e15081 Background: Comprehensive genomic profiling (CGP) is standard-of-care for identifying actionable mutations in advanced cancers. However, whether liquid biopsy (LBx) or tissue biopsy (TBx) alone captures all therapeutically relevant alterations remains unclear. We evaluated blood-tissue concordance and clinical impact of complementary NGS testing. Methods: We analyzed 10 patients with advanced solid tumors (colon n = 4, lung n = 3, breast/gastric/pancreas n = 1 each; median age 64 years, range 48-78) who underwent tissue and blood testing using Caris comprehensive genomic profiling. Specimens were collected at different timepoints (median 7 days apart, tissue performed first in 70%). Thirty-three variant observations across 8 evaluable cases were classified as concordant (detected in both), blood-only, or tissue-only. Actionable variants were defined as alterations with FDA-approved targeted therapies. Gene Ontology enrichment was also performed on concordant gene sets using clusterProfiler with org.Hs.eg.db. Results: Blood-tissue concordance was 87.9% (29/33 variants). ctDNA captured all tissue-detected variants plus 4 blood-only findings in 4 patients (12.1%), including one FDA-actionable alteration. One of the cases harbored an EML4::ALK fusion detected exclusively by LBx, missed by TBx. The patient initiated alectinib therapy 2 weeks prior to data cutoff on the 05 Jan 2026 (response assessment pending). Without complementary LBx, this actionable driver would have been missed, precluding access to an ALK inhibitor with expected PFS of 25-34 months. Concordant genes (n = 12: TP53, APC, KRAS, EGFR, CTNNB1, PIK3CA, others) were significantly enriched for canonical Wnt signaling (p.adj = 0.002), cell cycle G1/S transition (p.adj = 0.004), and regulation of apoptosis (p.adj = 0.004), representing core carcinogenic drivers. Conclusions: Liquid biopsy demonstrates high concordance with tissue-based testing for core driver mutations but uniquely captures actionable therapeutic targets (ALK fusions) missed by single-site tissue sampling. Liquid biopsy captured spatial/temporal tumor heterogeneity not represented in the single tissue sample. Complementary blood-tissue NGS testing identified actionable therapeutic targets in 10% of patients that would have been missed by single-modality profiling. These findings support dual modality testing to maximize detection of actionable alterations and optimize treatment selection. Validation in a larger prospective cohort is needed to establish clinical utility and inform testing guidelines.
Dawood et al. (2026) studied this question.