Skip to main content

Advertisement

Log in

Effect of KRAS Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

To investigate the prognostic value of KRAS in a large cohort of patients undergoing liver resection for colorectal liver metastases (CRLM).

Methods

Between 2003 and 2013, 334 patients underwent hepatic resection for CRLM at Johns Hopkins Hospital and met the inclusion criteria. Clinicopathologic characteristics, perioperative details, and outcomes were stratified by KRAS status—mutant KRAS (mtKRAS) versus wild-type KRAS (wtKRAS)—and analyzed.

Results

mtKRAS was identified in 115 (34.4 %) patients. At a median follow-up of 28.2 months, recurrence was observed in 59 (51.3 %) patients with mtKRAS and 117 (53.4 %) patients with wtKRAS (P = 0.79); there was no difference in the pattern of recurrence (liver: mtKRAS 39.0 % vs. wtKRAS 52.1 %; lung: mtKRAS 55.6 % vs. wtKRAS 64.3 %; both P > 0.05). Although 5-year log-rank overall survival (OS) was comparable among mtKRAS (41.6 %) vs. wtKRAS (48.5 %), on multivariable Cox survival analysis and after adjusting for known predictors of OS mtKRAS was associated with worse OS (hazard ratio 1.65; 95 % confidence interval 1.07–2.54; P = 0.02). Among patients who experienced a recurrence, 5-year OS was worse among those patients who had mtKRAS (mtKRAS 28.1 % vs. wtKRAS 44.5 %; P = 0.004). After controlling for tumor factors and receipt of chemotherapy, mtKRAS status remained independently associated with a worse outcome among patients who experienced recurrence (hazard ratio 2.07; 95 % confidence interval 1.31–3.27; P = 0.002).

Conclusions

mtKRAS was noted in one-third of patients with CRLM. Although KRAS status did not affect the pattern of recurrence and recurrence-free survival, mtKRAS was an independent predictor of worse OS. The effect was more pronounced among patients who experienced a recurrence after resection of CRLM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.

    Article  PubMed  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  3. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg. 1995;19:59–71.

    Article  CAS  PubMed  Google Scholar 

  4. House MG, Ito H, Gonen M, et al. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1600 patients during two decades at a single institution. J Am Coll Surg. 2010;210:744–52.

    Article  PubMed  Google Scholar 

  5. Vigano L, Russolillo N, Ferrero A, Langella S, Sperti E, Capussotti L. Evolution of long-term outcome of liver resection for colorectal metastases: analysis of actual 5-year survival rates over two decades. Ann Surg Oncol. 2012;19:2035–44.

    Article  PubMed  Google Scholar 

  6. Nathan H, de Jong MC, Pulitano C, et al. Conditional survival after surgical resection of colorectal liver metastasis: an international multi-institutional analysis of 949 patients. J Am Coll Surg. 2010;210:755–64.

    Article  PubMed  Google Scholar 

  7. 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;230:309–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Smith MD, McCall JL. Systematic review of tumour number and outcome after radical treatment of colorectal liver metastases. Br J Surg. 2009;96:1101–13.

    Article  CAS  PubMed  Google Scholar 

  9. Spolverato G, Ejaz A, Azad N, Pawlik TM. Surgery for colorectal liver metastases: the evolution of determining prognosis. World J Gastrointest Oncol. 2013;5:207–21.

    Article  PubMed Central  PubMed  Google Scholar 

  10. George B, Kopetz S. Predictive and prognostic markers in colorectal cancer. Curr Oncol Rep. 2011;13:206–15.

    Article  CAS  PubMed  Google Scholar 

  11. Nash GM, Gimbel M, Shia J, et al. KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol. 2010;17:572–8.

    Article  PubMed  Google Scholar 

  12. 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;119:4137–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Stremitzer S, Stift J, Gruenberger B, et al. KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab. Br J Surg. 2012;99:1575–82.

    Article  CAS  PubMed  Google Scholar 

  14. 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;258:619–26.

    Article  PubMed  Google Scholar 

  15. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.

    Article  CAS  PubMed  Google Scholar 

  16. Kemeny NE, Chou JF, Capanu M, et al. KRAS mutation influences recurrence patterns in patients undergoing hepatic resection of colorectal metastases. Cancer. 2014;120(24):3965–71.

    Article  Google Scholar 

  17. Petrowsky H, Sturm I, Graubitz O, et al. Relevance of Ki-67 antigen expression and K-ras mutation in colorectal liver metastases. Eur J Surg Oncol. 2001;27:80–7.

    Article  CAS  PubMed  Google Scholar 

  18. Teng HW, Huang YC, Lin JK, et al. BRAF mutation is a prognostic biomarker for colorectal liver metastasectomy. J Surg Oncol. 2012;106:123–9.

    Article  CAS  PubMed  Google Scholar 

  19. Reddy SK, Zorzi D, Lum YW, et al. Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis. Ann Surg Oncol. 2009;16:1809–19.

    Article  PubMed  Google Scholar 

  20. Couinaud C. Le foie: etudes anatomiques et chirurgicales. Paris: Masson & Cie; 1957.

    Google Scholar 

  21. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.

    Article  CAS  PubMed  Google Scholar 

  22. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.

    Article  CAS  PubMed  Google Scholar 

  23. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.

    Article  PubMed  Google Scholar 

  24. Soreide K, Sandvik OM, Soreide JA. KRAS mutation in patients undergoing hepatic resection for colorectal liver metastasis: a biomarker of cancer biology or a byproduct of patient selection? Cancer. 2014;120(24):3862–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Andreou A, Kopetz S, Maru DM, et al. Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases. Ann Surg. 2012;256:642–50.

    Article  PubMed  Google Scholar 

  26. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the “RASCAL II” study. Br J Cancer. 2001;85:692–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90:675–84.

    Article  CAS  PubMed  Google Scholar 

  28. 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;27:672–80.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. 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;27:5931–7.

    Article  CAS  PubMed  Google Scholar 

  31. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466–74.

    Article  CAS  PubMed  Google Scholar 

  32. Edkins S, O’Meara S, Parker A, et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006;5:928–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101:715–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Disclosure

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Timothy M. Pawlik MD, MPH, PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 116 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Margonis, G.A., Spolverato, G., Kim, Y. et al. Effect of KRAS Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases. Ann Surg Oncol 22, 4158–4165 (2015). https://doi.org/10.1245/s10434-015-4587-z

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-015-4587-z

Keywords

Navigation