Colorectal cancer

Optimal molecular profiling

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Guideline contents > PTH1: What is the optimal molecular profiling of colorectal cancer?

  Cite this page

A/Professor Charles Chan MB BS, PhD, FRCPA, Professor Pierre Chapuis D.S. (Qld), FRACS, Chetcuti, A, Ben Lee-Bates, Victoria Freeman, Cecilia Taing, Chetcuti, A, Cancer Council Australia Colorectal Cancer Guidelines Working Party. Clinical question:Molecular profiling of CRC . In: Clinical practice guidelines for the prevention, early detection and management of colorectal cancer. Sydney: Cancer Council Australia. [Version URL: https://wiki.cancer.org.au/australiawiki/index.php?oldid=173070, cited 2023 Sep 28]. Available from: https://wiki.cancer.org.au/australia/Guidelines:Colorectal_cancer.


Last modified:
7 November 2017 23:35:53

Background[edit source]

In recent years there has been an increasing focus on gene expression profiling to provide additional criteria for tumour sub-classification and improve prognostication, with the ultimate goal of individualising patient therapy. Numerous abnormalities in gene expression have been reported, the significance of which needs to be evaluated in well-designed studies of large clinical populations.

See Molecular pathology and biomarkers – implications for systemic chemotherapy.

Sampling and specimen handling considerations[edit source]

The procurement of adequate tissue to determine the status of predictive and or prognostic biomarkers has become necessary to guide important treatment decisions.

The primary pathologist plays a central role in reviewing all available tissue samples and selecting the most appropriate tissue suitable for biomarker analysis. If there is inadequate quantity of neoplastic cells for analysis, false-negative results may occur due to dilution of mutant alleles. This is particularly relevant to RAS mutation analysis.[1][2] Most molecular testing can now be performed on archival paraffin embedded tissue, and this may be required several years after resection of the primary tumour. It is recommended that a suitable tissue block be designated for this purpose, which contains a high proportion of cancer (preferably >70%).[3]



Practice pointQuestion mark transparent.png

A suitable tissue block with a high proportion of tumour tissue (preferably over 70%) should be designated for the purpose of further molecular testing if required.

Systematic review evidence[edit source]

In patients diagnosed with colorectal cancer who have undergone surgical resection or biopsy of the primary colorectal tumour, which molecular marker (BRAF/KRAS/NRAS/DNA mismatch repair /microsatellite instability) best predicts response to surgery, or adjuvant therapy or radiotherapy (disease-free survival, overall survival, disease-specific mortality, overall mortality, or relapse incidence)? (PTH1)

A total of 39 level II studies[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] and 66 level III-3 studies[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108] were identified that evaluated the prognostic value of microsatellite stability status, DNA mismatch repair function, KRAS or BRAF mutation status for various outcomes related to patient response to treatment. All studies were at high risk of bias except 6 which were at medium risk of bias.[17][24][48][72][77][107]

The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

Overall survival[edit source]

KRAS mutation status[edit source]

A total of 35 studies[6][12][15][19][23][24][28][29][30][39][42][45][46][49][55][56][58][62][64][65][74][77][79][80][81][85][86][91][95][97][98][99][102][106][108] reported the outcome of overall survival with respect to KRAS mutation status (any mutation versus wild type). All stages of colorectal cancer were included, as well as patients with metastatic disease.

Most studies reported a trend towards increased survival in those without KRAS mutations (wild-type KRAS), with half of the studies reporting at statistically significant difference.

No trends in overall survival and KRAS mutation status were reported against the clinical stage of colorectal cancer.

Thirteen studies[6][10][12][15][42][45][52][56][79][80][97][99][106] reported overall survival with respect to KRAS mutation status (any mutation versus wild type) in those who had anti-epidermal growth factor receptor (EGFR) treatment (cetuximab or panitumumab). Most studies reported a trend towards increased survival in those without KRAS mutations (wild-type KRAS), with nine of the studies reporting at statistically significant difference.

Nine studies[6][15][28][36][70][77][100][106][108] reported overall survival in respect to KRAS mutation status (any mutation versus wild-type) in those treated with the combination of leucovorin calcium (folinic acid), 5-fluorouracil (5FU) and oxaliplatin (FOLFOX). All but one study reported no statistically significant difference.

BRAF mutation status[edit source]

A total of 25 studies[4][14][15][18][19][24][29][30][42][43][52][53][55][58][60][62][77][79][90][95][96][97][99][102][103] reported overall survival as an outcome with respect to BRAF mutation status. The majority of studies report better survival in those with wild-type BRAF tumour gene, and this was statistically significantly different in all but six studies.[4][14][55][58][62][103]

Six studies[18][42][52][60][79][97] reported overall survival as an outcome with respect to BRAF mutation status in those who had anti-EGFR treatment (cetuximab or panitumumab). All studies report better survival in those with wild-type BRAF tumour gene, and this was statistically significantly different in all six studies.

Five studies[4][15][18][43][77] reported overall survival as outcome with respect to BRAF mutation status (any mutation versus wild type) in those who had FOLFOX. All studies report a trend towards increased survival in those without BRAF mutations (wild-type BRAF), with all but one study[4] reporting a statistically significant difference.

Microsatellite stability status[edit source]

A total of 20 studies[13][19][20][24][30][34][35][41][48][61][62][63][71][75][86][89][90][92][96][104] reported overall survival as an outcome with respect to microsatellite stability status. There was a slight trend towards better overall survival in those with microsatellite instability, with only nine studies[20][30][34][35][41][61][75][86][104] reporting a statistical significant difference.

Eighteen studies[4][5][14][15][17][21][31][32][34][35][53][61][67][68][69][76][93][107] reported overall survival as an outcome with respect to DNA mismatch repair function (proficient verse deficient, and vice versa). There was no reported consistent trends of significant between studies.

