Role of <i>RAS/BRAF</i> and <i>PIK3CA</i> mutations in tissue and plasma for prognostic assessment in metastatic colorectal cancer (mCRC).

281 Background: Mutations in RAS/BRAF ( RAS/BRAFm ) and PIK3CA ( PIK3CAm ) genes have been described as mechanisms of resistance to anti-EGFR agents in mCRC. However, the utility of liquid biopsy in their baseline detection remains unknown. We aim to analyse oncological outcomes according to RAS/BRAF and PIK3CA mutational status in tissue &amp; plasma in mCRC. Methods: We conducted aretrospective study in patients (pts) with mCRC from 2017 to 2024. RAS/BRAF and PIK3CA mutational status assessment was performed at baseline using Idylla (Biocartis) and Cobas PIK3CA kits, respectively. Cox models were used to analyse overall survival (OS) in RAS/BRAFm and PIK3CAm vs wild-type (WT) population. Results: We analysed 404 paired samples (tissue &amp; plasma) from 202p with mCRC. RAS/BRAFm was described in 45% (91p) in tissue and in 43.6% (88p) in plasma. PIK3CA was tested in 84p, with PIK3CAm detection in 19% (16p) in tissue and 11.9% (10p) in plasma. Liver involvement was more frequent in RAS/BRAFm vs WT (80.6% vs 63.9%; p=0.02), and in PIK3CAm vs WT population (94.4% vs 63.6%; p=0.01). Concordance study (tissue &amp; plasma) for RAS/BRAF and PIK3CA are presented (Table). Subjects with concordant results had worse OS in RAS/BRAFm (18.1m vs 51.1m, HR=2.60; p&lt;0.001) regardless of liver involvement, and showed the same trend in PIK3CAm (22.6m vs 28.1m, p=0.81). Patients with discordant results and plasma RAS/BRAFm or plasma PIK3CAm showed worse OS (23.7 m vs 51.1m; p = 0.006 and 16.4 m vs 42.5 m; p=0.18, respectively) and a lower disease control rate with anti-EGFR therapy (p = 0.04 and p=0.42, respectively). PIK3CAm were evenly distributed in RAS/BRAF WT vs mutated tumors (50% vs 51.5%; p=0.92) and had no independent prognostic impact in OS after stratifying by RAS/BRAF mutational status; RAS/BRAF WT (p=0,93) and RAS/BRAFm (p=0,91). Conclusions: Baseline determination of RAS/BRAFm and PIK3CAm by liquid biopsy in mCRC provide valuable prognostic and predictive information, extending its utility beyond tissue-based analysis. Correlation study of RAS/BRAF and PIK3CA mutational status in tissue and plasma in mCRC. RAS/BRAF tissue PIK3CA tissue RAS/BRAF Plasma Mutated n (%) WT n (%) Total n (%) PIK3CA Plasma Mutated n (%) WT n (%) Total n (%) Mutated n (%) 72 (80) 15 (13.4) 87 (43.1) Mutated n (%) 7 (43.8) 2 (2.9) 9 (10.7) WT n (%) 18 (20) 97 (86.6) 115 (56.9) WT n (%) 9 (56.2) 66 (97.1) 75 (89.3) Total n (%) 90 (100) 112 (100) 202 (100) Total n (%) 16 (100) 68 (100) 84 (100) Positive agreement: 72/90: 80% Positive agreement: 7/16: 43.8% Negative agreement: 97/112: 86.6% Negative agreement: 66/68: 97.1% Overall agreement: 169/202: 83.6%