e23120 Background: Targeted therapy can benefit advanced cancer patients in the context of a clinically relevant genomic alteration (CRGA) (Schwaederle, 26304871). Comprehensive genomic profiling (CGP) may facilitate this approach by assaying all classes of genomic alterations (GA) across many cancer related genes; in contrast focused (‘hotspot’) NGS assesses only specific changes in select genes. We reviewed the records of 57 consecutive advanced solid tumor patients assayed with both CGP and hotspot testing (Caris) via clinical care. Methods: > 50 ng of DNA per specimen was extracted from 57 formalin-fixed paraffin-embedded clinical tumor samples and CGP (hybrid capture-based NGS) was performed on adaptor ligation based libraries to high, uniform coverage ( > 500x) for all exons of 182/236 genes and 14/19 genes frequently rearranged in cancer. Hotspot testing was conducted on selected exons of 44 genes using an Illumina Truseq Amplicon panel, as well as IHC and FISH.. Results: The median age of the patients was 53 (range 21-85). Tumor types studied: breast carcinoma 17 cases (30%), colon cancer 10 cases (18%), and carcinoma of unknown primary 6 cases (11%) , and others. When tested by hotspot, 44 cases (77%) had at least one GA; 13 (22%) had no GA.When assayed with CGP, all but one case (98%) harbored at least one GA. For cases without GA on hotspot, CGP identified CRGA including three instances of PTEN GA, two each of CCND1 and FGFR1 amplifications, and an IDH1 mutation in all but one such case. In 17 breast cases, the most commonly studied tumor type, 108 GA were identified by CGP ( ≥ 1 in 17/17) , and 19 GA by hotspot testing ( ≥ 1 in 12/17). Strikingly, CGP in breast patients identified ESR1 mutations (n = 3 pts), FGFR1 amplifications (n = 2), CCND1 amplification (n = 1), and a PALB2 mutation (n = 1), all missed by hotspot testing. Conclusions: CGP in the course of clinical care identifies more CRGA than hotspot assays, as of cases negative for GA by hotspot testing, 76% had CRGA. For breast cancer cases, avenues of benefit were identified from targeted therapies such as PARP inhibitors, palbociclib, and various investigational agents.