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Annals of Surgical Oncology

, Volume 23, Issue 8, pp 2635–2643 | Cite as

RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases

  • Kristoffer Watten Brudvik
  • Yoshihiro Mise
  • Michael Hsiang Chung
  • Yun Shin Chun
  • Scott E. Kopetz
  • Guillaume Passot
  • Claudius Conrad
  • Dipen M. Maru
  • Thomas A. Aloia
  • Jean-Nicolas VautheyEmail author
Hepatobiliary Tumors

Abstract

Background

In patients undergoing resection of colorectal liver metastases (CLM), resection margin status is a significant predictor of survival, particularly in patients with suboptimal response to preoperative therapy. RAS mutations have been linked to more invasive and migratory tumor biology and poor response to modern chemotherapy.

Objective

The aim of this study was to evaluate the relationship between RAS mutation and resection margin status in patients undergoing resection of CLM.

Methods

Patients who underwent curative resection of CLM from 2005 to 2013 with known RAS mutation status were identified from a prospectively maintained database. A positive margin was defined as tumor cells <1 mm from the parenchymal transection line.

Results

The study included 633 patients, of whom 229 (36.2 %) had mutant RAS. The positive margin rate was 11.4 % (26/229) for mutant RAS and 5.4 % (22/404) for wild-type RAS (p = 0.007). In multivariate analysis, the only factors associated with a positive margin were RAS mutation (hazard ratio [HR] 2.439; p = 0.005) and carcinoembryonic antigen level 4.5 ng/mL or greater (HR 2.060; p = 0.026). Among patients presenting with liver-first recurrence during follow-up, those with mutant RAS had narrower margins at initial CLM resection (median 4 mm vs. 7 mm; p = 0.031). A positive margin (HR 3.360; p < 0.001) and RAS mutation (HR 1.629; p = 0.044) were independently associated with worse overall survival.

Conclusion

RAS mutations are associated with positive margins in patients undergoing resection of CLM. Tumors with RAS mutation should prompt careful efforts to achieve negative resection margins.

Keywords

Resection Margin Preoperative Chemotherapy Positive Margin Colorectal Liver Metastasis Viable Tumor Cell 
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.

Notes

Acknowledgment

The authors thank Stephanie Deming, an employee of the Department of Scientific Publications, MD Anderson Cancer Center, for copyediting the manuscript, and Ruth J. Haynes, an employee of the Department of Surgical Oncology, MD Anderson Cancer Center, for secretarial assistance in the preparation of the manuscript. This research was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant, CA016672. Dr. Brudvik is supported by the Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Norway, and was awarded the Unger–Vetlesen Medical Fund for 2014. Dr Passot is supported by the French Association of Surgery (AFC).

Disclosure

Kristoffer Watten Brudvik, Yoshihiro Mise, Michael Hsiang Chung, Yun Shin Chun, Scott E. Kopetz, Guillaume Passot, Claudius Conrad, Dipen M. Maru, Thomas A. Aloia, and Jean-Nicolas Vauthey report no conflicts of interest relevant to this article.

