RESUMO
BACKGROUND: Liquid biopsy offers the ability to non-invasively analyze the genome of a tumor through circulating tumor DNA (ctDNA) to identify targetable and prognostic genomic alterations. Few studies have rigorously analyzed ctDNA results and determined the fidelity with which they recapitulate the genomics of a sequenced tissue sample obtained from the same tumor. The clinical utility study (CUS) for the FoundationACT™ ctDNA assay (Foundation Medicine, Cambridge, MA, USA; NCT02620527) is a multi-center prospective clinical study for multiple solid tumor types to compare genomic profiling of paired tissue and blood samples from the same patient. In this subset of the study, paired specimens from 96 patients with colorectal cancer (CRC) were analyzed with comprehensive genomic profiling (CGP) of the tumor tissue sample (FoundationOne®) and blood sample (FoundationACT™). METHODS: Both samples underwent CGP using the hybrid capture-based Illumina Hi-Seq technology. Maximum somatic allele frequency (MSAF) was used to estimate the fraction of ctDNA in the sample. The set of genes and targeted regions common to both tumor and liquid were compared for each subject. RESULTS: Among these patients, 61% were male; 74% had clinical stage IV disease, 19% had clinical stage III disease, and 7% had clinical stage II disease. Time between the tissue biopsy and liquid biopsy (range, 0-709 days) had a significant impact on the positive percent agreement (PPA) between the two assays. Eighty percent of cases had evidence of ctDNA in the blood (MSAF >0). For all cases with MSAF >0, 171 base substitutions and insertions/deletions (indels) were identified in the tumor, and 79% (PPA) of these identical alterations were also identified in matched ctDNA samples; PPA increased to 87% for cases <270 days between the tissue and liquid biopsy, 95% for <90 days, and 100% PPA for <30 days. All known and likely short variants in KRAS, NRAS, and BRAF were analyzed independently as testing of these genes is recommended by the National Comprehensive Cancer Network (NCCN) for patients with CRC and have therapeutic implications. For NCCN genes, PPA was 80% for all time points for short variants; PPA increased to 90% for cases <270 days between the tissue and liquid biopsy. There was high concordance for KRAS G12X between tissue and liquid: overall percent agreement (97%), PPA (93%), negative percent agreement (NPA) (100%), positive predictive value (PPV) (100%), and negative predictive value (NPV) (96%) for the <270 day cohort. CONCLUSIONS: In cases where tumor tissue profiling is not possible, these results provide compelling evidence that genomic profiling of ctDNA in late stage CRC shows a high concordance with tumor tissue sequencing results and can be used to identify most clinically relevant alterations capable of guiding therapy for these patients.
RESUMO
BACKGROUND: This retrospective study was undertaken to determine if the plasma circulating tumor DNA (ctDNA) level and tumor biological features in patients with advanced solid tumors affected the detection of genomic alterations (GAs) by a plasma ctDNA assay. METHOD: Cell-free DNA (cfDNA) extracted from frozen plasma (N = 35) or fresh whole blood (N = 90) samples were subjected to a 62-gene hybrid capture-based next-generation sequencing assay FoundationACT. Concordance was analyzed for 51 matched FoundationACT and FoundationOne (tissue) cases. The maximum somatic allele frequency (MSAF) was used to estimate the amount of tumor fraction of cfDNA in each sample. The detection of GAs was correlated with the amount of cfDNA, MSAF, total tumor anatomic burden (dimensional sum), and total tumor metabolic burden (SUVmax sum) of the largest ten tumor lesions on PET/CT scans. RESULTS: FoundationACT detected GAs in 69 of 81 (85%) cases with MSAF > 0. Forty-two of 51 (82%) cases had ≥ 1 concordance GAs matched with FoundationOne, and 22 (52%) matched to the National Comprehensive Cancer Network (NCCN)-recommended molecular targets. FoundationACT also detected 8 unique molecular targets, which changed the therapy in 7 (88%) patients who did not have tumor rebiopsy or sufficient tumor DNA for genomic profiling assay. In all samples (N = 81), GAs were detected in plasma cfDNA from cancer patients with high MSAF quantity (P = 0.0006) or high tumor metabolic burden (P = 0.0006) regardless of cfDNA quantity (P = 0.2362). CONCLUSION: This study supports the utility of using plasma-based genomic assays in cancer patients with high plasma MSAF level or high tumor metabolic burden.