This study included plasma from 3,334 patients with advanced prostate cancer (including 856 mCRPC screening samples from the TRITON2 trial, 818 mCRPC screening samples from the TRITON3 trial, and 1,660 samples from routine clinical comprehensive genomic profiling) and was analyzed using hybrid-capture-based gene panel next-generation sequencing assays. Results were compared with comprehensive genomic profiling of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma next-generation sequencing results. The trial design is as follows:
There were 3,127 patients (94%) that had detectable ctDNA, with a median ctDNA fraction of 7.5%. Additionally, BRCA1/2 was mutated in 295 patients (8.8%). In concordance analysis, 72/837 (8.6%) patients had BRCA1/2 mutations detected in tissue, 67 (93%) of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue (23% of all patients identified using ctDNA). ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 (0.6%) routine clinical comprehensive genomic profiling samples. AR alterations, including amplifications and hotspot mutations, were detected in 940/2,213 patients (42%); rare AR compound mutations, rearrangements, and novel in-frame deletions were also identified. Altered pathways included PI3K/AKT/mTOR (14%), WNT/β-catenin (17%), and RAS/RAF/MEK (5%); microsatellite instability was detected in 31/2,213 patients (1.4%).
Most genes were altered at similar rates in liquid and tissue biopsies. Mutations were significantly enriched in ctDNA in 9 of 70 assayed genes, including (i) acquired resistance to therapy (AR), (ii) mutations rarely detected in mCRPC tissue and likely derived from clonal hematopoiesis (JAK2, IDH2), and (iii) mutations in ATM and CHEK2, which occur with some frequency in mCRPC tissue, but were enriched in ctDNA. As follows is a comparison of mutations detected in liquid biopsies and metastatic tissue biopsies:
The following conclusions were made for this study, the largest of mCRPC plasma samples conducted to date:
- Comprehensive genomic profiling of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in the detection of BRCA1/2alterations
- This study also identified patients who may have gained somatic BRCA1/2alterations since archival tissue was collected
- ctDNA detected more acquired resistance genomic alterations than tissue, including novel AR-activating variants
- The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2alterations position liquid biopsy as a compelling clinical complement to tissue comprehensive genomic profiling for patients with mCRPC
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021