NGS testing for patient selection in left-sided RAS/BRAF wild-type metastatic colorectal cancer receiving anti-EGFR therapy.

e15565 Background: RAS/BRAF polymerase chain reaction (PCR)-testing is currently used for the selection of monoclonal antibody for patients (pts) with left-sided metastatic colorectal cancer (LS mCRC). Recently PARADIGM trial showed that the use of Next-generation sequencing (NGS) for the selection of monoclonal antibody can improve the outcomes in patients (pts) with wild type (wt) RAS mCRC. The purpose of current study was to analyze the value of NGS-testing for therapy selection. Methods: We retrospectively analyzed archival PCR-based wt RAS/BRAF tumor specimens of pts with LS mCRC who received anti-EGFR therapy in the 1-st line setting from 2018 to 2023 in Moscow City Сlinical hospital named after S.S. Yudin. Custom NGS-panel evaluated formalin-fixed paraffin-embedded tumor specimens for mutations in the following genes associated with anti-EGFR resistance: AKT1/2, BRAF, ERBB2/3, FGFR1/2, KRAS, MET, NRAS, PIK3CA, PTEN, RAC1, RAF1, RIT1 and MSI status. Progression-free survival (PFS) in wt and mutant cohorts was assessed. Results: A total of 82 pts were included in the analysis. In 20 (24.4%) specimens NGS revealed additional gene alterations associated with anti-EGFR resistance (uncommon KRAS – 45%, BRAF class II/III - 20%, ERBB2 or 3 – 20%, PIK3CA – 5%, PTEN – 5%, MSI – 5%). Mutations were more common in tumors located in splenic flexure or descending colon compared to distal parts (62.5% vs 20.3%, respectively, р=0.02). Median PFS were 9.4 and 21.6 months for NGS-mutant and NGS-wt cohorts, respectively (HR=3.15, 95%CI 1.56 - 6.36). Mutation genotype was the only independent negative prognostic variable in multivariate сox` regression model (HR=3.04, 95%CI 1.50-6.18). Conclusions: NGS-based testing model improves the selection of pts for anti-EGFR therapy in LS mCRC and may substitute RAS/BRAF PCR-testing. Further prospective randomize trial is warranted to confirm these results. PFS in anti-EGFR therapy depending on gene alteration. Altered gene Median, months 95% CI for median, months KRAS (n=9) 8.9 5.9-11.8 BRAF (n=4) 9.8 0-19.9 ERBB (n=4) 5.8 NA MSI-H (n=1) 4.8 NA PIK3CA or PTEN (n=2) 21.3 NA