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ALTERATION OF FBXW7 IS ASSOCIATED WITH WORSE SURVIVAL IN PATIENTS UNDERGOING RESECTION OF COLORECTAL LIVER METASTASES
Yoshikuni Kawaguchi, The University of Texas MD Anderson Cancer Center, Houston, TX
Background: The genomic landscape and its impact on oncologic outcomes in colorectal cancer continue to evolve. F-box/WD repeat-containing protein 7 (FBXW7) is a tumor suppressor gene (in the Notch signaling pathway, Figure 1A) recognized in the degradation of mediators of cell cycle progression. We previously reported the effect of frequently altered somatic genes (TP53, RAS, and SMAD4) in patients with resected colorectal liver metastases (CLM), but the role of FBXW7 in disease progression is underreported in this patient group. We aimed to evaluate the frequency of FBXW7 alteration and its association with survival after CLM resection.
Methods: From a single institution database, we identified patients who underwent their first resection of CLM during 2007–2017, with multi-gene alteration data available. Using a multivariable Cox proportional hazards model, prognostic factors were assessed and model-adjusted overall survival (OS) rate was estimated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each factor.
Results: A total of 476 patients were included with a median age of 55 years (IQR 46-62 years). Multigene testing revealed alteration rates for TP53 (mutated in 70.8% of patients), APC (55.4%), RAS (50.4%), PIK3CA (15.1%), SMAD4 (10.7%), FBXW7 (5.7%), ERBB2 (2.9%), and BRAF (2.3%). 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 patients receiving concomitant anti-vascular endothelial growth factor agent. R0 resection rate was 79.6%. Alterations in TP53 (HR:2.0, 95%CI:1.4–3.0, P<0.001), RAS (HR:2.4, 95%CI:1.7–3.5, P<0.001), SMAD4 (HR:1.9, 95%CI:1.2–3.0, P=0.004), FBXW7 (HR:2.0, 95%CI:1.2–3.5, P=0.015), and BRAF (HR:2.5, 95%CI:1.1–5.4, P=0.023) were associated with worse OS together with the following clinicopathologic factors, use of prehepatectomy chemotherapy (HR:1.5, 95%CI:1.1–2.2, P=0.021), number of CLM (HR:1.1, 95%CI:1.0–1.1, P=0.007), and largest CLM diameter (HR:1.1, 95%CI:1.0–1.1, P=0.023). The rate of model-adjusted 5-year OS was significantly lower in patients with FBXW7 alteration than in patients with FBXW7 wild-type (40.4% vs. 59.4%, P=0.015) (Figure 1B).
Conclusion: FBXW7 was the 6th most common alteration in patients undergoing CLM resection. Alteration of FBXW7 was independently associated with worse OS, together with alterations in TP53, RAS, SMAD4, and BRAF. Further analyses of FBXW7 in combination with additional alterations and clinical factors may refine risk stratification and treatment decisions for patients considered for CLM resection.
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