Prevalence of ARID1A Mutations in Cell-Free Circulating Tumor DNA in a Cohort of 71,301 Patients and Association with Driver Co-Alterations

ARID1A abnormalities disturb transcriptional processes regulated by chromatin remodeling and correlate with immunotherapy responsiveness. We report the first blood-based cell-free DNA (cfDNA) next-generation sequencing (NGS) ARID1A analysis. From November 2016 through August 2019, 71,301 patients with advanced solid tumors underwent clinical blood-derived cfDNA testing. Of these patients, 62,851 (88%) had >= 1 cfDNA alteration, and 3137 (of the 62,851) (5%) had >= 1 deleterious ARID1A alteration (a frequency similar to the similar to 6% generally reported in tissue NGS), suggesting this non-invasive test's value in interrogating ARID1A. ARID1A cfDNA alterations were most frequent in endometrial cancer, 21.3% of patients; bladder cancer, 12.9%; gastric cancer, 11%; cholangiocarcinoma, 10.9%; and hepatocellular carcinoma, 10.6%. Blood samples with a functional ARID1A abnormality had more alterations/sample (median, 6 versus 4; p < 0.0001) and more frequent co-alterations in >= 1 gene in key oncogenic pathways: signal transduction, RAS/RAF/MAPK, PI3K/Akt/mTor, and the cell cycle. Taken together, our data suggest that liquid (blood) biopsies identify ARID1A alterations at a frequency similar to that found in primary tumor material. Furthermore, co-alterations in key pathways, some of which are pharmacologically tractable, occurred more frequently in samples with functional (deleterious) ARID1A alterations than in those without such aberrations, which may inform therapeutic strategies.

Automated summary

ARID1A abnormalities identified in blood samples are associated with immunotherapy responsiveness and have a frequency similar to that found in tissue samples. Furthermore, samples with functional ARID1A abnormalities show more co-alterations, potentially informing therapeutic strategies.