DNA mismatch repair status[edit source]

Five studies[4][15][67][69][107] reported overall survival as an outcome with respect to DNA mismatch repair function (proficient verse deficient, and vice versa) in those who had FOLFOX treatment. There were no consistently reported trends across the studies.

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Progression-free survival[edit source]

KRAS mutation status[edit source]

A total of 21 studies[7][10][12][18][28][29][36][39][42][45][52][56][57][60][70][78][97][100][102][106][108] reported progression-free survival as an outcome with respect to KRAS mutation status. All studies reported a trend towards longer progression-free survival in those without primary tumour KRAS mutation, but fewer than 50% of studies reported a statically significant difference.

A total of 10 studies[7][10][39][45][52][56][57][60][97][106] reported progression-free survival as outcome with respect to KRAS mutation status (any mutation versus wild type) in those who had anti-EGFR treatment (cetuximab or panitumumab). Most studies reported a trend towards longer progression-free survival in those without KRAS mutations (wild-type KRAS), with six of the studies[7][39][52][56][57][97] reporting at statistically significant difference.

Six studies[7][18][36][70][100][108] reported progression-free survival as outcome in respect to KRAS mutation status (any mutation versus wild type) in those who had FOLFOX treatment. There were no consistently reported trends across the studies.

BRAF mutation status[edit source]

Ten studies[18][26][29][42][52][57][60][96][97][102] reported progression-free survival as an outcome with respect to BRAF mutation status. All studies consistently reported longer progression free survival in those without BRAF mutation, and all but one study reported a statistically significant difference. All clinical grades of colorectal cancer were reported across these nine studies.[18][26][42][52][57][60][96][97][102]

A total of seven studies[18][26][42][52][57][60][97] reported progression free survival as an outcome with respect to BRAF mutation status in those who had anti-EGFR treatment (cetuximab or panitumumab). All studies reported longer progression-free survival in those with wild-type BRAF tumour gene, and this was statistically significantly different in six studies.[18][26][42][52][57][97]

Microsatellite stability status and DNA mismatch repair status[edit source]

Five studies[21][66][68][69][96] reported progression-free survival as an outcome with respect to either microsatellite stability status or mismatch repair function status. No significant trends or differences were reported.

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Disease-free survival[edit source]

KRAS mutation status[edit source]

Twelve studies[19][23][24][25][40][46][49][51][55][62][73][77] reported disease-free survival as an outcome with respect to KRAS mutation status. Most studies consistently reported a trend towards longer disease free survival in those without KRAS mutations (wild-type KRAS). This difference was statistically significantly in only 5 of these studies.[19][25][49][51][73]

Four studies[25][51][73][77] reported disease-free survival as an outcome with respect to KRAS mutation status in those who had FOLFOX treatment. All studies consistently reported a trend towards longer disease-free survival in those without KRAS mutations (wild-type KRAS), but only two studies reported a statistically significantly difference.[25][73]

BRAF mutation status[edit source]

Ten studies[14][19][24][53][55][62][74][77][82][90] reported disease free survival as an outcome with respect to BRAF mutation status. All studies consistently reported a trend towards longer disease free survival in those without BRAF mutations (wild-type BRAF). This difference was statistically significantly in five studies.[53][55][77][82][90]

Microsatellite stability status[edit source]

Seventeen studies[13][19][22][24][34][35][40][41][54][59][62][71][75][82][89][90][105] reported disease-free survival as an outcome with respect to microsatellite stability status. Reported results were inconsistent across studies.

DNA mismatch repair status[edit source]

Twelve studies[5][14][17][31][32][34][35][53][59][67][76][107] reported disease free survival as an outcome with respect to mismatch repair function. Most studies consistently reported a trend towards longer disease free survival in those with deficient mismatch repair function. This difference was statistically significant in eight studies.[5][14][17][31][32][35][53][107]

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Objective response rate[edit source]

RAS mutation status[edit source]

Five studies[10][12][27][70][79] reported objective response rate as an outcome with respect to KRAS or RAS (KRAS or NRAS) mutation status.

All studies consistently reported a trend towards greater response rate in those with wild-type KRAS tumours. This was statistically significant in three[12][27][79] of the five studies.

BRAF mutation status[edit source]

One study[79] reported objective response rate as an outcome with respect to tumour BRAF mutation status. This single study reported a significantly greater objective response rate in those with tumour BRAF mutations.

DNA mismatch repair status[edit source]

Three studies[21][68][69] reported objective response rate as an outcome with respect to mismatch repair function. No significant trends or differences were reported.

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Other outcomes[edit source]

A number of other outcomes relating to treatment response were reported. These outcomes included pathological complete response, overall mortality, disease control rate, disease-specific survival, time to progression, disease recurrence, recurrence free survival, recurrence-free interval, distant metastases, clinical response, risk of recurrence, and time to recurrence. All these outcomes were reported in a single or very few studies, with few or no reported significant trends.

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Evidence summary and recommendations[edit source]

Evidence summary Level References
Current evidence remains controversial as to the use of presently available molecular markers to predict prognosis and identify those patients who may benefit most from conventional adjuvant postoperative chemotherapy. There is emerging evidence to support the use of markers to inform specific targeted therapy. II, III-2 [4], [5], [6], [7], [10], [12], [13], [14], [15], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [34], [35], [36], [39], [40], [41], [42], [43], [45], [46], [48], [49], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [85], [86], [89], [90], [91], [92], [93], [95], [96], [97], [98], [99], [100], [102], [103], [104], [105], [106], [107], [108]
RAS

There is consistent evidence that KRAS mutations are predictive of decreased overall survival (all stages of diseases including metastatic disease), decreased progression free survival (all stages of diseases including metastatic disease), and poorer objective response rate.

There is moderate consistent evidence that KRAS mutation predicts decreased disease free survival (stages I–IV) and decreased recurrence free survival (stages I–IV).

There is moderate evidence that, among patients who received anti-EGFR treatment, those with RAS (KRAS or NRAS) mutated tumours had decreased overall survival and progression-free survival compared to anti-EGFR treated patients with wild-type RAS tumours.

