A new study from Foundation Medicine, Inc. and collaborators showed that the landscape of genomic alterations found using next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) via liquid biopsy demonstrated high concordance with targetable alterations identified with tissue-based comprehensive genomic profiling (CGP) in patients with metastatic castration-resistant prostate cancer (mCRPC).1
An estimated 1 in 8 men will be diagnosed with prostate cancer, the second-most common cancer in American men, in 2021.2 In patients with mCRPC, cancer grows and metastasizes despite treatment with androgen-deprivation therapy.
The study, published online in Clinical Cancer Research, aimed to assess the clinical validity of the genomic alterations detected in ctDNA from patients’ plasma using minimally invasive liquid biopsy. Researchers also compared the mutation landscape detected by ctDNA NGS with that of tissue-based CGP. The findings will also be presented at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium on Thursday, February 11.
Investigators analyzed plasma from 3334 patients with mCRPC, including 1674 samples taken during screening for the TRITON2 (NCT02952534) and TRITON3 (NCT02975934) trials, which utilized Foundation Medicine’s liquid biopsy test to screen patients for genomic mutations. A further 1660 samples were taken from routine clinical testing. The results were compared with CGP results from 2006 tissue biopsies. In the overall cohort, 3127 patients (94%) had detectable ctDNA, and 295 patients (8.8%) had BRCA1 or BRCA2 mutations.
Researchers evaluated concordance between the 2 methods in 837 patients with both tissue and plasma NGS results available. In that cohort, 8.6% of patients (n = 72) had tissue-detected BRCA1 or BRCA2 mutations, and 67 of those patients (93%) were also identified by ctDNA. This included 100% of predicted germline variants.
Of the patients identified using ctDNA, 20 (23%) were identified with ctDNA but not tissue. The ctDNA NGS also identified patients who may have acquired somatic mutations in the BRCA1 or BRCA2 genes in the time since archival tissue was collected. A range of potential androgen receptor resistance alterations were also detected in 42% of patients using ctDNA, including amplifications, mutations, rearrangements, and novel deletions in exon 8.
The authors concluded that the findings support ctDNA NGS as a clinical complement to tissue CGP in mCRPC, and that testing tissue is an option if ctDNA testing comes back negative for genetic variants that are actionable. The ctDNA NGS had a high level of concordance to tissue CGP in detecting BRCA1 or BRCA2 mutations and detected more variants indicating acquired resistance than tissue CGP. Overall, the ctDNA genomic analysis in the study recapitulated the landscape of mutations found in tissue biopsies for patients with mCRPC.
“One of the most important findings in this study is that the majority of patients with advanced prostate cancer have abundant circulating tumor DNA that can be tested using comprehensive genomic profiling to support doctors as they consider targeted therapies for their patients,” Geoff Oxnard, MD, vice president and global medical lead of the Liquid Franchise at Foundation Medicine, said in a statement. “When tumor tissue is difficult to obtain, as is often the case in patients in mCRPC, liquid biopsy is a proven, minimally-invasive method to secure genomic insights, with the option to reflex to a tissue biopsy if ctDNA turns out to be insufficient to analyze.”
1. Tukachinsky H, Madison RW, Chung JH, et al. Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms. Clin Cancer Res. Published online February 9, 2021. doi:10.1158/1078-0432.CCR-20-4805
2. Key Statistics for Prostate Cancer. American Cancer Society. Updated January 12, 2021. Accessed February 9, 2021. https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html