KRAS mutation status in colorectal cancer to predict response to EGFR targeted therapies: the need for a more precise definition.

摘要: Sir, The KRAS mutations in colorectal cancer (CRC) are associated with clinical resistance to treatment the epidermal growth factor receptor – targeted monoclonal antibodies. The confirmation of these findings independent retrospective reports as well a phase III trial has led European Medicines Agency (August 2008) license panitumumab and cetuximab only for patients CRC without (http://www.emea.europa.eu/humandocs/Humans/EPAR/erbitux/erbitux.htm http://www.emea.europa.eu/humandocs/Humans/EPAR/vectibix/vectibix.htm). In Public Assessment Report, natures were described ‘certain hot-spots (mainly codons 12 13)'. The most recent studies report seven somatic two 12–13 (Amado et al, 2008; Lievre 2008). They use either direct sequencing (Lievre 2008), which addresses few surrounding or focus techniques like Scorpion-ARM detects on high sensitivity. From March 2008, our genomic platform tested 70 status. Using pre-screening approach high-resolution melting curve analysis (Simi followed by sequencing, we found 35% cases mutation 12–13, agreement literature. However, also presenting codon 19 (c.57G>C, p.Leu19Phe), 12–13. No polymorphism been reported this (dbSNP http://www.ncbi.nlm.nih.gov/SNP/). cases, intensity mutated allele sequence electropherogram was under 30% normal allele. With heterozygous polymorphism, between should have similar. A functional study similar (c.57G>T, p.Leu19Phe) an activating proliferative consequences (Akagi 2007). large Netherlands Cohort Study (n=737 CRC), 37% 6.6% outside 8, 9, 10, 15, 16, 19, 20 25 (Brink 2003). A Polish population stressed finding 59, 61, 117 163 (Wojcik Those cannot be detected techniques. None those quoted assessing sensitivity Scientific Discussion at EMEA. Most limited test but additional KRAS-activating could considered choice treatment. France, 36 000 new estimated each year, leading potentially 800 harbouring false wild-type status would not respond treatments. Activating other than raise question precise definition routine laboratory practice.