References

  1. 1.
    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;230:309–18CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    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;247:125–35.CrossRefPubMedGoogle Scholar
  3. 3.
    Bradpiece HA, Benjamin IS, Halevy A, Blumgart LH. Major hepatic resection for colorectal liver metastases. Br J Surg. 1987;74:324–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Ekberg H, Tranberg KG, Andersson R, et al. Determinants of survival in liver resection for colorectal secondaries. Br J Surg. 1986;73:727–31.CrossRefPubMedGoogle Scholar
  5. 5.
    Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715–22.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Altendorf-Hofmann A, Scheele J. A critical review of the major indicators of prognosis after resection of hepatic metastases from colorectal carcinoma. Surg Oncol Clin N Am. 2003;12:165–92.CrossRefPubMedGoogle Scholar
  7. 7.
    Figueras J, Burdio F, Ramos E, et al. Effect of subcentimeter nonpositive resection margin on hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases. Evidences from 663 liver resections. Ann Oncol. 2007;18:1190–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Are C, Gonen M, Zazzali K, et al. The impact of margins on outcome after hepatic resection for colorectal metastasis. Ann Surg. 2007;246:295–300.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hughes KS, Simon R, Songhorabodi S, et al. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery. 1986;100:278–84.PubMedGoogle Scholar
  10. 10.
    Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg. 1995;19:59–71.CrossRefPubMedGoogle Scholar
  11. 11.
    de Haas RJ, Wicherts DA, Flores E, Azoulay D, Castaing D, Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–37.PubMedGoogle Scholar
  12. 12.
    Ayez N, Lalmahomed ZS, Eggermont AM, et al. Outcome of microscopic incomplete resection (R1) of colorectal liver metastases in the era of neoadjuvant chemotherapy. Ann Surg Oncol. 2012;19:1618–27.CrossRefPubMedGoogle Scholar
  13. 13.
    Truant S, Sequier C, Leteurtre E, et al. Tumour biology of colorectal liver metastasis is a more important factor in survival than surgical margin clearance in the era of modern chemotherapy regimens. HPB (Oxford). 2015;17:176–84.CrossRefPubMedGoogle Scholar
  14. 14.
    Andreou A, Aloia TA, Brouquet A, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg. 2013;257:1079–88.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sadot E, Groot Koerkamp B, Leal JN, et al. Resection margin and survival in 2368 patients undergoing hepatic resection for metastatic colorectal cancer: surgical technique or biologic surrogate? Ann Surg. 2015;262:476–85.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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;22:834–42.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 22.
    Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.CrossRefPubMedGoogle Scholar
  23. 23.
    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;65:1244–50.CrossRefPubMedGoogle Scholar
  24. 24.
    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;87:155–64.CrossRefPubMedGoogle Scholar
  25. 25.
    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;9:1308–17.CrossRefPubMedGoogle Scholar
  26. 26.
    Mbah NA, Scoggins C, McMasters K, Martin R. Impact of hepatectomy margin on survival following resection of colorectal metastasis: the role of adjuvant therapy and its effects. Eur J Surg Oncol. 2013;39:1394–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Vauthey JN, Chaoui A, Do KA, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery. 2000;127:512–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Shindoh J, Tzeng CW, Aloia TA, et al. Portal vein embolization improves rate of resection of extensive colorectal liver metastases without worsening survival. Br J Surg. 2013;100:1777–83.CrossRefPubMedGoogle Scholar
  29. 29.
    Aloia TA, Zorzi D, Abdalla EK, Vauthey JN. Two-surgeon technique for hepatic parenchymal transection of the noncirrhotic liver using saline-linked cautery and ultrasonic dissection. Ann Surg. 2005;242:172–7.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Blazer DG 3rd, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol. 2008;26:5344–51.CrossRefPubMedGoogle Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    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;102:1175–83.CrossRefPubMedGoogle Scholar
  33. 33.
    Hamady ZZ, Lodge JP, Welsh FK, et al. One-millimeter cancer-free margin is curative for colorectal liver metastases: a propensity score case-match approach. Ann Surg. 2014;259:543–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Yamaguchi J, Komuta K, Matsuzaki S, Okudaira S, Fujioka H, Kanematsu T. Mode of infiltrative growth of colorectal liver metastases is a useful predictor of recurrence after hepatic resection. World J Surg. 2002;26:1122–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Pinheiro RS, Herman P, Lupinacci RM, et al. Tumor growth pattern as predictor of colorectal liver metastasis recurrence. Am J Surg. 2014;207:493–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Nielsen K, Rolff HC, Eefsen RL, Vainer B. The morphological growth patterns of colorectal liver metastases are prognostic for overall survival. Mod Pathol. 2014;27:1641–8CrossRefPubMedGoogle Scholar
  37. 37.
    Nagashima I, Oka T, Hamada C, Naruse K, Osada T, Muto T. Histopathological prognostic factors influencing long-term prognosis after surgical resection for hepatic metastases from colorectal cancer. Am J Gastroenterol. 1999;94:739–43.CrossRefPubMedGoogle Scholar
  38. 38.
    Mentha G, Terraz S, Morel P, et al. Dangerous halo after neoadjuvant chemotherapy and two-step hepatectomy for colorectal liver metastases. Br J Surg. 2009;96:95–103.CrossRefPubMedGoogle Scholar
  39. 39.
    Kokudo N, Miki Y, Sugai S, et al. Genetic and histological assessment of surgical margins in resected liver metastases from colorectal carcinoma: minimum surgical margins for successful resection. Arch Surg. 2002;137:833–40.CrossRefPubMedGoogle Scholar
  40. 40.
    Holdhoff M, Schmidt K, Diehl F, et al. Detection of tumor DNA at the margins of colorectal cancer liver metastasis. Clin Cancer Res. 2011;17:3551–7.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wakai T, Shirai Y, Sakata J, et al. Histologic evaluation of intrahepatic micrometastases in patients treated with or without neoadjuvant chemotherapy for colorectal carcinoma liver metastasis. Int J Clin Exp Pathol. 2012;5:308–14.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Netzel BC, Grebe SK. Companion-diagnostic testing limited to KRAS codons 12 and 13 misses 17% of potentially relevant RAS mutations in colorectal cancer. Clin Chim Acta. 2013;425:1–2.CrossRefPubMedGoogle Scholar
  43. 43.
    Thierry AR, Mouliere F, El Messaoudi S, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20:430–5.CrossRefPubMedGoogle Scholar
  44. 44.
    Angelsen JH, Horn A, Eide GE, Viste A. Surgery for colorectal liver metastases: the impact of resection margins on recurrence and overall survival. World J Surg Oncol. 2014;12:127CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • Kristoffer Watten Brudvik
    • 1
  • Yoshihiro Mise
    • 1
  • Michael Hsiang Chung
    • 1
  • Yun Shin Chun
    • 1
  • Scott E. Kopetz
    • 2
  • Guillaume Passot
    • 1
  • Claudius Conrad
    • 1
  • Dipen M. Maru
    • 3
  • Thomas A. Aloia
    • 1
  • Jean-Nicolas Vauthey
    • 1
    Email author
  1. 1.Department of Surgical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of PathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

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