The genomic panorama of circulating tumor DNA (ctDNA) was akin to the panorama of tissue biopsies in a big examine of sufferers with metastatic castration-resistant prostate cancer (mCRPC), in line with researchers.
The kind and frequency of genomic alterations noticed had been largely related in ctDNA and tissue, and there was excessive concordance for BRCA1/2 alterations. Complete genomic profiling (CGP) of ctDNA detected extra acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In truth, alterations in 9 genes had been considerably enriched in ctDNA, however a few of these alterations could also be attributable to clonal hematopoiesis and never the tumor.
Nonetheless, the researchers concluded that CGP of ctDNA may complement tissue-based CGP.
“That is the most important examine of mCRPC plasma samples performed up to now, and CGP of ctDNA recapitulated the genomic panorama detected in tissue biopsies,” stated investigator Hanna Tukachinsky, PhD, from Basis Drugs, the corporate that developed the liquid biopsy checks used on this examine.
“The big proportion of sufferers with wealthy genomic sign from ctDNA and the delicate, particular detection of BRCA1/2 alterations place liquid biopsy as a compelling medical complement to tissue CGP for sufferers with mCRPC.”
Tukachinsky introduced outcomes from this examine on the 2021 Genitourinary Cancers Symposium (Abstract 25). The outcomes had been additionally printed in Clinical Cancer Research, however the next information are from the assembly presentation.
ctDNA Profiling Proves Possible, Comparable
The plasma samples had been profiled utilizing FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.
A lot of the liquid biopsy samples — 94% — had detectable ctDNA, and the median ctDNA fraction was 7.5%.
“Probably the most vital findings on this examine is the truth that the vast majority of sufferers with advanced prostate cancer — 94% of them — have ample ctDNA,” Tukachinsky stated.
“The general panorama we detected in ctDNA extremely resembles landscapes reported in tissue-based CGP research of mCRPC,” she added.
ctDNA outcomes confirmed a excessive proportion of TP53 and AR alterations, in addition to alterations in DNA restore genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase parts (PTEN, PIK3CA, and AKT1), and WNT parts (APC and CTNNB1).
“It ought to be famous that the 2 assays didn’t bait for TMPRSS2-ERT fusions or SPOP …and we’re lacking homozygous deletions, which impacts the frequency we detect PTEN, RB1, and BRCA alterations,” Tukachinsky stated.
When the researchers in contrast outcomes from the three,334 liquid biopsy samples and the two,006 tissue samples, they discovered that almost all genes had been altered at related charges.
Nonetheless, 9 genes had been considerably enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.
Tukachinsky famous that JAK2, GNAS, and IDH2 alterations are not often detected in mCRPC tissue and are seemingly attributable to clonal hematopoiesis. Alterations in TERT and NF1, in addition to among the alterations in ATM and CHEK2, may additionally be attributed to clonal hematopoiesis, she added.
Uncommon and Novel AR Alterations
“ctDNA detected extra acquired resistance genomic alterations than tissue, together with novel and uncommon AR-activating variants,” Tukachinsky stated.
She famous that F877L/T878A, a compound mutant that has been proven to confer synergistic resistance to enzalutamide, was present in 11 sufferers.
Equally, “fully novel” in-frame mutations spanning residues H875 to T878 had been present in 11 sufferers, and every shifted S885 into the T878 place.
“Though these require extra experiments to show that they’re activating, their repeated look in numerous sufferers with mCRPC and alignment of the serine residues is very suggestive that they’re activating,” Tukachinsky stated.
The researchers additionally discovered, in 160 sufferers, AR rearrangements that truncate the studying body simply after exon Three to yield a receptor with an intact DNA binding area however with no ligand binding area.
“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR goal genes,” Tukachinsky stated.
BRCA1/2: Excessive Concordance
To additional assess concordance between ctDNA and tissue, Tukachinsky and colleagues evaluated a subset of 837 sufferers with matched tissue and liquid biopsies.
The researchers noticed excessive concordance in BRCA1/2 brief variants and rearrangements. The optimistic % settlement was 93.1%, the damaging % settlement was 97.4%, and the general % settlement was 97.0%.
There have been 5 sufferers in whom BRCA1/2 alterations had been detected in tissue however not ctDNA, and there have been 20 sufferers in whom BRCA1/2 alterations had been detected in ctDNA however not tissue.
The false negatives might be the results of low ctDNA fraction, a minor clone, or filtering out by put up analytics, stated examine discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She additionally postulated that the false positives might be defined by clonal hematopoiesis or metastases from a subclone.
Implications for Observe
This examine confirmed that liquid and tissue biopsies can carry out comparably in figuring out sufferers with BRCA1/2 variants who might profit from PARP inhibition, Tukachinsky famous. Moreover, ctDNA revealed novel AR variants that could be driving resistance to AR-signaling inhibitors. Nonetheless, the presence of alterations which will derive from clonal hematopoiesis suggests ctDNA outcomes ought to be interpreted with some warning, she added.
“NCCN [National Comprehensive Cancer Network] pointers have not too long ago modified to incorporate liquid biopsy as an possibility. There’s positively some skepticism about liquid biopsy…That stated, liquid biopsy can be a fairly highly effective device,” Tukachinsky stated.
“We’re not advocating liquid biopsy over tissue. Within the instances the place tissue’s not accessible, or when you have a main, in some instances, liquid may function complement to provide the full image of what is going on on within the tumor,” she added.
“In the interim, tissue will nonetheless be our gold customary,” Gillessen stated. “And if we will not get the tissue examined, that will likely be then possibly some extent for the liquid biopsy.”
Tukachinsky’s analysis was funded by Basis Drugs and Clovis Oncology. She and her colleagues disclosed relationships with each corporations and a spread of different corporations. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and a number of other different corporations in addition to a patent for a biomarker technique (WO 3752009138392 A1).
This text initially appeared on MDedge.com, a part of the Medscape Skilled Community.