title: RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases.
abstract: OBJECTIVE
  To determine the impact of RAS mutation status on survival and patterns of recurrence in patients undergoing curative resection of colorectal liver metastases (CLM) after preoperative modern chemotherapy.
  
  
  BACKGROUND
  RAS mutation has been reported to be associated with aggressive tumor biology. However, the effect of RAS mutation on survival and patterns of recurrence after resection of CLM remains unclear.
  
  
  METHODS
  Somatic mutations were analyzed using mass spectroscopy in 193 patients who underwent single-regimen modern chemotherapy before resection of CLM. The relationship between RAS mutation status and survival outcomes was investigated.
  
  
  RESULTS
  Detected somatic mutations included RAS (KRAS/NRAS) in 34 (18%), PIK3CA in 13 (7%), and BRAF in 2 (1%) patients. At a median follow-up of 33 months, 3-year overall survival (OS) rates were 81% in patients with wild-type versus 52.2% in patients with mutant RAS (P = 0.002); 3-year recurrence-free survival (RFS) rates were 33.5% with wild-type versus 13.5% with mutant RAS (P = 0.001). Liver and lung recurrences were observed in 89 and 83 patients, respectively. Patients with RAS mutation had a lower 3-year lung RFS rate (34.6% vs 59.3%, P < 0.001) but not a lower 3-year liver RFS rate (43.8% vs 50.2%, P = 0.181). In multivariate analyses, RAS mutation predicted worse OS [hazard ratio (HR) = 2.3, P = 0.002), overall RFS (HR = 1.9, P = 0.005), and lung RFS (HR = 2.0, P = 0.01), but not liver RFS (P = 0.181).
  
  
  CONCLUSIONS
  RAS mutation predicts early lung recurrence and worse survival after curative resection of CLM. This information may be used to individualize systemic and local tumor-directed therapies and follow-up strategies.
authors.affiliation: Departments of *Surgical Oncology †Gastrointestinal Medical Oncology ‡Hematopathology §Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Vauthey
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zimmitti
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kopetz
authors.forename: Junichi
authors.initials: J
authors.lastname: Shindoh
authors.forename: Su S
authors.initials: SS
authors.lastname: Chen
authors.forename: Andreas
authors.initials: A
authors.lastname: Andreou
authors.forename: Steven A
authors.initials: SA
authors.lastname: Curley
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Aloia
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006498:Hepatectomy / Q000401:mortality; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary* / Q000601:surgery*; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human
references.citation: J Clin Oncol. 2012 Aug 20;30(24):2956-62
references.pmid: 22665543
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4830-5
references.pmid: 18676755
references.citation: Ann Surg. 2012 Oct;256(4):642-50
references.pmid: 22968062
references.citation: Ann Surg. 1999 Sep;230(3):309-18; discussion 318-21
references.pmid: 10493478
references.citation: J Clin Oncol. 2008 Nov 20;26(33):5344-51
references.pmid: 18936472
references.citation: J Clin Oncol. 2012 Dec 20;30(36):4566-72
references.pmid: 23150701
references.citation: Ann Surg Oncol. 2010 Feb;17(2):572-8
references.pmid: 19727962
references.citation: Lancet Oncol. 2010 Aug;11(8):753-62
references.pmid: 20619739
references.citation: Br J Cancer. 2012 Jul 10;107(2):340-4
references.pmid: 22617127
references.citation: J Clin Oncol. 2011 Mar 10;29(8):1083-90
references.pmid: 21263087
references.citation: Lancet. 2008 Mar 22;371(9617):963-5
references.pmid: 18358910
references.citation: J Am Coll Surg. 2010 Jan;210(1):31-8
references.pmid: 20123329
references.citation: PLoS One. 2009 Dec 18;4(12):e8199
references.pmid: 20020061
references.citation: Br J Cancer. 2011 Mar 15;104(6):1020-6
references.pmid: 21364579
references.citation: Br J Cancer. 2012 Oct 9;107(8):1442-3; author reply 1444
references.pmid: 23018559
references.citation: Oncologist. 2008 Dec;13(12):1270-5
references.pmid: 19056857
references.citation: Ann Surg. 2005 Aug;242(2):172-7
references.pmid: 16041206
references.citation: Cancer. 2011 Oct 15;117(20):4623-32
references.pmid: 21456008
references.citation: BMC Cancer. 2012 Aug 09;12:347
references.pmid: 22876814
references.citation: Nat Genet. 2007 Mar;39(3):347-51
references.pmid: 17293865
references.citation: JAMA. 2009 Dec 2;302(21):2338-44
references.pmid: 19952320
references.citation: Ann Surg. 2008 Jan;247(1):125-35
references.pmid: 18156932
references.citation: Ann Surg. 2013 Jun;257(6):1079-88
references.pmid: 23426338
references.citation: J Clin Oncol. 2009 Aug 1;27(22):3677-83
references.pmid: 19470929
references.citation: Curr Protoc Hum Genet. 2009 Jan;Chapter 2:Unit 2.12
references.pmid: 19170031
references.citation: Clin Cancer Res. 2011 Mar 1;17(5):1122-30
references.pmid: 21239505
references.citation: Cancer. 1996 Apr 1;77(7):1254-62
references.pmid: 8608500
references.citation: Br J Surg. 2012 Nov;99(11):1575-82
references.pmid: 23027075
references.citation: Ann Surg. 2004 Aug;240(2):205-13
references.pmid: 15273542
references.citation: Curr Oncol Rep. 2011 Jun;13(3):206-15
references.pmid: 21373987
references.citation: N Engl J Med. 2009 Apr 2;360(14):1408-17
references.pmid: 19339720
references.citation: Am J Surg Pathol. 2010 Sep;34(9):1287-94
references.pmid: 20697255
references.citation: Int J Cancer. 1991 Dec 2;49(6):875-9
references.pmid: 1959991
references.citation: Ann Surg Oncol. 2010 May;17(5):1429-34
references.pmid: 20049644
references.citation: PLoS One. 2009 Nov 18;4(11):e7887
references.pmid: 19924296