II, III-2 [6], [12], [15], [19], [23], [24], [28], [30], [29], [39], [42], [45], [46], [49], [55], [56], [58], [62], [65], [64], [74], [77], [79], [80], [81], [85], [86], [91], [95], [97], [98], [99], [102], [106], [108], [7], [10], [18], [25], [27], [36], [40], [51], [52], [57], [60], [70], [73], [78], [100]
BRAF

There is consistent evidence that BRAF gene mutation is predictive for both decreased overall survival (all stages of diseases including metastatic disease) and progression free survival (all stages of diseases including metastatic disease).

There is moderate consistent evidence that BRAF mutation is predictive for decreased disease free survival (stages I-IV) and recurrence free survival (stages I-IV).

There is moderate evidence that, among patients who received anti-EGFR treatment, those with BRAF mutated tumours had decreased overall survival and progression-free survival than those with wild-type BRAF tumours.

There is moderate evidence that, among patients who received FOLFOX treatment, those with BRAF mutated tumours had decreased overall survival than those with wild-type BRAF tumours.

II, III-2 [4], [14], [15], [18], [19], [24], [26], [29], [30], [42], [43], [52], [53], [55], [57], [58], [60], [62], [74], [77], [79], [82], [90], [95], [96], [97], [99], [102], [103]
Microsatellite Instability

There is consistent evidence that tumour microsatellite instability predicts longer time to disease recurrence (stages I–IV), increased recurrence free survival (stages II–III), and a longer recurrence free interval (stages II–III).

There is inconsistent evidence that tumour microsatellite instability predicts increase overall survival (stages I-IV).

Microsatellite stability status was not shown to predict progression-free survival or disease-free survival.

II, III-2 [4], [5], [13], [14], [15], [17], [19], [20], [21], [22], [24], [30], [31], [32], [34], [35], [40], [41], [48], [53], [54], [59], [61], [62], [63], [66], [67], [68], [69], [71], [75], [76], [82], [86], [89], [90], [92], [93], [96], [104], [105], [107]
Mismatch repair

There is consistent evidence that tumour mismatch repair deficiency predicts increased disease free survival (stage II–III) and decreased risk of recurrence (stages I–IV).

There is no consistent evidence that mismatch repair status predicts patient overall survival, progression free survival, or objective response rate.

II, III-2 [4], [5], [14], [15], [17], [21], [31], [32], [34], [35], [53], [59], [66], [67], [68], [69], [76], [96], [107]


Evidence-based recommendationQuestion mark transparent.png Grade
RAS mutation studies should be performed on patients with advanced (metastatic) colorectal cancer in whom anti-EGFR treatment is being considered. Cetuximab and panitumumab should only be considered for the treatment of patients with RAS wild-type metastatic colorectal cancer. 		D


Evidence-based recommendationQuestion mark transparent.png Grade
There is emerging evidence suggesting that BRAF mutation may be associated with poor response to anti-EGFR treatment, and that BRAF mutation studies should therefore be performed on patients with advanced (metastatic) colorectal cancer. 		D


Health system implications of these recommendations[edit source]

Clinical practice[edit source]

Implementation of the recommendation would not change the way that care is currently organised.

Resourcing[edit source]

No additional resourcing will be necessary to implement the recommendation.

Barriers to implementation[edit source]

No barriers to the implementation of this recommendation are envisaged.

Discussion[edit source]

Unresolved issues[edit source]

The prognostic value of molecular markers is yet to be defined to a degree that can be used in routine pathological analysis.

Studies currently underway[edit source]

Clinical trials are currently underway to test targeted therapies in BRAF-mutated metastatic colorectal cancer, akin to the development of therapies for BRAF-mutated metastatic melanoma. Early results are promising but have generally been less favourable than the melanoma trials.[109][110][111][112]

It is not known if there are other studies underway in this field.

Future research priorities[edit source]

It is suggested that further studies are done to more precisely define the prognostic value of these molecular markers.

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References[edit source]

