High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases.

Autor: Brunsell TH; Department 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., Sveen A; Department 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., Bjørnbeth BA; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway., Røsok BI; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway., Danielsen SA; Department 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., Brudvik KW; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway., Berg KCG; Department 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., Johannessen B; Department 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., Cengija V; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Department of Radiology and Nuclear Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway., Abildgaard A; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Department of Radiology and Nuclear Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway., Guren MG; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital Ullevål, Oslo, Norway., Nesbakken A; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway., Lothe RA; Department 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. Electronic address: Ragnhild.A.Lothe@rr-research.no.
Jazyk: angličtina
Zdroj: Clinical colorectal cancer [Clin Colorectal Cancer] 2020 Mar; Vol. 19 (1), pp. e26-e47. Date of Electronic Publication: 2019 Dec 12.
DOI: 10.1016/j.clcc.2019.09.003
Abstrakt: 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.
(Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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