Demystifying BRAF Mutation Status in Colorectal Liver Metastases: A Multi-institutional, Collaborative Approach to 6 Open Clinical Questions

Georgios Antonios Margonis, Thomas Boerner, Jean-Baptiste Bachet, Stefan Buettner, Roberto Moretto, Nikolaos Andreatos, Andrea Sartore-Bianchi, Jane Wang, Carsten Kamphues, Johan Gagniere, Sara Lonardi, Inger Marie Løes, Doris Wagner, Andrea Spallanzani, Kazunari Sasaki, Richard Burkhart, Filippo Pietrantonio, Emmanouil Pikoulis, Timothy M Pawlik, Stéphanie TruantArmando Orlandi, Anastasia Pikouli, Nicoletta Pella, Katharina Beyer, George Poultsides, Hendrik Seeliger, Federico N Aucejo, Peter Kornprat, Klaus Kaczirek, Per Eystein Lønning, Martin E Kreis, Christopher L Wolfgang, Matthew J Weiss, Chiara Cremolini, Stéphane Benoist, Michael D'Angelica*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)

Abstract

OBJECTIVE: To investigate the clinical implications of BRAF -mutated (mut BRAF ) colorectal liver metastases (CRLMs). BACKGROUND: The clinical implications of mut BRAF status in CRLMs are largely unknown. METHODS: Patients undergoing resection for mut BRAF CRLM were identified from prospectively maintained registries of the collaborating institutions. Overall survival (OS) and recurrence-free survival (RFS) were compared among patients with V600E versus non-V600E mutations, KRAS/BRAF comutation versus mut BRAF alone, microsatellite stability status (Microsatellite Stable (MSS) vs instable (MSI-high)), upfront resectable versus converted tumors, extrahepatic versus liver-limited disease, and intrahepatic recurrence treated with repeat hepatectomy versus nonoperative management. RESULTS: A total of 240 patients harboring BRAF -mutated tumors were included. BRAF V600E mutation was associated with shorter OS (30.6 vs 144 mo, P =0.004), but not RFS compared with non-V600E mutations. KRAS/BRAF comutation did not affect outcomes. MSS tumors were associated with shorter RFS (9.1 vs 26 mo, P <0.001) but not OS (33.5 vs 41 mo, P =0.3) compared with MSI-high tumors, whereas patients with resected converted disease had slightly worse RFS (8 vs 11 mo, P =0.01) and similar OS (30 vs 40 mo, P =0.4) compared with those with upfront resectable disease. Patients with extrahepatic disease had worse OS compared with those with liver-limited disease (8.8 vs 40 mo, P <0.001). Repeat hepatectomy after intrahepatic recurrence was associated with improved OS compared with nonoperative management (41 vs 18.7 mo, P =0.004). All results continued to hold true in the multivariable OS analysis. CONCLUSIONS: Although surgery may be futile in patients with BRAF -mutated CRLM and concurrent extrahepatic disease, resection of converted disease resulted in encouraging survival in the absence of extrahepatic spread. Importantly, second hepatectomy in select patients with recurrence was associated with improved outcomes. Finally, MSI-high status identifies a better prognostic group, with regard to RFS while patients with non-V600E mutations have excellent prognosis.

Original languageEnglish
Pages (from-to)e540-e548
JournalAnnals of Surgery
Volume278
Issue number3
Early online date1 Dec 2022
DOIs
Publication statusPublished - 1 Sept 2023
Externally publishedYes

Bibliographical note

Funding Information:
Partially funded by Italian Ministry of Health, Ricerca Finalizzata 2019, grant code J99C21000260001. This work was funded by National Cancer Institute award P30-CA008748.

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.

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