  1. ↑ Dijkstra JR, Heideman DA, Meijer GA, Boers JE, 't Hart NA, Diebold J, et al. KRAS mutation analysis on low percentage of colon cancer cells: the importance of quality assurance. Virchows Arch 2013 Jan;462(1):39-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23242173.
  2. ↑ Tsiatis AC, Norris-Kirby A, Rich RG, Hafez MJ, Gocke CD, Eshleman JR, et al. Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J Mol Diagn 2010 Jul;12(4):425-32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20431034.
  3. ↑ Royal College of Pathologists of Australasia. Colorectal Cancer Structured Reporting Protocol (3rd edition). Royal College of Pathologists of Australasia; 2016 Available from: https://www.rcpa.edu.au/Library/Practising-Pathology/Structured-Pathology-Reporting-of-Cancer/Cancer-Protocols/Gastrointestinal/Protocol-colorectal-cancer.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol 2015 Dec 10;33(35):4176-87 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26527776.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Bertagnolli MM, Redston M, Compton CC, Niedzwiecki D, Mayer RJ, Goldberg RM, et al. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer--a study of CALGB 9581 and 89803. J Clin Oncol 2011 Aug 10;29(23):3153-62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21747089.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011 Jul;22(7):1535-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21228335.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009 Feb 10;27(5):663-71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19114683.
  8. ↑ Chang EY, Dorsey PB, Frankhouse J, Lee RG, Walts D, Johnson W, et al. Combination of microsatellite instability and lymphocytic infiltrate as a prognostic indicator in colon cancer. Arch Surg 2009 Jun;144(6):511-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19528382.
  9. ↑ Chow OS, Kuk D, Keskin M, Smith JJ, Camacho N, Pelossof R, et al. KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy. Ann Surg Oncol 2016 Aug;23(8):2548-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27020587.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Cohn AL, Shumaker GC, Khandelwal P, Smith DA, Neubauer MA, Mehta N, et al. An open-label, single-arm, phase 2 trial of panitumumab plus FOLFIRI as second-line therapy in patients with metastatic colorectal cancer. Clin Colorectal Cancer 2011 Sep;10(3):171-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21855038.
  11. ↑ de Weger VA, Turksma AW, Voorham QJ, Euler Z, Bril H, van den Eertwegh AJ, et al. Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite-stable and microsatellite-instable colon cancer. Clin Cancer Res 2012 Feb 1;18(3):882-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22156611.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 Díaz-Rubio E, Gómez-España A, Massutí B, Sastre J, Reboredo M, Manzano JL, et al. Role of Kras status in patients with metastatic colorectal cancer receiving first-line chemotherapy plus bevacizumab: a TTD group cooperative study. PLoS One 2012;7(10):e47345 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23174912.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Ferri M, Lorenzon L, Onelli MR, La Torre M, Mercantini P, Virgilio E, et al. Lymph node ratio is a stronger prognostic factor than microsatellite instability in colorectal cancer patients: results from a 7 years follow-up study. Int J Surg 2013;11(9):1016-21 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23747976.
  14. ↑ 14.00 14.01 14.02 14.03 14.04 14.05 14.06 14.07 14.08 14.09 14.10 French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R, et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 2008 Jun 1;14(11):3408-15 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18519771.
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 15.12 Gavin PG, Colangelo LH, Fumagalli D, Tanaka N, Remillard MY, Yothers G, et al. Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value. Clin Cancer Res 2012 Dec 1;18(23):6531-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23045248.
  16. ↑ Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011 Apr 1;29(10):1261-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21383284.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J, et al. The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status. Eur J Cancer 2009 Feb;45(3):365-73 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18722765.
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 Kaczirek K, Ciuleanu TE, Vrbanec D, Marton E, Messinger D, Liegl-Atzwanger B, et al. FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study. Clin Colorectal Cancer 2015 Jun;14(2):91-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25666295.
  19. ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 Kadowaki S, Kakuta M, Takahashi S, Takahashi A, Arai Y, Nishimura Y, et al. Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer. World J Gastroenterol 2015 Jan 28;21(4):1275-83 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25632202.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 Klingbiel D, Saridaki Z, Roth AD, Bosman FT, Delorenzi M, Tejpar S. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Ann Oncol 2015 Jan;26(1):126-32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25361982.
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 2009 Jan 27;100(2):266-73 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19165197.
  22. ↑ 22.0 22.1 22.2 22.3 Nehls O, Okech T, Hsieh CJ, Enzinger T, Sarbia M, Borchard F, et al. Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX. Br J Cancer 2007 May 7;96(9):1409-18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17426704.
  23. ↑ 23.0 23.1 23.2 23.3 23.4 Ogino S, Meyerhardt JA, Irahara N, Niedzwiecki D, Hollis D, Saltz LB, et al. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res 2009 Dec 1;15(23):7322-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19934290.
  24. ↑ 24.00 24.01 24.02 24.03 24.04 24.05 24.06 24.07 24.08 24.09 24.10 24.11 Ogino S, Shima K, Meyerhardt JA, McCleary NJ, Ng K, Hollis D, et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 2012 Feb 1;18(3):890-900 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22147942.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, et al. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer 2015 May 10;15:384 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25956750.
