The genomic landscape of circulating tumor DNA (ctDNA) became identical to the landscape of tissue biopsies in see of sufferers with metastatic castration-resistant prostate most cancers (mCRPC), per researchers.
The type and frequency of genomic alterations observed had been largely identical in ctDNA and tissue, and there became excessive concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected extra received resistance alterations, which included unique androgen receptor (AR)–activating variants. In actual fact, alterations in nine genes had been vastly enriched in ctDNA, nevertheless a majority of these alterations would possibly possibly presumably well even be attributable to clonal hematopoiesis and no longer the tumor.
Peaceful, the researchers concluded that CGP of ctDNA would possibly possibly presumably well also complement tissue-primarily based CGP.
“Right here’s the largest see of mCRPC plasma samples performed up to now, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” mentioned investigator Hanna Tukachinsky, PhD, from Basis Remedy, the company that developed the liquid biopsy assessments outdated in this see.
“The total percentage of sufferers with rich genomic signal from ctDNA and the sensitive, insist detection of BRCA1/2 alterations situation liquid biopsy as a compelling clinical complement to tissue CGP for sufferers with mCRPC.”
Tukachinsky offered outcomes from this see on the 2021 Genitourinary Cancers Symposium (Abstract 25). The outcomes had been moreover published in Clinical Cancer Research, nevertheless the following data are from the meeting presentation.
ctDNA Profiling Proves Feasible, Connected
The plasma samples had been profiled the utilize of FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.
Many of the liquid biopsy samples — 94% — had detectable ctDNA, and the median ctDNA share became 7.5%.
“One in all an awfully powerful findings in this see is the reality that most of sufferers with superior prostate most cancers — 94% of them — maintain abundant ctDNA,” Tukachinsky mentioned.
“The total landscape we detected in ctDNA extremely resembles landscapes reported in tissue-primarily based CGP look at of mCRPC,” she added.
ctDNA outcomes showed a excessive percentage of TP53 and AR alterations, as properly as alterations in DNA restore genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase parts (PTEN, PIK3CA, and AKT1), and WNT parts (APC and CTNNB1).
“It desires to be infamous that the 2 assays did no longer bait for TMPRSS2-ERT fusions or SPOP …and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Tukachinsky mentioned.
When the researchers when compared outcomes from the three,334 liquid biopsy samples and the 2,006 tissue samples, they found that practically all genes had been altered at identical charges.
Nonetheless, nine genes had been vastly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.
Tukachinsky infamous that JAK2, GNAS, and IDH2 alterations are no longer regularly detected in mCRPC tissue and are doubtless attributable to clonal hematopoiesis. Alterations in TERT and NF1, as properly as just some of the alterations in ATM and CHEK2, would possibly possibly presumably well moreover be attributed to clonal hematopoiesis, she added.
Rare and Original AR Alterations
“ctDNA detected extra received resistance genomic alterations than tissue, including unique and rare AR-activating variants,” Tukachinsky mentioned.
She infamous that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, became found in 11 sufferers.
Similarly, “completely unique” in-physique mutations spanning residues H875 to T878 had been found in 11 sufferers, and each shifted S885 into the T878 situation.
“Though these require extra experiments to expose that they are activating, their repeated look in varied sufferers with mCRPC and alignment of the serine residues is extremely suggestive that they are activating,” Tukachinsky mentioned.
The researchers moreover found, in 160 sufferers, AR rearrangements that truncate the reading physique excellent after exon 3 to yield a receptor with an intact DNA binding arena nevertheless without a ligand binding arena.
“These truncated receptors had been demonstrated to confer resistance to AR signaling inhibitors and pressure transcription of the AR target genes,” Tukachinsky mentioned.
BRCA1/2: High Concordance
To further assess concordance between ctDNA and tissue, Tukachinsky and colleagues evaluated a subset of 837 sufferers with matched tissue and liquid biopsies.
The researchers observed excessive concordance in BRCA1/2 brief variants and rearrangements. The actual p.c settlement became 93.1%, the detrimental p.c settlement became 97.4%, and the total p.c settlement became 97.0%.
There had been 5 sufferers in whom BRCA1/2 alterations had been detected in tissue nevertheless no longer ctDNA, and there had been 20 sufferers in whom BRCA1/2 alterations had been detected in ctDNA nevertheless no longer tissue.
The spurious negatives would possibly possibly be the break outcomes of low ctDNA share, a minor clone, or filtering out by put up analytics, mentioned see discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She moreover postulated that the spurious positives would be defined by clonal hematopoiesis or metastases from a subclone.
Implications for Notice
This see showed that liquid and tissue biopsies can type comparably in figuring out sufferers with BRCA1/2 variants who would possibly possibly presumably well also make a selection pleasure in PARP inhibition, Tukachinsky infamous. Furthermore, ctDNA printed unique AR variants that can be using resistance to AR-signaling inhibitors. Nonetheless, the presence of alterations that can acquire from clonal hematopoiesis suggests ctDNA outcomes desires to be interpreted with some warning, she added.
“NCCN [National Comprehensive Cancer Network] tricks maintain currently changed to embody liquid biopsy as an possibility. There’s positively some skepticism about liquid biopsy…That mentioned, liquid biopsy is moreover a reasonably extremely effective tool,” Tukachinsky mentioned.
“We are no longer advocating liquid biopsy over tissue. Within the cases the establish tissue’s no longer on hand, or at the same time as you occur to maintain a major, in some cases, liquid would possibly possibly presumably well also abet as a correct complement to come up with the fleshy image of what’s occurring within the tumor,” she added.
“For the time being, tissue will unexcited be our gold accepted,” Gillessen mentioned. “And if we are able to no longer fetch the tissue examined, that can be then presumably some extent for the liquid biopsy.”
Tukachinsky’s look at became funded by Basis Remedy and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a differ of varied companies. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several varied companies as properly as a patent for a biomarker formulation (WO 3752009138392 A1).
This text on the starting up regarded on MDedge.com, piece of the Medscape Educated Network.