Rare and novel AR alterations
“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.
She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.
Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.
“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.
The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.
“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.
BRCA1/2: High concordance
To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.
The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.
There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.
The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.
Implications for practice
This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.
“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.
“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.
“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”
Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).