Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 8/2016

01-08-2016 | Hepatobiliary Tumors

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

Authors: Kristoffer Watten Brudvik, MD, PhD, Yoshihiro Mise, MD, PhD, Michael Hsiang Chung, BS, Yun Shin Chun, MD, Scott E. Kopetz, MD, Guillaume Passot, MD, PhD, Claudius Conrad, MD, PhD, Dipen M. Maru, MD, Thomas A. Aloia, MD, Jean-Nicolas Vauthey, MD

Published in: Annals of Surgical Oncology | Issue 8/2016

Login to get access

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.
Literature
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;230:309–18CrossRefPubMedPubMedCentral
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.CrossRefPubMed
3.
Bradpiece HA, Benjamin IS, Halevy A, Blumgart LH. Major hepatic resection for colorectal liver metastases. Br J Surg. 1987;74:324–6.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
8.
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.PubMed
10.
Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg. 1995;19:59–71.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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;27:1641–8CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
40.
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.PubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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;12:127CrossRefPubMedPubMedCentral
Metadata
Title
RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases
Authors
Kristoffer Watten Brudvik, MD, PhD
Yoshihiro Mise, MD, PhD
Michael Hsiang Chung, BS
Yun Shin Chun, MD
Scott E. Kopetz, MD
Guillaume Passot, MD, PhD
Claudius Conrad, MD, PhD
Dipen M. Maru, MD
Thomas A. Aloia, MD
Jean-Nicolas Vauthey, MD
Publication date
01-08-2016
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 8/2016
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-016-5187-2

Other articles of this Issue 8/2016

Annals of Surgical Oncology 8/2016 Go to the issue

Breast Oncology

Same-Day Major Breast Cancer Surgery is Safe: An Analysis of Short-Term Outcomes Using NSQIP Data

Colorectal Cancer

Evaluation of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Origin in the Era of Value-Based Medicine

Colorectal Cancer

Laparoscopic Radical Extended Right Hemicolectomy Using a Caudal-to-Cranial Approach

Melanomas

Breslow Thickness Measurements of Melanomas Around American Joint Committee on Cancer Staging Cut-Off Points: Imprecision and Terminal Digit Bias Have Important Implications for Staging and Patient Management

Hepatobiliary Tumors

Defining Surgical Difficulty According to the Perceived Complexity of Liver Resection: Validation of a Complexity Classification in Patients with Hepatocellular Carcinoma

Breast Oncology

Late Axillary Recurrence After Negative Sentinel Lymph Node Biopsy is Uncommon