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. 2025 Jan;32(1):408-417.
doi: 10.1245/s10434-024-16319-0. Epub 2024 Oct 8.

Evaluating Combinations of Biological and Clinicopathologic Factors Linked to Poor Outcomes in Resected Colorectal Liver Metastasis: An External Validation Study

Kazunari Sasaki  1 , Jane Wang  2 , Carsten Kamphues  3 , Stefan Buettner  2 , Johan Gagniere  4 , Victoria Ardilles  5 , Katsunori Imai  6 , Doris Wagner  7 , Ioannis Pozios  3 , Dimitris Papakonstantinou  8 , Emmanouil Pikoulis  8 , Efstathios Antoniou  8 , Daisuke Morioka  9 , Inger Marie Løes  10   11 , Per Eystein Lønning  10   11 , Peter Kornprat  7 , Federico N Aucejo  12 , Hideo Baba  6 , Eduardo de Santibañes  5 , Klaus Kaczirek  13 , Richard Burkhart  2 , Itaru Endo  9 , Katharina Beyer  3 , Martin E Kreis  3 , Timothy M Pawlik  14 , Georgios Antonios Margonis  15   16
Affiliations

Evaluating Combinations of Biological and Clinicopathologic Factors Linked to Poor Outcomes in Resected Colorectal Liver Metastasis: An External Validation Study

Kazunari Sasaki et al. Ann Surg Oncol. 2025 Jan.

Abstract

Background: Recent studies have suggested that certain combinations of KRAS or BRAF biomarkers with clinical factors are associated with poor outcomes and may indicate that surgery could be "biologically" futile in otherwise technically resectable colorectal liver metastasis (CRLM). However, these combinations have yet to be validated through external studies.

Patients and methods: We conducted a systematic search to identify these studies. The overall survival (OS) of patients with these combinations was evaluated in a cohort of patients treated at 11 tertiary centers. Additionally, the study investigated whether using high-risk KRAS point mutations in these combinations could be associated with particularly poor outcomes.

Results: The recommendations of four studies were validated in 1661 patients. The first three studies utilized KRAS, and their validation showed the following median and 5-year OS: (1) 30 months and 16.9%, (2) 24.3 months and 21.6%, and (3) 46.8 months and 44.4%, respectively. When analyzing only patients with high-risk KRAS mutations, median and 5-year OS decreased to: (1) 26.2 months and 0%, (2) 22.3 months and 15.1%, and (3) not reached and 44.9%, respectively. The fourth study utilized BRAF, and its validation showed a median OS of 10.4 months, with no survivors beyond 21 months.

Conclusion: The combinations of biomarkers and clinical factors proposed to render surgery for CRLM futile, as presented in studies 1 (KRAS high-risk mutations) and 4, appear justified. In these studies, there were no long-term survivors, and survival was similar to that of historic cohorts with similar mutational profiles that received systemic therapies alone for unresectable disease.

Keywords: Biomarker; Colorectal liver metastases; Poor outcomes; Surgery.

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Conflict of interest statement

Disclosure. None to report.

Figures

FIG. 1
FIG. 1
Prisma flowchart of study selection
FIG. 2
FIG. 2
Overall survival after CRLM resection of patients with wild-type tumors, with tumors that harbor low-risk KRAS point mutations, with tumors that harbor high-risk KRAS point mutations, and with tumors that harbor BRAF mutations
FIG. 3
FIG. 3
Overall survival after CRLM resection stratified by the recommendations by Passot et al.
FIG. 4
FIG. 4
Overall survival after CRLM resection stratified by the recommendations by Margonis et al.
FIG. 5
FIG. 5
Overall survival after CRLM resection stratified by the recommendations by Brudvik et al.
FIG. 6
FIG. 6
Overall survival after CRLM resection stratified by the recommendations by Gagniere et al.
See this image and copyright information in PMC

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