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 26.6 Peeters M, Oliner KS, Parker A, Siena S, Van Cutsem E, Huang J, et al. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res 2013 Apr 1;19(7):1902-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23325582.
  27. ↑ 27.0 27.1 27.2 27.3 27.4 Price TJ, Bruhn MA, Lee CK, Hardingham JE, Townsend AR, Mann KP, et al. Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer. Br J Cancer 2015 Mar 17;112(6):963-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25742472.
  28. ↑ 28.0 28.1 28.2 28.3 28.4 28.5 Reinacher-Schick A, Schulmann K, Modest DP, Bruns N, Graeven U, Jaworska M, et al. Effect of KRAS codon13 mutations in patients with advanced colorectal cancer (advanced CRC) under oxaliplatin containing chemotherapy. Results from a translational study of the AIO colorectal study group. BMC Cancer 2012 Aug 9;12:349 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22876876.
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 29.7 Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, 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 Dec 10;27(35):5931-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19884549.
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 30.8 Roth AD, Delorenzi M, Tejpar S, Yan P, Klingbiel D, Fiocca R, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst 2012 Nov 7;104(21):1635-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23104212.
  31. ↑ 31.0 31.1 31.2 31.3 31.4 31.5 31.6 Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010 Jul 10;28(20):3219-26 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20498393.
  32. ↑ 32.0 32.1 32.2 32.3 32.4 32.5 32.6 Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, Labianca R, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst 2011 Jun 8;103(11):863-75 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21597022.
  33. ↑ Sinicrope FA, Mahoney MR, Smyrk TC, Thibodeau SN, Warren RS, Bertagnolli MM, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 2013 Oct 10;31(29):3664-72 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24019539.
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 34.6 34.7 34.8 Sinicrope FA, Rego RL, Halling KC, Foster N, Sargent DJ, La Plant B, et al. Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 2006 Sep;131(3):729-37 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16952542.
  35. ↑ 35.0 35.1 35.2 35.3 35.4 35.5 35.6 35.7 35.8 35.9 Sinicrope FA, Rego RL, Halling KC, Foster NR, Sargent DJ, La Plant B, et al. Thymidylate synthase expression in colon carcinomas with microsatellite instability. Clin Cancer Res 2006 May 1;12(9):2738-44 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16675565.
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 Smith JC, Brooks L, Hoff PM, McWalter G, Dearden S, Morgan SR, et al. KRAS mutations are associated with inferior clinical outcome in patients with metastatic colorectal cancer, but are not predictive for benefit with cediranib. Eur J Cancer 2013 Jul;49(10):2424-32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23510802.
  37. ↑ Srdjan M, Jadranka A, Ivan D, Branimir Z, Daniela B, Petar S, et al. Microsatellite instability & survival in patients with stage II/III colorectal carcinoma. Indian J Med Res 2016 May;143(Supplement):S104-S111 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27748284.
  38. ↑ Taieb J, Zaanan A, Le Malicot K, Julié C, Blons H, Mineur L, et al. Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab: A Post Hoc Analysis of the PETACC-8 Trial. JAMA Oncol 2016 Jan 14;:1-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26768652.
  39. ↑ 39.0 39.1 39.2 39.3 39.4 39.5 39.6 Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009 Feb 5;360(6):563-72 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19196673.
  40. ↑ 40.0 40.1 40.2 40.3 40.4 40.5 Westra JL, Schaapveld M, Hollema H, de Boer JP, Kraak MM, de Jong D, et al. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol 2005 Aug 20;23(24):5635-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16110022.
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 Yoon YS, Yu CS, Kim TW, Kim JH, Jang SJ, Cho DH, et al. Mismatch repair status in sporadic colorectal cancer: immunohistochemistry and microsatellite instability analyses. J Gastroenterol Hepatol 2011 Dec;26(12):1733-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21615788.
  42. ↑ 42.00 42.01 42.02 42.03 42.04 42.05 42.06 42.07 42.08 42.09 42.10 42.11 42.12 Saridaki Z, Tzardi M, Sfakianaki M, Papadaki C, Voutsina A, Kalykaki A, et al. BRAFV600E mutation analysis in patients with metastatic colorectal cancer (mCRC) in daily clinical practice: correlations with clinical characteristics, and its impact on patients' outcome. PLoS One 2013 Dec 18;8(12):e84604 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24367680.
  43. ↑ 43.0 43.1 43.2 43.3 43.4 Alonso-Espinaco V, Cuatrecasas M, Alonso V, Escudero P, Marmol M, Horndler C, et al. RAC1b overexpression correlates with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX chemotherapy. Eur J Cancer 2014 Jul;50(11):1973-81 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24833563.
  44. ↑ Andrici J, Farzin M, Sioson L, Clarkson A, Watson N, Toon CW, et al. Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer. Mod Pathol 2016 Mar;29(3):266-74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26769140.
  45. ↑ 45.0 45.1 45.2 45.3 45.4 45.5 45.6 Azuara D, Santos C, Lopez-Doriga A, Grasselli J, Nadal M, Sanjuan X, et al. Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies. Mol Cancer Ther 2016 May;15(5):1106-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27037411.
  46. ↑ 46.0 46.1 46.2 46.3 46.4 Bengala C, Bettelli S, Bertolini F, Sartori G, Fontana A, Malavasi N, et al. Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy. Br J Cancer 2010 Sep 28;103(7):1019-24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20842128.
  47. ↑ Cappuzzo F, Sacconi A, Landi L, Ludovini V, Biagioni F, D'Incecco A, et al. MicroRNA signature in metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies. Clin Colorectal Cancer 2014 Mar;13(1):37-45.e4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24503111.
  48. ↑ 48.0 48.1 48.2 48.3 48.4 Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004 Feb;126(2):394-401 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14762775.
