Prognostic significance of  KRAS, NRAS,   and  BRAF  mutations in patients with colorectal cancer and liver metastases: results of a single-center retrospective study

Georgii G. Makiev; Макиев Георгий Георгиевич; Mikhail Yu. Fedyanin; Федянин М. Ю.; Rukiyat Sh. Abdulaeva; Абдулаева Р. Ш.; Sofiya I. Polyanskaya; Полянская С. И.; Aleksey E. Kalinin; Калинин А. Е.; Alexander N. Polyakov; Поляков А. Н.; Anastasia B. Rays; Райс А. Б.; Nikita M. Kutakov; Кутаков Н. М.; Alina V. Korshak; Коршак А. В.; Alina Yu. Kashcheeva; Кащеева А. Ю.; Ksenia S. Lezina; Лезина К. С.; Anna M. Stroganova; Строганова А. М.; Alexey A. Tryakin; Трякин А. А.

doi:10.17650/1726-9784-2026-25-2-51-63

Prognostic significance of KRAS, NRAS, and BRAF mutations in patients with colorectal cancer and liver metastases: results of a single-center retrospective study

Authors: Makiev G.G.¹^,2, Fedyanin M.Y.¹^,3, Abdulaeva R.S.¹, Polyanskaya S.I.¹^,4, Kalinin A.E.¹, Polyakov A.N.¹, Rays A.B.⁵, Kutakov N.M.⁶, Korshak A.V.¹, Kashcheeva A.Y.¹, Lezina K.S.¹, Stroganova A.M.¹, Tryakin A.A.¹
Affiliations:
1. N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
2. “OncoStop” Radiation Therapy Center
3. N.I. Pirogov National Medical and Surgical Center, Ministry of Health of Russia
4. Lomonosov Moscow State University
5. Moscow Multidisciplinary Clinical Center “Kommunarka”
6. Lapino Clinical Hospital of the “Mother and Child” Group of Companies
Issue: Vol 25, No 2 (2026)
Pages: 51-63
Section: ORIGINAL REPORTS
Published: 15.07.2026
URL: https://bioterapevt.abvpress.ru/jour/article/view/1626
DOI: https://doi.org/10.17650/1726-9784-2026-25-2-51-63
ID: 1626

Cite item

Full Text

Open Access
Restricted Access

Access granted
Restricted Access

Subscription or Fee Access

Abstract
About the authors
References
Supplementary files
Statistics

Abstract

Background. The significance of specific mutation variants, particularly rare ones, in patients with colorectal cancer (CRC) and isolated liver metastases is insufficiently studied, while the possibility of achieving resectability is critical in the context of prognosis and survival.

Aim. To assess the prognostic significance of various mutations in the KRAS, NRAS, and BRAF genes in patients with CRC.

Materials and methods. The study included 366 patients with CRC and isolated liver metastases. Group 1 (n = 198) included patients with mutations in KRAS, NRAS, BRAF (Mut) genes, and Group 2 (n = 168) included those without activating mutations (wild-type – wt). Progression-free survival (PFS), risk of progression, rate and chance of achieving resectability were assessed.

Results. Group 1 showed worse outcomes compared to Group 2: a lower rate of liver resection (36.9 % vs 49.4 %; p = 0.016) and a shorter median PFS (10.3 vs 12.9 months; hazard ratio 1.57 [95 % confidence interval 1.24–1.99; p < 0.001). Significant heterogeneity was revealed among Mut patients. The worst prognosis was associated with KRAS G12D mutations (median PFS 5.9 months; hazard ratio 2.99 [95 % confidence interval 2.08–4.3; p < 0.001), as well as G12C, G12A, and BRAF mutations. However, performing liver resection improves long-term outcomes even in this patient subgroup. In contrast, patients with KRAS G13D mutations and rare A146 / K117 / Q61 mutations demonstrated significantly better long-term outcomes and a high rate of resectability.

Conclusion. This study evaluates the prognostic value of RAS / BRAF mutations in patients with CRC and isolated liver involvement. These findings are essential for patient stratification in the current era of personalized therapy.

Keywords

colorectal cancer, KRAS / NRAS / BRAF, liver metastases, resectability of metastases

