Abstract
Numerous clinical studies have shown that anti-EGFR therapies are effective only in a subset of patients with colorectal cancer. Even though mutations in the KRAS gene have been confirmed as negative predictors of the response to EGFR-targeted therapies, not all KRAS wild-type (wt-KRAS) patients will respond to treatment. Recent studies have demonstrated that additionally wild-type BRAF (wt-BRAF) genotype is required for response to panitumumab or cetuximab, suggesting that BRAF genotype criteria should be used together with KRAS genotype for selecting the patients who are about to benefit from the anti-EGFR therapy. In this study, 239 samples obtained from 215 patients with metastatic colorectal cancer were tested for the presence of the seven most common mutations in the KRAS gene and the V600E mutation in the BRAF gene. Among the tested patients, 53.8% of patients had wt-KRAS genotype and 46.2% were KRAS mutants. Around five percent (5.1%) of the tested patients bore the V600E mutation in BRAF gene. All the patients showing to have the V600E mutation in BRAF were wt-KRAS. The concordance of KRAS and BRAF mutational status between primary and metastatic tumor tissue samples was 100%. We have shown that the proportions of mutated and non-mutated KRAS in Slovene patients, as well as the proportion of V600E mutations in BRAF is similar to genotyping results reported by other authors. The tested seven KRAS mutations on codons 12 and 13 were mutually exclusive with the V600E mutation in the BRAF gene. Summing up the results about the KRAS and the BRAF mutation carriers from our study, the portion of potentially non-responsive patients for the anti-EGFR treatment is 51.3%.
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References
Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation. Bioll Cell. 2001;93:53–62.
Harari PM, Allen GW, Bonner JA. Biology of interactions: anti-epidermal growth factor receptor agents. J Clin Oncol. 2007;25:4057–65.
Hemming AW, et al. Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol. 1992;51:147–52.
Kluftinger AM, Robinson BW, Quenville NF, Finley RJ, Davies NJ. Correlation of epidermal growth factor receptor and c-erbB2 oncogene product to known prognostic indicators of colorectal cancer. J Surg Oncol. 1992;1:97–105.
Mayer A, et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer. 1993;71:2454–60.
Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183–232.
Spano JP, et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol. 2005;16:102–8.
Bonomi PD, Buckingham L, Coon J. Selecting patients for treatment with epidermal growth factor tyrosine kinase inhibitors. Clin Cancer Res. 2007;13:4606s–12s.
Dassonville O, Bozec A, Fischel JL, Milano G. EGFR targeting therapies: monoclonal antibodies versus tyrosine kinase inhibitors. Similarities and differences. Crit Rev Oncol Hematol. 2007;62:53–61.
Amado RG, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Cancer J Clin Oncol. 2008;26:1626–34.
Kimura H, et al. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 2007;98:1275–80.
Lievre A, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with Cetuximab. J Clin Oncol. 2008;26(3):374–9.
De Roock W, et al. KRAS mutation status and early radiological response predict survival in colorectal cancer treated with Cetuximab. Ann Oncol. 2008;19:508–15.
Zenker M, et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007;44:131–5.
Van Krieken JHJM, et al. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch. 2008;453(5):417–31.
Linardou H, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008;9:962–72.
Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2001;417:949–54.
Sala E, et al. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res. 2008;6(5):751–9.
Kim IJ, et al. Mutational analysis of BRAF and K-ras in gastric cancers: absence of BRAF mutations in gastric cancers. Hum Genet. 2003;114:118–20.
Kumar R, et al. BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res. 2003;9:3362–8.
Di Nicolantino F, et al. Wild Type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705–12.
Bardelli A, Sienna S. Molecular mechanysms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010;28(7):1254–61.
Laurent-Puig P, 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(35):5924–31.
Benlloch S, et al. Detection of BRAF V600E mutation in colorectal cancer: comparison of automatic sequencing and real-time chemistry methodology. J Mol Diagn. 2006;8(5):540–3.
Bos JL, et al. Prevalence of ras mutations in human colorectal cancers. Nature. 1987;327:293–7.
Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85:692–6.
Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–99.
Di Fiore F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166–9.
Gnanasampanthan G, Elsaleh H, McCaul K, Iacopetta B. Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes’ C colorectal cancer. J Pathol. 2001;195:543–8.
Neuman J, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205(12):858–62.
Yuen S, et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res. 2002;62:6451–5.
Roth AD, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2009;28(3):466–74.
Rajagopalan H, et al. Tumorigenesis: RAF/RAS oncogenes, mismatch-repair status. Nature. 2002;418:934.
Artale S, Sartore-Bianchi A, Veronese SM. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol. 2008;26(25):4217–9.
Santini D, Loupakis F, Vincenzi B. High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practise. Oncologist. 2008;13:1270–5.
Velho S, et al. BRAF, KRAS, PIK3CA mutations in colorectal serrated polyps, cancer: primary or secondary genetic events in colorectal carcinogenesis. BMC Cancer. 2008;8:255.
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Ličar, A., Cerkovnik, P. & Novaković, S. Distribution of some activating KRAS and BRAF mutations in Slovene patients with colorectal cancer. Med Oncol 28, 1048–1053 (2011). https://doi.org/10.1007/s12032-010-9631-z
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DOI: https://doi.org/10.1007/s12032-010-9631-z