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Alteration of FBXW7 is Associated with Worse Survival in Patients Undergoing Resection of Colorectal Liver Metastases

  • SSAT Plenary Presentation
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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

For patients undergoing resection of colorectal liver metastases (CLMs), the prognostic role of somatic gene alterations is increasingly recognized. F-box/WD repeat–containing protein 7 (FBXW7) is a tumor suppressor gene found in approximately 10% of patients with colorectal cancer. The aim of this study is to assess the association of FBXW7 with overall survival after CLM resection.

Methods

Patients who underwent initial CLM resection during 2001–2016 and had genetic sequencing data were studied. Risk factors for overall survival (OS) were evaluated with Cox proportional hazards models using backward elimination.

Results

Of 2045 patients who underwent CLM resection during the study period, 476 were included. The majority (90.5%) underwent prehepatectomy chemotherapy. A total of 27 patients (5.7%) had FBXW7 alteration, along with 240 (50.4%) RAS, 337 (70.8%) TP53, 51 (10.7%) SMAD4, and 27 (5.7%) BRAF. Cox proportional hazards model analyses including 5 somatic gene alteration status and 12 clinicopathologic factors revealed FBXW7(hazard ratio [HR] 1.99, P = 0.015), BRAF (HR 2.47, P = 0.023), RAS (HR 2.42, P < 0.001), TP53 (HR 2.00, P < 0.001), and SMAD4 alterations (HR 1.90, P = 0.004) as significantly associated with OS, together with three clinicopathologic factors, prehepatectomy chemotherapy > 6 cycles (HR 1.51, P = 0.021), number of CLM (HR 1.05, P = 0.007), and largest liver metastasis diameter (HR 1.07, P = 0.023). The covariate-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).

Conclusions

FBXW7 alterations are associated with worse survival after CLM resection. The information on multiple somatic gene alterations is imperative for risk stratification and patient selection for CLM resection.

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Abbreviations

CLM:

colorectal liver metastases

FBXW7 :

F-box/WD repeat–containing protein 7

OS:

overall survival

HR:

hazard ratio

CI:

confidence intervals

VEGF:

vascular endothelial growth factor

EGFR:

epidermal growth factor receptor

MAPK:

mitogen-activated protein kinase

TGF-β:

transforming growth factor-β

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Acknowledgements

The authors thank Ms. Ruth Haynes for the administrative support in the preparation of this manuscript.

Statement of Author Contribution

Substantial contributions to:

The conception or design of the work: YK, TN, JNV

The acquisition, analysis, or interpretation of data for the work: YK, TN, HT, CWT, YSH, TA, SK, JNV

Drafting the work or revising it critically for important intellectual content: all authors

Final approval of the version to be published: all authors

Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors

Funding

This research was supported in part by the National Institutes of Health through MD Anderson Cancer Center Support Grant, CA016672.

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Author notes

  1. Yoshikuni Kawaguchi and Timothy E. Newhook contributed equally to this work.

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484, Houston, TX, 77030, USA

    Yoshikuni Kawaguchi, Timothy E. Newhook, Hop S. Tran Cao, Ching-Wei D. Tzeng, Yun Shin Chun, Thomas A. Aloia & Jean-Nicolas Vauthey

  2. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Arvind Dasari & Scott Kopetz

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  1. Yoshikuni Kawaguchi
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Correspondence to Jean-Nicolas Vauthey.

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Previous communication to a society or meeting: This study was presented on June 3, 2020 in the Society for Surgery of the Alimentary Tract Wednesday Webinars due to the cancellation of the 61th Annual Meeting of the Society for Surgery of the Alimentary Tract Plenary Session.

Supplementary Information

Supplementary Figure 1

Patient selection. *In patients who completed 2-stage hepatectomy, only the second-stage hepatectomy was included. The first-stage hepatectomy was excluded not to include patients twice in our analysis. (DOCX 357 kb)

Supplementary Figure 2

Overall survival (OS) by TP53 and FBXW7 alteration status. (A) OS curves. (B) OS curves after adjustment for somatic gene alteration status (BRAF, RAS, and SMAD4), prehepatectomy chemotherapy (> 6 cycles vs. ≤ 6 cycles or no prehepatectomy chemotherapy), number of CLM, and largest liver metastasis diameter. (DOCX 380 kb)

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Kawaguchi, Y., Newhook, T.E., Tran Cao, H.S. et al. Alteration of FBXW7 is Associated with Worse Survival in Patients Undergoing Resection of Colorectal Liver Metastases. J Gastrointest Surg 25, 186–194 (2021). https://doi.org/10.1007/s11605-020-04866-2

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