References

Федянин М.Ю., Гладков О.А., Гордеев С.С. и др. Рак ободочной кишки, ректосигмоидного соединения и прямой кишки. Практические рекомендации RUSSCO, часть 1.1. Злокачественные опухоли 2024;14(3s2):266–325. doi: 10.18027/2224-5057-2024-14-3s2-1.1-14 Fedyanin M.Yu., Gladkov O.A., Gordeev S.S. et al. Practical recommendations for the treatment of patients with colon and rectosigmoid cancer. RUSSCO practical recommendations, part 1.1. Zlokachestvennye opukholi = Malignant Tumours 2024;14(3s2):266–325. (In Russ.). doi: 10.18027/2224-5057-2024-14-3s2-1.1-14
Downward J. The RAS superfamily of small GTP-binding proteins. Trends Biochem Sci 1990;15(12):469–72. doi: 10.1016/0968-0004(90)90300-z
Li Z.N., Zhao L., Yu L.F. BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy. Gastroenterol Rep (Oxf) 2020;8(3):192–205. doi: 10.1093/gastro/goaa022
Scheffzek K., Ahmadian M.R., Kabsch W. et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997;277(5324):333–8. doi: 10.1126/science.277.5324.333
Rumpold H., Niedersüß-Beke D., Heiler C. et al. Prediction of mortality in metastatic colorectal cancer in a real-life population: a multicenter explorative analysis. BMC Cancer 2020;20(1):1149. doi: 10.1186/s12885-020-07656-w
Saridaki Z., Androulakis N., Vardakis N. et al. A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Br J Cancer 2012;107(12):1932–7. doi: 10.1038/bjc.2012.509
Mao C., Wu X.Y., Yang Z.Y. et al. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep 2015;5:8065. doi: 10.1038/srep08065
Muñoz-Maldonado C., Zimmer Y., Medová M. A comparative analysis of individual RAS mutations in cancer biology. Front Oncol 2019;9:1088. doi: 10.3389/fonc.2019.01088
van ‘t Erve I., Wesdorp N.J., Medina J.E. et al. KRAS A146 mutations are associated with distinct clinical behavior in patients with colorectal liver metastases. JCO Precis Oncol 2021;5:PO.21.00223. doi: 10.1200/PO.21.00223
Guo T., Wu Y., Huang D. et al. Prognostic value of KRAS exon 3 and exon 4 mutations in colorectal cancer patients. J Cancer 2021;12(17):5331–7. doi: 10.7150/jca.59193
Ahn H.M., Kim D.W., Oh H.J. et al. Different oncological features of colorectal cancer codon-specific KRAS mutations: not codon 13 but codon 12 have prognostic value. World J Gastroenterol 2023;29(32):4883–99. doi: 10.3748/wjg.v29.i32.4883
Bond M.G., Bolhuis K., Loosveld O.L. et al. First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group. Lancet Oncol 2023;24(7):757–71. doi: 10.1016/S1470-2045(23)00219-X
Hurwitz H.I., Tan B.R., Reeves J.A. et al. Phase II randomized trial of sequential or concurrent FOLFOXIRI-bevacizumab versus FOLFOX-bevacizumab for metastatic colorectal cancer (STEAM). Oncologist 2019;24(7):921–32. doi: 10.1634/theoncologist.2018-0344
van der Geest L.G., Lam-Boer J., Koopman M. et al. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 2015;32(5):457–65. doi: 10.1007/s10585-015-9719-0
Fernández Montes A., Alonso Orduña V., Asensio Martínez E. et al. The frequency of specific KRAS mutations, and their impact on treatment choice and survival, in patients with metastatic colorectal cancer. Oncologist 2023;28(10):e902–9. doi: 10.1093/oncolo/oyad117
Zocche D.M., Ramirez C., Fontao F.M. et al. Global impact of KRAS mutation patterns in FOLFOX treated metastatic colorectal cancer. Front Genet 2015;6:116. doi: 10.3389/fgene.2015.00116
Zlobec I., Kovac M., Erzberger P. et al. Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer 2010;127:2569–75. doi: 10.1002/ijc.25265
Andreyev H.J., Norman A.R., Cunningham D. et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 2001;85:692–6. doi: 10.1054/bjoc.2001.1964
Imamura Y., Morikawa T., Liao X. et al. Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin Cancer Res 2012;18(17): 4753–63. doi: 10.1158/1078-0432.CCR-11-3210
Roncato R., Polesel J., Tosi F. et al. The challenge of molecular selection in liver-limited metastatic colorectal cancer for surgical resection: a systematic review and meta-analysis in the context of current and future approaches. Oncol Res 2024;32(9):1407–22. doi: 10.32604/or.2024.049181
Ferreira R.O., Boieiro Loca Mendes J.P., Furtado I. et al. Comparing survival outcomes in KRAS G12 vs KRAS G13-mutated metastatic colorectal cancer (mCRC): a 13-year cohort study. ESMO Open 2025;10(7):105618. doi: 10.1016/j.esmoop.2025.105618
Carrasco A.N., Querol Ninerola R., Ribera Fernandez P. et al. Prognostic analysis of KRAS mutations in metastatic colorectal cancer: a real-world cohort study. ESMO Open 2025;10(7):105716. doi: 10.1016/j.esmoop.2025.105716

Supplementary files

Supplementary Files

Action

1. JATS XML

Download

Username
Password
Remember me

Forgot password?	Register

Username
Password
Remember me

Forgot password?	Register