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Current Oncology Reports
Published in: Current Oncology Reports 3/2010

01-05-2010

KRAS Testing and Its Importance in Colorectal Cancer

Authors: Deepa T. Patil, Cory R. Fraser, Thomas P. Plesec

Published in: Current Oncology Reports | Issue 3/2010

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Abstract

Cetuximab and panitumumab are monoclonal antibodies used in the treatment of metastatic colorectal cancer (mCRC) by selectively targeting the epidermal growth factor receptor (EGFR) axis. Studies have shown that mutations in codons 12/13 of exon 2 of the KRAS gene render these therapies ineffective. As a result, the National Comprehensive Cancer Network and American Society of Clinical Oncology recommend KRAS mutation testing in mCRC. Appropriate testing depends on the coordinated efforts of the entire treatment team, including the pathologist, who selects the tumor sample and testing platform as well as interprets and reports results. In addition to describing rationale and methodologies for KRAS mutation testing, the authors also summarize their algorithmic approach and elaborate the potential role of newer molecular biomarkers to predict anti-EGFR resistance in wild-type KRAS tumors.
Literature
1.
2.
Engstrom PF: Systemic therapy for advanced or metastatic colorectal cancer: National Comprehensive Cancer Network guidelines for combining anti-vascular endothelial growth factor and anti-epidermal growth factor receptor monoclonal antibodies with chemotherapy. Pharmacotherapy 2008, 28:18S–22S.CrossRefPubMed
3.
Mendelsohn J: Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002, 20:1S–13S.PubMed
4.
Burgess AW, Cho HS, Eigenbrot C, et al.: An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003, 12:541–552.CrossRefPubMed
5.
Spano JP, Fagard R, Soria JC, et al.: Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann Oncol 2005, 16:189–194.CrossRefPubMed
6.
Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004, 351:337–345.CrossRefPubMed
7.
Lockhart AC, Berlin JD: The epidermal growth factor receptor as a target for colorectal cancer therapy. Semin Oncol 2005, 32:52–60.CrossRefPubMed
8.
Goldstein NS, Armin M: Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer 2001, 92:1331–1346.CrossRefPubMed
9.
10.
Edkins S, O’Meara S, Parker A, et al.: Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther 2006, 5:928–932.PubMedCrossRef
11.
Saltz LB, Meropol NJ, Loehrer PJ Sr, et al.: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004, 22:1201–1208.CrossRefPubMed
12.
Lenz HJ, Van Cutsem E, Khambata-Ford S, et al.: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006, 24:4914–4921.CrossRefPubMed
13.
14.
15.
Schubbert S, Shannon K, Bollag G: Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007, 7:295–308.CrossRefPubMed
16.
Samowitz WS, Curtin K, Schaffer D, et al.: Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiol Biomarkers Prev 2000, 9:1193–1197.PubMed
17.
Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al.: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 2007, 67:2643–2648.CrossRefPubMed
18.
Di Fiore F, Blanchard F, Charbonnier F, et al.: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 2007, 96:1166–1169.CrossRefPubMed
19.
• Di Nicolantonio F, Martini M, Molinari F, et al.: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008, 26:5705–5712. BRAF mutations in KRAS wild-type tumors were inversely associated with response to therapy, with none of the BRAF V600E cases responding to anti-EGFR therapy versus 32% of KRAS wild-type/BRAF wild-type tumors.CrossRefPubMed
20.
Lievre A, Bachet JB, Boige V, et al.: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008, 26:374–379.CrossRefPubMed
21.
Souglakos J, Philips J, Wang R, et al.: Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 2009, 101:465–472.CrossRefPubMed
22.
Van Cutsem E, Kohne CH, Hitre E, et al.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009, 360:1408–1417.CrossRefPubMed
23.
•• Karapetis CS, Khambata-Ford S, Jonker DJ, et al.: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008, 359:1757–1765. The effectiveness of cetuximab was significantly associated with KRAS mutation status compared to basic supportive care alone; significantly improved OS and PFS were noted in patients with wild-type KRAS tumors treated with cetuximab.CrossRefPubMed
24.
