Precision oncology in practice: Comprehensive genomic profiling identifies actionable alterations and guides therapeutic selection in 756 clinical solid tumors

Background: Comprehensive genomic profiling (CGP) of solid tumors is increasingly used to inform targeted and immune-directed therapies; real-world performance data are needed to guide further adoption. This study reports multi‑laboratory experience running the TSO500 (TruSight Oncology 500) solid tumor assay on 756 clinical FFPE samples across different tumor types and evaluates, variant tier and biomarker distribution that impacts treatment decisions. Methods: TSO500 was performed on 756 routine clinical specimens, where DNA/RNA were isolated from FFPE specimens. Sequencing was performed at two sites using NovaSeq600. Post sequencing, NGS data was analyzed using Illumina TSO500 analysis pipeline. SNVs, INDELs, Copy Number Alterations were estimated from DNA whereas gene fusions were estimated and reported using tumor RNA. Variants were classified as per AMP/ASCO/CAP tiers. Other biomarkers including tumor mutational burden (TMB) and microsatellite instability (MSI) were reported. Clinical decision impact was assessed by variant Tier classification. Results: Of the 756 clinically reported samples, major disease types included lung cancer (63.3%), colorectal cancer (11.51%), solid neoplasm (9.26%), pancreatic cancer (5.16%), melanoma (1.72%) and breast cancer (1.19%). of the 12,461 reported variants across all samples, 19.3% (2407/12461) were classified by AMP variant classification. 50% (1216/2407) of these variants were actionable variants (AMP Tier I/II). Tier III variants of unknown significance comprised 29.3% (705/2407) and Tier IV/benign 20.2% (486/2407). Clinically relevant biomarkers detected included high TMB (≥10 mut/Mb) in 32.8% and MSI‑high in 3.3% of cases; gene fusions were detected in 9.8% (74/756). CGP results informed treatment selection (Variants with strong clinical significance (e.g., those with FDA-approved therapies or included in professional guidelines) in 30% of cases and Variants with potential clinical significance (e.g., supported by preclinical data, case reports, or ongoing clinical trials in 58% of overall specimens tested. Additionally, Tier 3 variants of unknown significance were reported in 60% of cases. Conclusions: In this large real‑world study, our CGP assay delivered identified actionable genomic alterations in nearly half of cases across diverse solid tumors. These results demonstrate the high‑throughput CGP assay, provide scalable detection of molecular alterations to support precision oncology, enabling reporting and therapy selection of hundreds of samples per week.