  49. ↑ 49.0 49.1 49.2 49.3 49.4 49.5 Cejas P, López-Gómez M, Aguayo C, Madero R, de Castro Carpeño J, Belda-Iniesta C, et al. KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis. PLoS One 2009 Dec 18;4(12):e8199 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20020061.
  50. ↑ Dahlin AM, Palmqvist R, Henriksson ML, Jacobsson M, Eklöf V, Rutegård J, et al. The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. Clin Cancer Res 2010 Mar 15;16(6):1845-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20197478.
  51. ↑ 51.0 51.1 51.2 51.3 51.4 51.5 Deng Y, Wang L, Tan S, Kim GP, Dou R, Chen D, et al. KRAS as a predictor of poor prognosis and benefit from postoperative FOLFOX chemotherapy in patients with stage II and III colorectal cancer. Mol Oncol 2015 Aug;9(7):1341-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25864038.
  52. ↑ 52.00 52.01 52.02 52.03 52.04 52.05 52.06 52.07 52.08 52.09 52.10 52.11 52.12 52.13 Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008 Dec 10;26(35):5705-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19001320.
  53. ↑ 53.00 53.01 53.02 53.03 53.04 53.05 53.06 53.07 53.08 53.09 53.10 Donada M, Bonin S, Barbazza R, Pettirosso D, Stanta G. Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision. BMC Gastroenterol 2013 Feb 27;13:36 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23446022.
  54. ↑ 54.0 54.1 54.2 54.3 Du C, Zhao J, Xue W, Dou F, Gu J. Prognostic value of microsatellite instability in sporadic locally advanced rectal cancer following neoadjuvant radiotherapy. Histopathology 2013 Apr;62(5):723-30 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23425253.
  55. ↑ 55.0 55.1 55.2 55.3 55.4 55.5 55.6 55.7 55.8 55.9 Fariña-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ, et al. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol 2010 Dec;21(12):2396-402 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20501503.
  56. ↑ 56.0 56.1 56.2 56.3 56.4 56.5 56.6 56.7 Gajate P, Sastre J, Bando I, Alonso T, Cillero L, Sanz J, et al. Influence of KRAS p.G13D mutation in patients with metastatic colorectal cancer treated with cetuximab. Clin Colorectal Cancer 2012 Dec;11(4):291-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22537608.
  57. ↑ 57.00 57.01 57.02 57.03 57.04 57.05 57.06 57.07 57.08 57.09 57.10 Gao J, Wang TT, Yu JW, Li YY, Shen L. Wild-Type KRAS and BRAF Could Predict Response to Cetuximab in Chinese Colorectal Cancer Patients. Chin J Cancer Res 2011 Dec;23(4):271-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23357879.
  58. ↑ 58.0 58.1 58.2 58.3 58.4 58.5 58.6 Garrido-Laguna I, Hong DS, Janku F, Nguyen LM, Falchook GS, Fu S, et al. KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors. PLoS One 2012;7(5):e38033 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22675430.
  59. ↑ 59.0 59.1 59.2 59.3 59.4 59.5 Huh JW, Kim HC, Kim SH, Park YA, Cho YB, Yun SH, et al. Mismatch repair system and p53 expression in patients with T1 and T2 colorectal cancer: predictive role of lymph node metastasis and survival. J Surg Oncol 2014 Jun;109(8):848-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24623275.
  60. ↑ 60.00 60.01 60.02 60.03 60.04 60.05 60.06 60.07 60.08 60.09 60.10 Igarashi H, Kurihara H, Mitsuhashi K, Ito M, Okuda H, Kanno S, et al. Association of MicroRNA-31-5p with Clinical Efficacy of Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer. Ann Surg Oncol 2015 Aug;22(8):2640-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25472647.
  61. ↑ 61.0 61.1 61.2 61.3 61.4 61.5 Jensen SA, Vainer B, Kruhøffer M, Sørensen JB. Microsatellite instability in colorectal cancer and association with thymidylate synthase and dihydropyrimidine dehydrogenase expression. BMC Cancer 2009 Jan 20;9:25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19154585.
  62. ↑ 62.00 62.01 62.02 62.03 62.04 62.05 62.06 62.07 62.08 62.09 62.10 62.11 Vogelaar F, Van Erning F, Reimers M, Van Der Linden J, Pruijt J, Van Den Brule A, et al. The prognostic value of Microsatellite Instability, KRAS, BRAF and PIK3CA mutations in stage II colon cancer patients. Mol Med 2015 Dec 17;:1-26 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26716438.
  63. ↑ 63.0 63.1 63.2 63.3 Kang BW, Kim JG, Lee SJ, Chae YS, Moon JH, Sohn SK, et al. Clinical significance of microsatellite instability for stage II or III colorectal cancer following adjuvant therapy with doxifluridine. Med Oncol 2011 Dec;28 Suppl 1:S214-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20953739.
  64. ↑ 64.0 64.1 64.2 64.3 Karagkounis G, Torbenson MS, Daniel HD, Azad NS, Diaz LA Jr, Donehower RC, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer 2013 Dec 1;119(23):4137-44 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24104864.
  65. ↑ 65.0 65.1 65.2 65.3 Kemeny NE, Chou JF, Capanu M, Gewirtz AN, Cercek A, Kingham TP, et al. KRAS mutation influences recurrence patterns in patients undergoing hepatic resection of colorectal metastases. Cancer 2014 Dec 15;120(24):3965-71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25155157.
  66. ↑ 66.0 66.1 66.2 66.3 66.4 Kim JC, Roh SA, Cho DH, Kim TW, Yoon SN, Kim CW, et al. Chemoresponsiveness associated with canonical molecular changes in colorectal adenocarcinomas. Anticancer Res 2009 Aug;29(8):3115-23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19661324.
  67. ↑ 67.0 67.1 67.2 67.3 67.4 67.5 67.6 Kim JE, Hong YS, Kim HJ, Kim KP, Lee JL, Park SJ, et al. Defective Mismatch Repair Status was not Associated with DFS and OS in Stage II Colon Cancer Treated with Adjuvant Chemotherapy. Ann Surg Oncol 2015 Dec;22 Suppl 3:S630-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26271397.
  68. ↑ 68.0 68.1 68.2 68.3 68.4 68.5 68.6 Kim JE, Hong YS, Ryu MH, Lee JL, Chang HM, Lim SB, et al. Association between deficient mismatch repair system and efficacy to irinotecan-containing chemotherapy in metastatic colon cancer. Cancer Sci 2011 Sep;102(9):1706-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21679278.
  69. ↑ 69.0 69.1 69.2 69.3 69.4 69.5 69.6 69.7 Kim ST, Lee J, Park SH, Park JO, Lim HY, Kang WK, et al. The effect of DNA mismatch repair (MMR) status on oxaliplatin-based first-line chemotherapy as in recurrent or metastatic colon cancer. Med Oncol 2010 Dec;27(4):1277-85 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19949897.
  70. ↑ 70.0 70.1 70.2 70.3 70.4 70.5 70.6 Kim ST, Park KH, Kim JS, Shin SW, Kim YH. Impact of KRAS Mutation Status on Outcomes in Metastatic Colon Cancer Patients without Anti-Epidermal Growth Factor Receptor Therapy. Cancer Res Treat 2013 Mar;45(1):55-62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23613671.
