Coexistence of KRAS mutation with mutant but not wild-type EGFR predicts response to tyrosine-kinase inhibitors in human lung cancer

EGFR and KRAS mutations occur mutually exclusively in NSCLC, suggesting functional redundancy ( Kosaka et al, 2004 ; Pao et al, 2005 ; Shigematsu et al, 2005 ; Tam et al, 2006 ). However, they predict contrasting response rates to tyrosine-kinase inhibitors (TKIs) – while EGFR mutation predicts longer progression-free survival rate ( Lynch et al, 2004 ; Mok et al, 2009 ; Fukuoka et al, 2011 ; Chougule et al, 2013 ), adverse prognosis is associated with patients harbouring KRAS mutations ( Mao et al, 2010 ; Ihle et al, 2012 ). The recently reported co-occurrence of KRAS and EGFR activating mutations ( Li et al, 2014 ) in 30 of 5125 patients raises questions about the relative values of EGFR and KRAS mutation status as predictors of outcome in NSCLC. This has obvious implications for routine KRAS testing in this disease, potentially precluding EGFR TKI therapy from some patients, similar to the current practice in colorectal cancer ( Lievre et al, 2006 ).