The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.
Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.
“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.
“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”
Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (). The results were also published in , but the following data are from the meeting presentation.
ctDNA profiling proves feasible, comparable
CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in theand trials.
The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.
Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.
“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.
“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.
ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).
“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.
When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.
However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.
Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.