Survival impact of Neo <i>RAS</i> wild-type metastatic colorectal cancer: A SCRUM-Japan GOZILA substudy.

3530 Background: The “Neo RAS ’’ phenomenon refers to KRAS or NRAS mutant (MT) metastatic colorectal cancer (mCRC) that becomes RAS wild-type (WT) following treatment and may represent a novel indication for anti-epidermal growth factor receptor monoclonal antibodies. We previously described the incidence and clinicopathological characteristics of Neo RAS WT mCRC (Osumi et al. Nat Commun 2024); here we share the impact of Neo RAS WT on survival for patients with mCRC. Methods: Patients enrolled in the large-scale nationwide screening platform SCRUM-Japan GOZILA who had mCRC, tumor tissue tested for RAS and BRAF V600E (MEBGEN RASKET-B), and received systemic therapy were included. Prior to subsequent treatment, all patients underwent next-generation sequencing of circulating tumor DNA (ctDNA) (Guardant360) and were classified into cohorts according to original tissue and subsequent ctDNA genotypes: persistent RAS/BRAF V600 WT ( RAS WT), persistent RAS MT, change from RAS MT to RAS WT (Neo RAS WT, including ctDNA not detected), change from RAS WT to RAS MT (acquired RAS MT), persistent BRAF V600E ( BRAF MT). BRAF MT outside V600 were not considered. We evaluated the clinicopathological characteristics and overall survival (OS) of patients in each cohort. OS was measured from time of first-line treatment initiation to the date of death. Results: The 1,352 patients (median age 61 years) included RAS WT: 526 (38.9%), RAS MT: 387 (28.7%), acquired RAS MT: 223 (16.5%), Neo RAS WT: 91 (6.7%), and BRAF MT: 125 (9.2%).Median number of therapy lines from tissue assessment to ctDNA testing was 2 (range 1-13). Neo RAS WT had low prevalence of liver (23.1%, P &lt; 0.001), lymph node (16.5%, P &lt; 0.001) and multi-organ metastasis (42.9%, P &lt; 0.001), whereas lung (56.0%, P &lt; 0.001) and peritoneal metastases (41.8%, P = 0.004) were more common in other groups. Left-sided primary tumors were more common with RAS WT (80.2%) followed by Neo RAS WT (70.3%) and RAS MT (67.7%), (P &lt; 0.001). Patients with BRAF MT had significantly shorter median OS (28.1 months) compared to others ( P Log-rank &lt; 0.001, hazard ratio (HR), 1.91; 95% confidence interval (CI), 1.52-2.40). Patients with Neo RAS WT had median OS (45.6 months) that was between RAS WT (51.9 months) and RAS MT (41.0 months) ( P Log-rank &lt; 0.001). On the other hand, patients with acquired RAS MT had a significantly shorter median OS (43.3 months) compared to RAS WT ( P Log-rank &lt; 0.001). In multivariate analysis, BRAF MT (HR: 2.06, 95%CI, 1.62-2.61, P &lt; 0.001), ctDNA fraction (≥1.0%, HR: 1.41, 95%CI, 1.17-1.71, P = 0.00035), RAS MT (HR: 1.37, 95%CI, 1.17-1.62, P = 0.0001), and lymph node metastasis (HR: 0.85, 95%CI, 0.72-0.99, P = 0.046) were independent factors associated with shorter OS. Conclusions: Patients with Neo RAS WT mCRC exhibited distinct characteristics, and intermediate survival between the RAS WT and RAS MT groups.