Prognostic impact of <i>RAS/BRAF</i> mutations and clinical factors in 441 patients undergoing pulmonary metastasectomy for colorectal cancer.

Abstract

214 Background: Pulmonary metastasectomy (PM) is a curative treatment option for colorectal cancer (CRC) patients with lung metastases. While several clinical and molecular factors such as RAS / BRAF mutations (MTs) have been reported as poor prognostic markers, few large-scale studies have comprehensively assessed these variables. Methods: We retrospectively analyzed 441 CRC patients who underwent PM at our hospital between January 2015 and December 2024. Follow-up continued until April 30, 2025. Clinical and molecular data were collected, including age, sex, performance status (PS), smoking history, resection type, primary tumor location, RAS / BRAF V600E MTs status, the number and size of lung metastases, and preoperative carcinoembryonic antigen (CEA) levels. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Prognostic factors were evaluated using univariate and multivariate Cox proportional hazards models. Results: Among 441 patients, median DFS was 31.0 months (95% CI: 19.0-not reached), and median OS was not reached (19.0-NR). RAS / BRAF V600E MTs status was assessed in 347 patients; RAS / BRAF wild type (WT): n=157 (45.2%), RAS MTs: n=184 (53.0%; KRAS : n=173, NRAS : n=11), BRAF V600E MTs: n=6 (1.7%). Median DFS was 22.8 months (14.2-NR) in WT, 31.0 months (13.2-NR, HR: 0.97, 95% CI, 0.72-1.30, p=0.83) in RAS MTs, 9.5 months (2.9-44.7, HR: 2.65, 1.15-6.13, p=0.023) in BRAF V600E MTs; median OS was not reached (19.0-NR), 98.6 months (83.2-NR, HR: 1.43, 0.88-2.30, p=0.15), 37.8 months (20.9-NR, HR: 7.52, 2.54-22.3, p&lt;0.01), respectively. Clinical characteristics were broadly similar across groups, except for primary tumor location; right-sided primaries were more common in BRAF V600E MTs cases (66.7%, p&lt;0.01). In multivariate analysis, elevated preoperative CEA (HR: 2.24, 95%CI 1.58-3.19, p&lt;0.01), BRAF V600E MTs (HR: 1.64, 1.09-2.47, p=0.018), RAS MTs (HR: 1.58, 1.05-2.36, p=0.027), and ≥2 lung tumors (HR: 1.40, 1.17-1.66, p&lt;0.01) were independently associated with shorter DFS. For OS, multivariate analysis showed that PS=1 (HR: 3.57, 1.90-6.69, p&lt;0.01) and elevated preoperative CEA (HR: 2.32, 1.40-3.85, p&lt;0.01) were associated with shorter OS. Conclusions: Both RAS / BRAF MTs increase the risk of recurrence following PM, consistent with their prognostic role in other disease stages. Integration of these mutations with clinical factors such as preoperative CEA levels and the number of lung metastases enables a more comprehensive risk assessment for postoperative management strategies. Multivariate Cox analysis. Variable HR 95% CI p-value DFS  CEA ≥5 ng/mL (vs. &lt;5) 2.24 1.58–3.19 &lt;0.01   BRAF V600E MTs (vs. RAS / BRAF WT) 1.64 1.09–2.47 0.018   RAS MTs (vs. RAS / BRAF WT) 1.58 1.05–2.36 0.027  ≥2 lung tumors (vs. single) 1.40 1.17–1.66 &lt;0.01 OS  PS = 1 (vs. 0) 3.57 1.90–6.69 &lt;0.01  CEA ≥5 ng/mL (vs. &lt;5) 2.32 1.40–3.85 &lt;0.01