predict how the disease will progress, leading to more personalized treatment plans,” said Scott Dehm, PhD, a professor at the U of M Medical School and member of the Masonic Cancer Center, in a press release.
Prostate cancer is initially treated with therapies that inhibit the androgen receptor (AR), but the disease will eventually progress to metastatic castration resistant prostate cancer (mCRPC). Most patients remain AR dependent and are treated with drugs targeting the androgen receptor, but approximately 20–30% of mCRPC patients have primary resistance to these agents and may instead benefit from AR-independent therapies, the authors write. “There is an unmet need for cfDNA assays able to prognosticate outcomes in mCRPC patients, particularly in the context of AR-targeted therapies.”
The team from the University of Minnesota and Duke University set out to meet that need.
“The AR-ctDETECT assay is a comprehensive panel focused on genes relevant to prostate cancer and hormone resistance, particularly the androgen receptor and critical structural alterations not currently detected by other commercial tests,” said Andrew Armstrong, MD, a professor at Duke University School of Medicine, an oncologist with Duke Cancer Institute and co-senior author on the study. “Incorporating genomic profiling into clinical decision-making may enhance personalized treatment strategies and inform the design of future clinical trials.”
AR-ctDETECT was developed to find DNA alterations in AR with paired-end DNA sequencing, and other known actionable alterations that occur in metastatic prostate cancer patients, using low input volumes of plasma, the authors write. “A unique aspect of the AR-ctDETECT cfDNA-seq assay design is the ability to identify ctDNA uniquely in mCRPC patients via comprehensive profiling of AR alterations including mutations, amplification, enhancer amplification, and gene structural rearrangements (GSRs), as well as gains in MYC and/or MYCN, due to the high sensitivity for detecting these alterations relative to normal cells,” they continue.
The groups tested their assay with plasma collected prior to treatment in the phase 3 Alliance A031201 trial, which randomized men 1:1 to treatment with enzalutamide or enzalutamide plus abiraterone. “While this trial did not demonstrate improved survival with the combination therapy, it represented an important opportunity to evaluate the AR-ctDETECT assay in both treatment arms for prognostic utility,” the authors write. The assay was used on 789 samples from this trial and 776 of those samples passed quality control checks during library preparation and DNA-seq.
“Our team demonstrated the ability of AR-ctDETECT to effectively identify distinct groups of patients based on their genomic profiles,” said Susan Halabi, PhD, a James B. Duke Distinguished Professor of Biostatistics at Duke University School of Medicine. “Notably, our study is the first to demonstrate, within a phase 3 cohort, that metastatic prostate cancer patients with positive ctDNA treated with standard therapies had worse overall survival compared to ctDNA-negative patients.”
The authors outline some limitations to their work including the low volumes of plasma available for analysis leading to low yields of cfDNA in many samples and that targeted DNA-seq was performed on cfDNA without patient-matched germline controls, blood, or tumor tissue, which limits the assay’s ability to accurately distinguish between somatic or germline alterations in target genes. They plan to focus future research on integrating genetic data from the AR-ctDETECT test with patient clinical data to improve patient prognostication, and to evaluate whether the AR-ctDETECT test could be used to predict patient outcomes in the context of specific treatments, which could guide optimal therapy.