Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients.
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.
Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Leonie J M
LJ
Mekenkamp
Jolien
J
Tol
Jeroen R
JR
Dijkstra
Inge
I
de Krijger
M Elisa
ME
Vink-Börger
Shannon
S
van Vliet
Steven
S
Teerenstra
Eveline
E
Kamping
Eugène
E
Verwiel
Miriam
M
Koopman
Gerrit A
GA
Meijer
J Han Jm
JH
van Krieken
Roland
R
Kuiper
Cornelis J A
CJ
Punt
Iris D
ID
Nagtegaal
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D000068818:Cetuximab; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D015999:Multivariate Analysis; D009154:Mutation; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016032:Randomized Controlled Trials as Topic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; C542359:MIRN143 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; D000068258:Bevacizumab; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab