604 Background: Amps, as oncogenic and resistance drivers, have therapeutic implications, but unlike mutations, have been sparsely described in mCRC. Functional account is piecemeal due to vague definitions, limited data on co-occurring alterations and use of primary tissue samples nonrepresentative of tumor heterogeneity. Our aim was to define the amp landscape in mCRC using tissue and ctDNA sequencing. Methods: We performed systematic analyses of copy-number variation in 2 cohorts of mCRC patients (pts) [tissue (TC) (N = 1,134) and ctDNA (BC) (N = 3,218)] who had high sensitivity targeted sequencing with MSK-IMPACT (341-468 genes) or Guardant Health (70-73 genes) panel, respectively. For BC, plasma copy number was adjusted (ApCN) to account for variable tumor DNA shedding using max allele frequency and high amp (HAmp) was defined as > 4 copies (similar to predefined tissue cutoff). Results: 166 (15%) and 405 (13%) pts in TC and BC harbored amp in at least one of 18 genes assessed by both panels (Table). Amp prevalence for individual gene was similar in both cohorts ( r = 0.9; P < .01) with RTK amps ( EGFR, ERBB2, MET, FGFR1/2, PDGFRA) seen in 8% pts. Key RTK amps were enriched in RAS/BRAF wild type (RB WT) compared to mutant (RB MUT) (OR 3.5; P < .01) pts in both cohorts, in contrast to low prevalence RTK and non-RTK amps. Median ApCN was higher for RTKs in RB WT vs MUT cases ( ERBB2: 12 vs 5; P = .02). Using validated EGFRab exposure (EGFRi) ctDNA signature, we found that EGFRi pts had higher prevalence of EGFR, MET, BRAF, KRAS, PIK3CA and FGFR1 amps compared to EGFRab naïve pts. Conclusions: While individually uncommon, amps occur across key oncogenic pathways in mCRC and after adjusting for ctDNA shedding, are seen at similar prevalence in tissue and plasma. Amps in RTKs are seen in 10-12% of RB WT tumors, suggesting clinically relevant roles as oncogenic effectors and targets. After EGFRi, a number of amps emerge, including PIK3CA and FGFR1 amps, not previously implicated in acquired resistance. [Table: see text]