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Updated: Dec 30, 2025
Competing-Risk Nomogram for Predicting Cancer-Specific Survival in Multiple Primary Colorectal Cancer Patients after Surgery
Published on: September 27, 2024
High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver
Tuva Høst Brunsell1, Anita Sveen1, Bjørn Atle Bjørnbeth2
1Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
Background:
The prevalence and clinical implications of genetic heterogeneity in patients with multiple colorectal liver metastases remain largely unknown. In a prospective series of patients undergoing resection of colorectal liver metastases, the aim was to investigate the inter-metastatic and primary-to-metastatic heterogeneity of mutations in KRAS, NRAS, BRAF, and PIK3CA and their prognostic impact.
Patients And Methods:
We analyzed the mutation status among 372 liver metastases and 78 primary tumors from 106 patients by methods used in clinical routine testing, by Sanger sequencing, by next-generation sequencing (NGS), and/or by droplet digital polymerase chain reaction. The 3-year cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method.
Results:
Although Sanger sequencing indicated inter-metastatic mutation heterogeneity in 14 of 97 patients (14%), almost all cases were refuted by high-sensitive NGS. Also, heterogeneity among metastatic deposits was concluded only for PIK3CA in 2 patients. Similarly, primary-to-metastatic heterogeneity was indicated in 8 of 78 patients (10%) using Sanger sequencing but for only 2 patients after NGS, showing the emergence of 1 KRAS and 1 PIK3CA mutation in the metastatic lesions. KRAS mutations were present in 53 of 106 patients (50%) and were associated with poorer 3-year CSS after liver resection (37% vs. 61% for KRAS wild-type; P = .004). Poor prognostic associations were found also for the combination of KRAS/NRAS/BRAF mutations compared with triple wild-type (P = .002).
Conclusion:
Intra-patient mutation heterogeneity was virtually undetected, both between the primary tumor and the liver metastases and among the metastatic deposits. KRAS mutations separately, and KRAS/NRAS/BRAF mutations combined, were associated with poor patient survival after partial liver resection.
