FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer
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FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. / Bokemeyer, C; Köhne, C-H; Ciardiello, F; Lenz, H-J; Heinemann, V; Klinkhardt, U; Beier, F; Duecker, K; van Krieken, J H; Tejpar, S.
in: EUR J CANCER, Jahrgang 51, Nr. 10, 07.2015, S. 1243-52.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer
AU - Bokemeyer, C
AU - Köhne, C-H
AU - Ciardiello, F
AU - Lenz, H-J
AU - Heinemann, V
AU - Klinkhardt, U
AU - Beier, F
AU - Duecker, K
AU - van Krieken, J H
AU - Tejpar, S
N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.
PY - 2015/7
Y1 - 2015/7
N2 - BACKGROUND: The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing.PATIENTS AND METHODS: Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%).RESULTS: Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4.CONCLUSION: Patients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.
AB - BACKGROUND: The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing.PATIENTS AND METHODS: Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%).RESULTS: Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4.CONCLUSION: Patients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.
KW - Antibodies, Monoclonal, Humanized
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Codon
KW - Colorectal Neoplasms
KW - Disease-Free Survival
KW - Exons
KW - Fluorouracil
KW - Genes, ras
KW - Humans
KW - Leucovorin
KW - Mutation
KW - Organoplatinum Compounds
U2 - 10.1016/j.ejca.2015.04.007
DO - 10.1016/j.ejca.2015.04.007
M3 - SCORING: Journal article
C2 - 25937522
VL - 51
SP - 1243
EP - 1252
JO - EUR J CANCER
JF - EUR J CANCER
SN - 0959-8049
IS - 10
ER -