FBXW7 mutation is associated with decreased survival following hepatectomy for metastatic colorectal cancer

Abstract

Introduction: Improved understanding of tumor genomics has transformed the treatment of colorectal liver metastases (CLM). F-box/WD repeat-containing protein 7 (FBXW7) is a tumor suppressor gene recognized in the degradation of mediators of cell cycle progression. We have previously reported the effect of frequently mutations in the setting of CLM, however the role of FBXW7 in the progression of this disease is underreported. We aimed to evaluate the impact of FBXW7 mutation on survival following hepatectomy for CLM. Method: Clinicopathologic data was abstracted for patients with documented mutational analysis who underwent hepatectomy from 2001-2016. Kaplan-Meier analysis was performed for overall survival (OS) and compared by log-rank test. Risk factors for overall survival were determined by Cox proportional hazards model. Result: In total, 462 patients were included with a median age of 55 years (IQR 46-62 years). Most had colon primary tumors (68.5%), were ≥T3 (87.5%), and had lymph node-positive primary disease (70.9%). Synchronous metastasis occurred in 76.5%, yet the minority had extrahepatic metastases (16.6%). Most (90.5%) underwent neoadjuvant chemotherapy, with 71% of these receiving concomitant targeted therapy. Few patients (20.4%) underwent R1 resection. The most common mutation associated with survival was TP53 (prevalence: 70.7%,HR:2.0, 95%CI 1.4-3.0, p<0.001), followed byRAS (50.4%, HR:2.4, 95%CI 1.7-3.5, p<001). Mutation in FBXW7 was found in 5.7% of patients, and it was a strong negative prognostic factor for OS (HR 1.99, p=0.015). BRAF was the least common mutation, found in 2.3%, but it was the strongest negative prognostic factor for OS (HR 2.47, p=0.023). Conclusion: Mutation of FBXW7 is a strong negative predictor of OS and is detected more frequently than other accepted mutations used for prognostication following hepatectomy for CLM. Further analyses of FBXW7 in combination with additional mutations and clinical factors may refine risk stratification and treatment decisions for patients with CLM.