  71. ↑ 71.0 71.1 71.2 71.3 71.4 Kim YH, Min BH, Choi HK, Kim SJ, Kim KM, Kim JY, et al. Sporadic colorectal carcinomas with low-level microsatellite instability in Korea: do they form a distinct subgroup with distinguished clinicopathological features? J Surg Oncol 2009 May 1;99(6):351-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19204939.
  72. ↑ 72.0 72.1 Lanza G, Gafà R, Santini A, Maestri I, Guerzoni L, Cavazzini L. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol 2006 May 20;24(15):2359-67 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16710035.
  73. ↑ 73.0 73.1 73.2 73.3 73.4 73.5 73.6 Lee DW, Kim KJ, Han SW, Lee HJ, Rhee YY, Bae JM, et al. KRAS mutation is associated with worse prognosis in stage III or high-risk stage II colon cancer patients treated with adjuvant FOLFOX. Ann Surg Oncol 2015 Jan;22(1):187-94 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24889488.
  74. ↑ 74.0 74.1 74.2 74.3 74.4 74.5 Lee JW, Lee JH, Shim BY, Kim SH, Chung MJ, Kye BH, et al. KRAS Mutation Status Is Not a Predictor for Tumor Response and Survival in Rectal Cancer Patients Who Received Preoperative Radiotherapy With 5-Fluoropyrimidine Followed by Curative Surgery. Medicine (Baltimore) 2015 Aug;94(31):e1284 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26252300.
  75. ↑ 75.0 75.1 75.2 75.3 75.4 75.5 Lee SY, Kim DW, Lee HS, Ihn MH, Oh HK, Min BS, et al. Low-Level Microsatellite Instability as a Potential Prognostic Factor in Sporadic Colorectal Cancer. Medicine (Baltimore) 2015 Dec;94(50):e2260 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26683947.
  76. ↑ 76.0 76.1 76.2 76.3 76.4 76.5 Li P, Fang YJ, Li F, Ou QJ, Chen G, Ma G. ERCC1, defective mismatch repair status as predictive biomarkers of survival for stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy. Br J Cancer 2013 Apr 2;108(6):1238-44 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23481186.
  77. ↑ 77.00 77.01 77.02 77.03 77.04 77.05 77.06 77.07 77.08 77.09 77.10 77.11 77.12 Lin Q, Ye Q, Zhu D, Wei Y, Ren L, Ye L, et al. Determinants of long-term outcome in patients undergoing simultaneous resection of synchronous colorectal liver metastases. PLoS One 2014 Aug 27;9(8):e105747 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25162714.
  78. ↑ 78.0 78.1 78.2 78.3 Lin YL, Liau JY, Yu SC, Tseng LH, Lin LI, Liang JT, et al. Oxaliplatin-based Chemotherapy Might Provide Longer Progression-Free Survival in KRAS Mutant Metastatic Colorectal Cancer. Transl Oncol 2013 Jun;6(3):363-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23730417.
  79. ↑ 79.00 79.01 79.02 79.03 79.04 79.05 79.06 79.07 79.08 79.09 79.10 Llovet P, Sastre J, Ortega JS, Bando I, Ferrer M, García-Alfonso P, et al. Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy. Mol Diagn Ther 2015 Dec;19(6):397-408 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26341080.
  80. ↑ 80.0 80.1 80.2 80.3 80.4 Ma BB, Mo F, Tong JH, Wong A, Wong SC, Ho WM, et al. Elucidating the prognostic significance of KRAS, NRAS, BRAF and PIK3CA mutations in Chinese patients with metastatic colorectal cancer. Asia Pac J Clin Oncol 2015 Jun;11(2):160-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25865669.
  81. ↑ 81.0 81.1 81.2 81.3 Margonis GA, Kim Y, Spolverato G, Ejaz A, Gupta R, Cosgrove D, et al. Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis. JAMA Surg 2015 Aug;150(8):722-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26038887.
  82. ↑ 82.0 82.1 82.2 82.3 82.4 82.5 82.6 Markovic S, Antic J, Dragicevic N, Hamelin R, Krivokapic Z. High-frequency microsatellite instability and BRAF mutation (V600E) in unselected Serbian patients with colorectal cancer. J Mol Histol 2012 Apr;43(2):137-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22210186.
  83. ↑ Merok MA, Ahlquist T, Røyrvik EC, Tufteland KF, Hektoen M, Sjo OH, et al. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol 2013 May;24(5):1274-82 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23235802.
  84. ↑ Mori K, Toiyama Y, Saigusa S, Fujikawa H, Hiro J, Kobayashi M, et al. Systemic Analysis of Predictive Biomarkers for Recurrence in Colorectal Cancer Patients Treated with Curative Surgery. Dig Dis Sci 2015 Aug;60(8):2477-87 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25840921.
  85. ↑ 85.0 85.1 85.2 85.3 Nakanishi R, Harada J, Tuul M, Zhao Y, Ando K, Saeki H, et al. Prognostic relevance of KRAS and BRAF mutations in Japanese patients with colorectal cancer. Int J Clin Oncol 2013 Dec;18(6):1042-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23188063.
  86. ↑ 86.0 86.1 86.2 86.3 86.4 86.5 86.6 Nash GM, Gimbel M, Cohen AM, Zeng ZS, Ndubuisi MI, Nathanson DR, et al. KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer. Ann Surg Oncol 2010 Feb;17(2):416-24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19813061.
  87. ↑ Nehls O, Hass HG, Okech T, Zenner S, Hsieh CJ, Sarbia M, et al. Prognostic implications of BAX protein expression and microsatellite instability in all non-metastatic stages of primary colon cancer treated by surgery alone. Int J Colorectal Dis 2009 Jun;24(6):655-63 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19221769.
  88. ↑ Nitsche U, Rosenberg R, Balmert A, Schuster T, Slotta-Huspenina J, Herrmann P, et al. Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer. Ann Surg 2012 Nov;256(5):763-71; discussion 771 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23095620.
  89. ↑ 89.0 89.1 89.2 89.3 89.4 Oh SY, Kim DY, Kim YB, Suh KW. Oncologic outcomes after adjuvant chemotherapy using FOLFOX in MSI-H sporadic stage III colon cancer. World J Surg 2013 Oct;37(10):2497-503 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23754140.
  90. ↑ 90.0 90.1 90.2 90.3 90.4 90.5 90.6 90.7 90.8 Ooki A, Akagi K, Yatsuoka T, Asayama M, Hara H, Takahashi A, et al. Combined microsatellite instability and BRAF gene status as biomarkers for adjuvant chemotherapy in stage III colorectal cancer. J Surg Oncol 2014 Dec;110(8):982-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25154726.
  91. ↑ 91.0 91.1 91.2 91.3 Osumi H, Shinozaki E, Suenaga M, Matsusaka S, Konishi T, Akiyoshi T, et al. RAS mutation is a prognostic biomarker in colorectal cancer patients with metastasectomy. Int J Cancer 2016 Aug 15;139(4):803-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27004837.
