Annals of Surgical Oncology

, Volume 23, Issue 6, pp 1890–1896 | Cite as

KRAS Mutation Status Predicts Site-Specific Recurrence and Survival After Resection of Colorectal Liver Metastases Irrespective of Location of the Primary Lesion

  • Junichi Shindoh
  • Yujiro Nishioka
  • Ryuji Yoshioka
  • Toshitaka Sugawara
  • Yoshihiro Sakamoto
  • Kiyoshi Hasegawa
  • Masaji Hashimoto
  • Norihiro Kokudo
Colorectal Cancer



The KRAS mutation status is reportedly correlated with poor survival outcome in patients with colorectal liver metastases (CLM); however, its true prognostic impact and the reason for the poor prognosis remain unclear.


Data on 163 patients with a known KRAS mutation status who underwent curative resection for CLM were retrospectively reviewed. The long-term survival and site-specific incidence of recurrence were then compared between patients with a KRAS mutation (mtKRAS) and those without a mutation (wtKRAS).


The mtKRAS group had a poorer 3-year disease-specific survival (DSS) rate (59.8 vs. 83.6 %, p = 0.016), 3-year recurrence-free survival (RFS) rate (0 vs. 20.2 %, p = 0.069), and median time to surgical failure (TSF) [18.8 vs. 39.7 months, p = 0.001] than the wtKRAS group. The cumulative incidences of liver recurrence and lung recurrence at 3 years were also higher in the mtKRAS group (76.2 vs. 54.7 %, p = 0.060; and 71.9 vs. 37.3 %, p < 0.001, respectively). A multivariate analysis confirmed that an mtKRAS status had a significant effect on the DSS rate (hazard ratio [HR] 2.9, p = 0.006), RFS (HR 2.0, p = 0.004), TSF (HR 2.4, p < 0.001), liver recurrence (HR 1.7, p < 0.001), and lung recurrence (HR 2.6, p < 0.001). Lung-related unresectable recurrences were more frequent (41 vs. 18 %, p = 0.048) and were associated with an earlier TSF (9.6 vs. 14.0 months, p = 0.14) in the mtKRAS group, regardless of the location of the primary lesions.


mtKRAS is associated with poor survival outcome after CLM resection because of a relatively high incidence of lung recurrence and a relatively short TSF.


Primary Lesion Colorectal Liver Metastasis Future Liver Remnant KRAS Mutation Status Poor Survival Outcome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by a study grant from Okinaka Memorial Institute for Medical Disease (No. 2015-15) and JSPS KAKENHI Grant No. 26861063.

Conflict of interest

Junichi Shindoh, Yujiro Nishioka, Ryuji Yoshioka, Toshitaka Sugawara, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Masaji Hashimoto, and Norihiro Kokudo have no conflicts of interest to declare that are directly relevant to the content of this study.

Supplementary material

10434_2016_5087_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 23 kb)


  1. 1.
    Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27(22):3677–83.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–18; discussion 18–21.Google Scholar
  3. 3.
    Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer. 1996;77(7):1254–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Rees M, Tekkis PP, Welsh FK, O’Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008;247(1):125–35.CrossRefPubMedGoogle Scholar
  5. 5.
    George B, Kopetz S. Predictive and prognostic markers in colorectal cancer. Curr Oncol Rep. 2011;13(3):206–15.CrossRefPubMedGoogle Scholar
  6. 6.
    Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer. 2013;119(23):4137–44.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Stremitzer S, Stift J, Gruenberger B, et al. KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab. Br J Surg. 2012;99(11):1575–82.CrossRefPubMedGoogle Scholar
  8. 8.
    Vauthey JN, Zimmitti G, Kopetz SE, et al. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg. 2013;258(4):619–26; discussion 26–7.Google Scholar
  9. 9.
    Brudvik KW, Kopetz SE, Li L, Conrad C, Aloia TA, Vauthey JN. Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases. Br J Surg. 2015;102(10):1175–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Oba M, Hasegawa K, Matsuyama Y, et al. Discrepancy between recurrence-free survival and overall survival in patients with resectable colorectal liver metastases: a potential surrogate endpoint for time to surgical failure. Ann Surg Oncol. 2014;21(6):1817–24.CrossRefPubMedGoogle Scholar
  11. 11.
    Tie J, Lipton L, Desai J, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res. 2011;17(5):1122–30.CrossRefPubMedGoogle Scholar
  12. 12.
    Gonsalves W, Mahoney M, Sargent D, et al. Patient and tumor chracteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. J Natl Cancer Inst. 2014;106(7):dju106.Google Scholar
  13. 13.
    Pollock CB, Shirasawa S, Sasazuki T, Kolch W, Dhillon AS. Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells. Cancer Res. 2005;65(4):1244–50.CrossRefPubMedGoogle Scholar
  14. 14.
    Schramm K, Krause K, Bittroff-Leben A, Goldin-Lang P, Thiel E, Kreuser ED. Activated K-ras is involved in regulation of integrin expression in human colon carcinoma cells. Int J Cancer. 2000;87(2):155–64.CrossRefPubMedGoogle Scholar
  15. 15.
    Serova M, Astorgues-Xerri L, Bieche I, et al. Epithelial-to-mesenchymal transition and oncogenic Ras expression in resistance to the protein kinase Cbeta inhibitor enzastaurin in colon cancer cells. Mol Cancer Ther. 2010;9(5):1308–17.CrossRefPubMedGoogle Scholar
  16. 16.
    Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85(5):692–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27(5):672–80.CrossRefPubMedGoogle Scholar
  18. 18.
    Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103–14.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009;27(35):5931–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Mise Y, Zimmitti G, Shindoh J, et al. RAS mutations predict radiologic and pathologic response in patients treated with chemotherapy before resection of colorectal liver metastases. Ann Surg Oncol. 2015;22(3):834–42.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • Junichi Shindoh
    • 1
    • 2
  • Yujiro Nishioka
    • 1
    • 3
  • Ryuji Yoshioka
    • 3
  • Toshitaka Sugawara
    • 1
  • Yoshihiro Sakamoto
    • 3
  • Kiyoshi Hasegawa
    • 3
  • Masaji Hashimoto
    • 1
  • Norihiro Kokudo
    • 3
  1. 1.Hepatobiliary-Pancreatic, Surgery Division, Department of Digestive SurgeryToranomon HospitalTokyoJapan
  2. 2.Okinaka Memorial Institute for Medical DiseaseTokyoJapan
  3. 3.Hepatobiliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of MedicineThe University of TokyoTokyoJapan

Personalised recommendations