ctDNA TO DETECT NEUROENDOCRINE PROSTATE CANCER

Detection of castration-resistant neuroendocrine prostate cancer (CRPC-NE) may be possible using noninvasive profiling of circulating tumor DNA (ctDNA), according to results from a new study that will presented on Thursday, February 13, during the 2020 Genitourinary Cancers Symposium (Abstract 8).

Approximately 20% of treatment-resistant prostate cancers undergo a loss of androgen receptor signaling dependence, which may manifest as transformation to CRPC-NE. Currently, diagnosis of this malignancy relies on a metastatic tumor biopsy, an invasive procedure with potential for morbidity. Researchers led by Himisha Beltran, MD, of the Dana-Farber Cancer Institute, examined whether ctDNA could be used to identify CRPC-NE–associated genomic and epigenomic changes. They also examined whether ctDNA analyses could be used as a tool to explore tumor heterogeneity and clonal dynamics associated with the malignancyThe study included 64 patients with metastatic prostate cancer; of those, 10 patients were diagnosed with hormone-naive prostate cancer, 35 patients with CRPC adenocarcinoma, and 17 patients with CRPC-NE. The cohort was prospectively enrolled for matched metastatic biopsy and blood collection. A total of 24 patients had results from multiple time points, yielding 69 plasma tissue samples and 98 metastatic tissue samples. The researchers conducted whole exome sequencing and whole genome bisulfite sequencing of ctDNA, germline DNA, and the metastatic biopsy tissue.

“Overal,l there was high concordance of alterations between ctDNA and patient-matched metastasis,” the study authors reported. The highest concordance was seen in the patients with CRPC-NE, and there was also less heterogeneity across patients with this malignancy.

The frequencies of alterations were consistent with those seen in published tissue-based studies; AR alterations were enriched in the patients with CRPC adenocarcinoma, while TP53 and RB1 loss were enriched in the ctDNA of patients with CRPC-NE. Further, clonal and subclonal tumor cell populations could be detected and tracked using allele-specific copy number analysis and serial sampling; cell-free DNA methylation was found to be reflective of methylation patterns in biopsies.

The authors noted that the prognostic significance of these alterations differed based on histologic subtype. They found that a targeted set combining genomic and epigenomic markers was capable of identifying patients with CRPC-NE; this set included four genomic targets (TP53, RB1, CYLD, and AR) and 20 differential DNA methylation sites.

“The results of this study are encouraging, supporting the chance of avoiding more invasive biopsies in the future,” said Francesco Montorsi, MD, of IRCCS Ospedale San Raffaele, in Milan, who will co-chair the session. “However, the clinical utility of these findings should be carefully evaluated.” Dr. Montorsi provided his comments to ASCO Daily News in advance of the presentation.

“The results of this study are encouraging, supporting the chance of avoiding more invasive biopsies in the future. However, the clinical utility of these findings should be carefully evaluated.”—Dr. Francesco Montorsi

Dr. Montorsi added that the proliferation of new therapies for metastatic CRPC suggests that ctDNA analysis might be used to establish predictive biomarkers and help guide choices among those systemic agents, as well as potentially guide a change in therapy based on early alterations in ctDNA.

“Therefore, specific clinical trials are needed to test the clinical implications of ctDNA in the therapeutic pathways,” Dr. Montorsi said.