•• Bokemeyer C, Bondarenko I, Makhson A, et al.: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009, 27:663–671. This randomized controlled trial showed that addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancers led to significantly increased chance of response and lower risk of disease progression in patients with KRAS wild-type tumors.CrossRefPubMed
25.
• 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, 26:1626–1634. This subgroup analysis from a randomized phase 3 study demonstrated significant response rate and longer OS with panitumumab therapy in patients with wild-type KRAS tumors compared to mutant group.CrossRefPubMed
26.
Jimeno A, Messersmith WA, Hirsch FR, et al.: KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. J Clin Oncol 2009, 27:1130–1136.CrossRefPubMed
27.
Simi L, Pratesi N, Vignoli M, et al.: High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer. Am J Clin Pathol 2008, 130:247–253.CrossRefPubMed
28.
Ogino S, Kawasaki T, Brahmandam M, et al.: Sensitive sequencing method for KRAS mutation detection by Pyrosequencing. J Mol Diagn 2005, 7:413–421.PubMed
29.
Packham D, Ward RL, Ap Lin V, et al.: Implementation of novel pyrosequencing assays to screen for common mutations of BRAF and KRAS in a cohort of sporadic colorectal cancers. Diagn Mol Pathol 2009, 18:62–71.CrossRefPubMed
30.
• Weichert W, Schewe C, Lehmann A, et al.: KRAS genotyping of paraffin-embedded colorectal cancer tissue in routine diagnostics: comparison of methods and impact of histology. J Mol Diagn 2009, 12:35–42. This is a comparative analysis involving Sanger sequencing, array analysis, melt curve analysis, and pyrosequencing, including sensitivity, laboratory working time, and costs. All were equally effective for routine diagnostic KRAS mutation analysis.CrossRefPubMed
31.
32.
Plesec TP, Hunt JL: KRAS mutation testing in colorectal cancer. Adv Anat Pathol 2009, 16:196–203.CrossRefPubMed
33.
Troncone G, Malapelle U, Cozzolino I, Palombini L: KRAS mutation analysis on cytological specimens of metastatic colo-rectal cancer. Diagn Cytopathol 2010 Jan 4. doi:10.​1002/​dc.​21302.
34.
Solomon SB, Zakowski MF, Pao W, et al.: Core needle lung biopsy specimens: adequacy for EGFR and KRAS mutational analysis. AJR Am J Roentgenol 2010, 194:266–269.CrossRefPubMed
35.
van Krieken JH, Jung A, Kirchner T, et al.: KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch 2009, 454:233–235.CrossRef
36.
Allegra CJ, Jessup JM, Somerfield MR, et al.: American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009, 27:2091–2096.CrossRefPubMed
37.
38.
Loupakis F, Ruzzo A, Cremolini C, et al.: KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009, 101:715–721.CrossRefPubMed
39.
Sartore-Bianchi A, Martini M, Molinari F, et al.: PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009, 69:1851–1857.CrossRefPubMed
40.
Perrone F, Lampis A, Orsenigo M, et al.: PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 2009, 20:84–90.CrossRefPubMed
41.
Moroni M, Veronese S, Benvenuti S, et al.: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005, 6:279–286.CrossRefPubMed
42.
Frattini M, Saletti P, Romagnani E, et al.: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 2007, 97:1139–1145.CrossRefPubMed
43.
Jhawer M, Goel S, Wilson AJ, et al.: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 2008, 68:1953–1961.CrossRefPubMed
44.
Razis E, Briasoulis E, Vrettou E, et al.: Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study. BMC Cancer 2008, 8:234.CrossRefPubMed
45.
Laurent-Puig P, Cayre A, Manceau G, et al.: Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009, 27:5924–5930.CrossRefPubMed
46.
Italiano A, Follana P, Caroli FX, et al.: Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number. Ann Surg Oncol 2008, 15:649–654.CrossRefPubMed
47.
Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, et al.: Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 2009, 4:e7287.CrossRefPubMed
48.
Prenen H, De Schutter J, Jacobs B, et al.: PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 2009, 15:3184–3188.CrossRefPubMed
49.
Lievre A, Bachet JB, Le Corre D, et al.: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006, 66:3992–3995.CrossRefPubMed
Metadata
Title
KRAS Testing and Its Importance in Colorectal Cancer
Authors
Deepa T. Patil
Cory R. Fraser
Thomas P. Plesec
Publication date
01-05-2010
Publisher
Current Science Inc.
Published in
Current Oncology Reports / Issue 3/2010
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-010-0099-y

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