Blood-Based Next-Generation Sequencing in Adrenocortical Carcinoma

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with poor prognosis. We aimed to evaluate the feasibility of next-generation sequencing (NGS) testing of circulating cell-free tumor DNA (ctDNA) in patients with ACC, to characterize the genomic landscape of alterations, and to identify potential clinically actionable mutations. METHODS: Retrospective analysis of genomic data from 120 patients with ACC who had ctDNA testing between 12/2016 and 10/2021 using Guardant360 (Guardant Health, CA) was performed. ctDNA NGS analysis interrogated single nucleotide variants, fusions, indels, and copy number amplifications of up to 83 genes. The frequency of genomic alterations, landscape of co-occurring mutations, and pathogenic/likely pathogenic alterations with potential targeted therapies was identified. The prevalence of alterations identified in ctDNA was compared to those detected in tissue using a publicly available database (cBioPortal). RESULTS: The median age of this cohort was 53 years (range 21-81), and 56% of patients were female. Ninety-six patients (80%) had ≥1 somatic alteration detected. TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%) were found to be the most frequently altered genes in ACC samples. Pathogenic and/or likely pathogenic mutations in therapeutically relevant genes were observed in 56 patients (47%) and included EGFR, BRAF, MET, CDKN2A, CDK4/6, and ATM. The most frequent co-occurring mutations were EGFR + MET (9%), MET + CDK4 (7%), EGFR + CDK4 (7%), and BRAF + MET (7%). The frequencies of mutations detected in ctDNA were similar to those detected in tissue. CONCLUSIONS: Utilizing blood-based NGS to characterize genomic alterations in advanced ACC is feasible in over 80% of patients. Almost half of the patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options or identify clinical trials available for this aggressive malignancy.