  92. ↑ 92.0 92.1 92.2 92.3 Parc Y, Gueroult S, Mourra N, Serfaty L, Fléjou JF, Tiret E, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut 2004 Mar;53(3):371-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14960518.
  93. ↑ 93.0 93.1 93.2 93.3 Park JH, Powell AG, Roxburgh CS, Horgan PG, McMillan DC, Edwards J. Mismatch repair status in patients with primary operable colorectal cancer: associations with the local and systemic tumour environment. Br J Cancer 2016 Mar 1;114(5):562-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26859693.
  94. ↑ Pentheroudakis G, Kotoula V, De Roock W, Kouvatseas G, Papakostas P, Makatsoris T, et al. Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes. BMC Cancer 2013 Feb 2;13:49 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23374602.
  95. ↑ 95.0 95.1 95.2 95.3 95.4 95.5 Renaud S, Romain B, Falcoz PE, Olland A, Santelmo N, Brigand C, et al. KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer. Br J Cancer 2015 Feb 17;112(4):720-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25688918.
  96. ↑ 96.0 96.1 96.2 96.3 96.4 96.5 96.6 96.7 96.8 96.9 Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H, et al. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' outcome. Br J Cancer 2010 Jun 8;102(12):1762-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20485284.
  97. ↑ 97.00 97.01 97.02 97.03 97.04 97.05 97.06 97.07 97.08 97.09 97.10 97.11 97.12 97.13 97.14 Saridaki Z, Tzardi M, Papadaki C, Sfakianaki M, Pega F, Kalikaki A, et al. Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients. PLoS One 2011 Jan 20;6(1):e15980 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21283802.
  98. ↑ 98.0 98.1 98.2 98.3 Sasaki K, Margonis GA, Wilson A, Kim Y, Buettner S, Andreatos N, et al. Prognostic Implication of KRAS Status after Hepatectomy for Colorectal Liver Metastases Varies According to Primary Colorectal Tumor Location. Ann Surg Oncol 2016 Oct;23(11):3736-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27352204.
  99. ↑ 99.0 99.1 99.2 99.3 99.4 99.5 99.6 Sasaki Y, Hamaguchi T, Yamada Y, Takahashi N, Shoji H, Honma Y, et al. Value of KRAS, BRAF, and PIK3CA Mutations and Survival Benefit from Systemic Chemotherapy in Colorectal Peritoneal Carcinomatosis. Asian Pac J Cancer Prev 2016;17(2):539-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26925640.
  100. ↑ 100.0 100.1 100.2 100.3 100.4 100.5 Sharma N, Saifo M, Tamaskar IR, Bhuvaneswari R, Mashtare T, Fakih M. KRAS status and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFOX chemotherapy. J Gastrointest Oncol 2010 Dec;1(2):90-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22811812.
  101. ↑ Søreide K, Slewa A, Stokkeland PJ, van Diermen B, Janssen EA, Søreide JA, et al. Microsatellite instability and DNA ploidy in colorectal cancer: potential implications for patients undergoing systematic surveillance after resection. Cancer 2009 Jan 15;115(2):271-82 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19109816.
  102. ↑ 102.0 102.1 102.2 102.3 102.4 102.5 102.6 102.7 102.8 Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 2009 Aug 4;101(3):465-72 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19603024.
  103. ↑ 103.0 103.1 103.2 103.3 103.4 Stec R, Bodnar L, Charkiewicz R, Korniluk J, Rokita M, Smoter M, et al. K-Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan- or oxaliplatin-based chemotherapy. Cancer Biol Ther 2012 Nov;13(13):1235-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22909976.
  104. ↑ 104.0 104.1 104.2 104.3 104.4 Thomas ML, Hewett PJ, Ruszkiewicz AR, Moore JW. Clinicopathological predictors of benefit from adjuvant chemotherapy for stage C colorectal cancer: Microsatellite unstable cases benefit. Asia Pac J Clin Oncol 2015 Dec;11(4):343-51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26471980.
  105. ↑ 105.0 105.1 105.2 105.3 Yang L, Sun Y, Huang XE, Yu DS, Zhou JN, Zhou X, et al. Carcinoma microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for stage II rectal cancer. Asian Pac J Cancer Prev 2015;16(4):1545-51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25743829.
  106. ↑ 106.0 106.1 106.2 106.3 106.4 106.5 106.6 106.7 Yang YH, Lin JK, Chen WS, Lin TC, Yang SH, Jiang JK, et al. Comparison of cetuximab to bevacizumab as the first-line bio-chemotherapy for patients with metastatic colorectal cancer: superior progression-free survival is restricted to patients with measurable tumors and objective tumor response--a retrospective study. J Cancer Res Clin Oncol 2014 Nov;140(11):1927-36 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24934725.
  107. ↑ 107.0 107.1 107.2 107.3 107.4 107.5 107.6 107.7 107.8 Zaanan A, Fléjou JF, Emile JF, Des GG, Cuilliere-Dartigues P, Malka D, et al. Defective mismatch repair status as a prognostic biomarker of disease-free survival in stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy. Clin Cancer Res 2011 Dec 1;17(23):7470-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21998335.
  108. ↑ 108.0 108.1 108.2 108.3 108.4 108.5 108.6 Zocche DM, Ramirez C, Fontao FM, Costa LD, Redal MA. Global impact of KRAS mutation patterns in FOLFOX treated metastatic colorectal cancer. Front Genet 2015 Mar 30;6:116 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25870609.
  109. ↑ Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. J Clin Oncol 2015 Dec 1;33(34):4023-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26392102.
  110. ↑ Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2012 Mar;2(3):227-35 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22448344.
  111. ↑ Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 2015 Aug 20;373(8):726-36 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26287849.
  112. ↑ Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012 Jan 26;483(7387):100-3 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22281684.

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Referring to the large bowel, comprising the colon and rectum.

A recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.

5-fluorouracil is a systemic chemotherapy using fluorouracil.

Systemic chemotherapy using a combination of the drugs Leucovorin (folinic acid), Fluorouracil, and Oxaliplatin.

A recommendation formulated after a systematic review of the evidence, indicating supporting references.

A medical professional who treats acute and chronic illnesses and provides preventive care and health education to a wide range of patients.

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