Title: High throughput somatic profiling of the Ras-Raf-MAP and PI3K-PTEN-Akt pathways in advanced colorectal cancer and correlations with response to cetuximab
Authors: Smith, Christopher
Claes, Bart
Fisher, D
Adams, R
Kaplan, R
Meade, A
Lambrechts, Diether
Maughan, T
Cheadle, J #
Issue Date: Oct-2010
Publisher: Kluwer Academic Publishers
Host Document: Annals of Oncology vol:21 issue:suppl 8 pages:190-190
Conference: ESMO congress edition:35 location:Milan date:8-12 October 2010
Abstract: Response to treatment of colorectal cancer (CRC) is influenced by each tumour’s somatic genetic profile. For example, cetuximab, a monoclonal antibody against EGFR, has proven efficacy in K-ras wild-type tumours but is in general ineffective against K-ras mutant tumours. We developed Pyrosequencing and Sequenom assays for somatic profiling of codons 12, 13 and 61 of K-ras and codon 600 of B-raf. Both assays detected low levels of mutant alleles (?4%), had 99.12% (8642/8719) and 98.14% (1319/1344) genotype concordance for K-ras and B-raf mutations, respectively and high genotype success rates (96.7% for Sequenom vs. 92.5% for Pyrosequencing). Three multiplex Sequenom assays allowed high-throughput screening for additional somatic mutations within the Ras-Raf-MAP kinase and PI3K-PTEN-Akt pathways (codons 594 of B-raf, 12 of N-ras and 542, 545, 546, 1047 of PIK3CA). In total, we screened 1,976 CRCs from patients on the COIN trial (ISRCTN27286448) and found thirteen different K-ras mutations in a total of 42.27% of CRCs, two B-raf mutations in 9.01% of CRCs, four N-ras mutations in 3.56% of CRCs and five PIK3CA mutations in 12.81% of CRCs. We have previously shown that the addition of cetuximab improves progression free survival (PFS) in patients with K-ras, B-raf and N-ras wild-type tumours, where the partner chemotherapy was OxMdG and when disease extent was limited to 0 or 1 metastatic sites (HR=0.73, p=0.04). Here, we analysed individual somatic mutations with respect to response. We observed some interesting differences including a trend toward favourable response (PFS) to cetuximab in patients with K-ras G12V CRCs (HR=0.92, n=141 patients; and HR=0.78 for those 55 patients treated with OxMdG). However, the individual groups did not reach statistical significance and therefore warrant further investigation in additional cohorts. In collaboration with the COIN Collaborative Group.
ISSN: 0923-7534
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Vesalius Research Centre (-)
Laboratory of Translational Genetics (Vesalius Research Center) (+)
# (joint) last author

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