The assessment of the genomic profiling (comprehensive genomic profiling, CGP) by NGS (next-generation sequencing) of circulating tumor DNA (ctDNA) provides a minimally invasive method for identifying genomic changes and resistance mechanisms in patients with castration-resistant metastatic prostate cancer (mCRPC)
During the 2021 Genitourinary Cancers Symposium, it was presented a trial that detected tumor genomic changes through the ctDNA-based genomic profiling, evaluating consistency with tissue-based genomic changes.
Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from TRITON2/3 trials and 1,660 routine clinical CGP samples) was analyzed through NGS (next-generation sequencing). The results were compared with CGP of 2,006 biopsies of metastatic prostate cancer tissue. Consistency was evaluated in 837 patients with tissue (filed or contemporary) and plasma NGS results.
In total, 3,127 patients (94%) had detectable ctDNA. A brca1/2 mutation was observed in 295 patients (8.8%).
In the consistency analysis, mutations in BRCA1/2 identified in the tissue occurred in 72 of 837 (8.6%) individuals, of which 67 (93%) also had such changes detected by ctDNA. Twenty patients were identified only by ctDNA, but not in tissue, corresponding to 23% of all participants identified based on ctDNA.
The method revealed subclonal reversals of BRCA1/2 in 10 of 1,660 (0.6) clinical samples of routine CGP. Alterations in the androgen receptor, including amplifications and hotspot mutations, were detected in 940 of 2,213 patients (42%).
Rare components of mutations, rearrangements and new in-frame exclusions of the androgen receptor have been identified. Altered pathways included PI3K/AKT/mTOR (14%), WNT/β-catenin (17%) and RAS/RAF/MEK (5%). Microsatellite instability was detected in 31 of 2,213 patients (1.4%).
In the largest trial of mCRPC plasma samples performed to date, the authors conclude that ctDNA CGP detected genomic changes observed in tissue biopsies, with a high level of consistency for BRCA1/2 mutations. In addition, the method also identified individuals who may have acquired somatic changes of BRCA1/2 since the collection of the tissue file. ctDNA revealed more genomic changes in acquired resistance than tissue samples, including new variants of androgen receptor activation. Therefore, the large percentage of patients with a rich genomic signal from ctDNA and the precise detection of BRCA1/2 alterations provide the opportunity for liquid biopsy to be a relevant clinical complement for tissue CGP to patients with mCRPC.
Tukachinsky H, et al. Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms. Abstract 25. 2021 Genitourinary Cancers Symposium. DOI:10.1200/JCO.2021.39.6_suppl.25