TY - JOUR
T1 - Beyond KRAS mutation status
T2 - influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients
AU - Mekenkamp, Leonie J M
AU - Tol, Jolien
AU - Dijkstra, Jeroen R
AU - de Krijger, Inge
AU - Vink-Börger, M Elisa
AU - van Vliet, Shannon
AU - Teerenstra, Steven
AU - Kamping, Eveline
AU - Verwiel, Eugène
AU - Koopman, Miriam
AU - Meijer, Gerrit A
AU - van Krieken, J Han Jm
AU - Kuiper, Roland
AU - Punt, Cornelis J A
AU - Nagtegaal, Iris D
N1 - Funding Information:
We thank Begona Diosdado for her practical support and expertise in analyzing the miRNA experiments. This study was supported by the Dutch Colorectal Cancer Group and the Netherlands Organization for Health Research and Development (ZonMw). No potential conflicts of interest were disclosed.
PY - 2012/7/17
Y1 - 2012/7/17
N2 - 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.
AB - 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.
KW - Antibodies, Monoclonal/administration & dosage
KW - Antibodies, Monoclonal, Humanized/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Bevacizumab
KW - Cetuximab
KW - Chromosomes, Human, Pair 12/genetics
KW - Clinical Trials, Phase III as Topic
KW - Colorectal Neoplasms/drug therapy
KW - DNA Copy Number Variations
KW - Disease-Free Survival
KW - Female
KW - Humans
KW - Male
KW - MicroRNAs/genetics
KW - Middle Aged
KW - Multicenter Studies as Topic
KW - Multivariate Analysis
KW - Mutation
KW - Neoplasm Metastasis
KW - Organoplatinum Compounds/administration & dosage
KW - Oxaliplatin
KW - Proto-Oncogene Proteins/genetics
KW - Proto-Oncogene Proteins p21(ras)
KW - Randomized Controlled Trials as Topic
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Treatment Outcome
KW - ras Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=84870275439&partnerID=8YFLogxK
U2 - 10.1186/1471-2407-12-292
DO - 10.1186/1471-2407-12-292
M3 - Article
C2 - 22804917
SN - 1471-2407
VL - 12
SP - 292
JO - BMC cancer
JF - BMC cancer
M1 - 292
ER -