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BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Beyond KRAS mutation status: influence of KRAScopy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients

Authors: Leonie JM Mekenkamp, Jolien Tol, Jeroen R Dijkstra, Inge de Krijger, M Elisa Vink-Börger, Shannon van Vliet, Steven Teerenstra, Eveline Kamping, Eugène Verwiel, Miriam Koopman, Gerrit A Meijer, J Han JM van Krieken, Roland Kuiper, Cornelis JA Punt, Iris D Nagtegaal

Published in: BMC Cancer | Issue 1/2012

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Abstract

Background

KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab.

Methods

Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17) or poor (n = 17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR.

Results

Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model.

Conclusions

Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.
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Literature
1.
Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008, 359: 1757-1765. 10.1056/NEJMoa0804385.CrossRefPubMed
2.
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008, 26: 1626-1634. 10.1200/JCO.2007.14.7116.CrossRefPubMed
3.
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009, 360: 1408-1417. 10.1056/NEJMoa0805019.CrossRefPubMed
4.
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010, 28: 4697-4705. 10.1200/JCO.2009.27.4860.CrossRefPubMed
5.
Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouche O, Landi B, Louvet C, 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. 10.1200/JCO.2007.12.5906.CrossRefPubMed
6.
Knijn N, Mekenkamp LJ, Klomp M, Vink-Borger ME, Tol J, Teerenstra S, Meijer JW, Tebar M, Riemersma S, van Krieken JH, et al: KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer. 2011, 104: 1020-1026. 10.1038/bjc.2011.26.CrossRefPubMedPubMedCentral
7.
Oliveira C, Westra JL, Arango D, Ollikainen M, Domingo E, Ferreira A, Velho S, Niessen R, Lagerstedt K, Alhopuro P, et al: Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. Hum Mol Genet. 2004, 13: 2303-2311. 10.1093/hmg/ddh238.CrossRefPubMed
8.
De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, et al: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010, 304: 1812-1820. 10.1001/jama.2010.1535.CrossRefPubMed
9.
Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, 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. 10.1038/sj.bjc.6605177.CrossRefPubMedPubMedCentral
10.
Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, et al: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008, 26: 5705-5712. 10.1200/JCO.2008.18.0786.CrossRefPubMed
11.
Tol J, Nagtegaal ID, Punt CJ: BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009, 361: 98-99. 10.1056/NEJMc0904160.CrossRefPubMed
12.
Tol J, Dijkstra JR, Klomp M, Teerenstra S, Dommerholt M, Vink-Borger ME, van Cleef PH, van Krieken JH, Punt CJ, Nagtegaal ID: Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer. 2010, 46: 1997-2009. 10.1016/j.ejca.2010.03.036.CrossRefPubMed
13.
Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, et al: PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009, 69: 1851-1857. 10.1158/0008-5472.CAN-08-2466.CrossRefPubMed
14.
Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, Mazzucchelli L, et al: Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One. 2009, 4: e7287-10.1371/journal.pone.0007287.CrossRefPubMedPubMedCentral
15.
Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, Etienne LL, Cavalli F, Mazzucchelli L: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007, 97: 1139-1145. 10.1038/sj.bjc.6604009.CrossRefPubMedPubMedCentral
16.
De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, et al: Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010, 11: 753-762. 10.1016/S1470-2045(10)70130-3.CrossRefPubMed
17.
Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007, 25: 3230-3237. 10.1200/JCO.2006.10.5437.CrossRefPubMed
18.
Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, et al: Amphiregulin and epiregulin mRNA expression in primary tumours predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2009, 27: 5068-5074. 10.1200/JCO.2008.21.3744.CrossRefPubMed
19.
Pander J, Gelderblom H, Antonini NF, Tol J, van Krieken JH, van der Straaten T, Punt CJ, Guchelaar HJ: Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. Eur J Cancer. 2010, 46: 1829-1834. 10.1016/j.ejca.2010.03.017.CrossRefPubMed
20.
Bibeau F, Lopez-Crapez E, Di Fiore F, Thezenas S, Ychou M, Blanchard F, Lamy A, Penault-Llorca F, Frebourg T, Michel P, et al: Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol. 2009, 27: 1122-1129. 10.1200/JCO.2008.18.0463.CrossRefPubMed
21.
Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, Chang HM, Borucka E, Lurje G, Sherrod AE, et al: FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007, 25: 3712-3718. 10.1200/JCO.2006.08.8021.CrossRefPubMed
22.
Scaltriti M, Baselga J: The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 2006, 12: 5268-5272. 10.1158/1078-0432.CCR-05-1554.CrossRefPubMed
23.
Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B: Evidence that genetic instability occurs at an early stage of colorectal tumourigenesis. Cancer Res. 2001, 61: 818-822.PubMed
24.
Poulogiannis G, Ichimura K, Hamoudi RA, Luo F, Leung SY, Yuen ST, Harrison DJ, Wyllie AH, Arends MJ: Prognostic relevance of DNA copy number changes in colorectal cancer. J Pathol. 2010, 220: 338-347. 10.1002/path.2640.CrossRefPubMed
25.
Postma C, Koopman M, Buffart TE, Eijk PP, Carvalho B, Peters GJ, Ylstra B, van Krieken JH, Punt CJ, Meijer GA: DNA copy number profiles of primary tumours as predictors of response to chemotherapy in advanced colorectal cancer. Ann Oncol. 2009, 20: 1048-1056. 10.1093/annonc/mdn738.CrossRefPubMed
26.
Smith G, Bounds R, Wolf H, Steele RJ, Carey FA, Wolf CR: Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours - implications for personalised cancer medicine. Br J Cancer. 2010, 102: 693-703. 10.1038/sj.bjc.6605534.CrossRefPubMedPubMedCentral
27.
Soh J, Okumura N, Lockwood WW, Yamamoto H, Shigematsu H, Zhang W, Chari R, Shames DS, Tang X, MacAulay C, et al: Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumour cells. PLoS One. 2009, 4: e7464-10.1371/journal.pone.0007464.CrossRefPubMedPubMedCentral
28.
Slaby O, Svoboda M, Michalek J, Vyzula R: MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009, 8: 102-10.1186/1476-4598-8-102.CrossRefPubMedPubMedCentral
29.
Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, et al: A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005, 353: 1793-1801. 10.1056/NEJMoa050995.CrossRefPubMed
30.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ: RAS is regulated by the let-7 microRNA family. Cell. 2005, 120: 635-647. 10.1016/j.cell.2005.01.014.CrossRefPubMed
31.
Akao Y, Nakagawa Y, Naoe T: let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull. 2006, 29: 903-906. 10.1248/bpb.29.903.CrossRefPubMed
32.
Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y, Cai X, Wang K, Wang G, Ba Y, et al: Role of miR-143 targeting KRAS in colorectal tumourigenesis. Oncogene. 2009, 28: 1385-1392. 10.1038/onc.2008.474.CrossRefPubMed
33.
Tsang WP, Kwok TT: The miR-18a* microRNA functions as a potential tumour suppressor by targeting on K-Ras. Carcinogenesis. 2009, 30: 953-959. 10.1093/carcin/bgp094.CrossRefPubMed
34.
Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, et al: Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009, 360: 563-572. 10.1056/NEJMoa0808268.CrossRefPubMed
35.
Tol J, Dijkstra JR, Vink-Borger ME, Nagtegaal ID, Punt CJ, van Krieken JH, Ligtenberg MJ: High sensitivity of both sequencing and real-time PCR analysis of KRAS mutations in colorectal cancer tissue. J Cell Mol Med. 2010, 14: 2122-2131.CrossRefPubMed
36.
van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL, Delabesse E, Davi F, Schuuring E, Garcia-Sanz R, et al: Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003, 17: 2257-2317. 10.1038/sj.leu.2403202.CrossRefPubMed
37.
Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, et al: Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007, 370: 135-142. 10.1016/S0140-6736(07)61086-1.CrossRefPubMed
38.
Bandres E, Cubedo E, Agirre X, Malumbres R, Zarate R, Ramirez N, Abajo A, Navarro A, Moreno I, Monzo M, et al: Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoural tissues. Mol Cancer. 2006, 5: 29-CrossRefPubMedPubMedCentral
39.
Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008, 3: 1101-1108. 10.1038/nprot.2008.73.CrossRefPubMed
40.
Andersen CL, Jensen JL, Orntoft TF: Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004, 64: 5245-5250. 10.1158/0008-5472.CAN-04-0496.CrossRefPubMed
41.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002, 3: RESEARCH0034 Epub 2002 June 18
42.
Adam L, Zhong M, Choi W, Qi W, Nicoloso M, Arora A, Calin G, Wang H, Siefker-Radtke A, McConkey D, et al: miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res. 2009, 15: 5060-5072. 10.1158/1078-0432.CCR-08-2245.CrossRefPubMed
43.
Punt CJ, Tol J: More is less – combining targeted therapies in metastatic colorectal cancer. Nat Rev Clin Oncol. 2009, 6: 731-733. 10.1038/nrclinonc.2009.168.CrossRefPubMed
Metadata
Title
Beyond KRAS mutation status: influence of KRAScopy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients
Authors
Leonie JM Mekenkamp
Jolien Tol
Jeroen R Dijkstra
Inge de Krijger
M Elisa Vink-Börger
Shannon van Vliet
Steven Teerenstra
Eveline Kamping
Eugène Verwiel
Miriam Koopman
Gerrit A Meijer
J Han JM van Krieken
Roland Kuiper
Cornelis JA Punt
Iris D Nagtegaal
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-292

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