Prognostic And Predictive Effects Of Kras Mutation Subtype In Completely Resected Non-Small Cell Lung Cancer (Nsclc): A Lace-Bio Study

7007 Background: We reported previously that KRAS is weakly prognostic and not significantly predictive of benefit from adjuvant chemotherapy (ACT) in NSCLC (Tsao et al. Proc ESMO 2012, Abst 4217). In colorectal cancer (CRC), KRAS mutation predicts resistance to EGFR monoclonal antibodies, but recent reports suggest that this may not be true for all mutation subtypes (De Roock et al. JAMA 2010). Smoking-related KRAS mutations in NSCLC differ from those of CRC. To explore the influence of KRAS mutation subtype, we undertook an analysis of KRAS subtype in LACE-Bio. Methods: KRAS mutation was determined in blinded fashion in 3 laboratories by direct sequencing. Exploratory analyses were performed to identify relationships between mutation status and subtype, overall (OS) and disease-free survival (DFS) using a Cox model stratified by trial and adjusted for covariates. Results: KRAS subtype was available in 1,532 patients (756 observation [OBS], 776 ACT). There were 300 mutations (275 codon 12, 24 codon 13, 1 codon 14). In the OBS arm, there was no difference in prognosis for OS for codon 12 (Hazard Ratio [HR] mutation v wild-type [WT] KRAS 1.04, CI .77-1.4) or codon 13 (HR 1.01, CI 0.47-2.17) mutations. A trend for benefit from ACT was observed in WT (HR ACT v OBS 0.89 CI 0.76-1.04, p=0.15) but not in patients with codon 12 mutations (HR 0.95, CI .67-1.35, p=0.77). In patients with codon 13 mutations, chemotherapy was deleterious (HR 5.78, CI 2.06-16.2, p<0.001), test for equality among 3 HRs p=0.002. Results were similar for DFS. Among codon 12 mutations, there was no prognostic effect based on specific amino acid substitution. Patients with G12A or G12R mutations appeared to derive greater benefit from ACT (HR 0.66 p=0.48) compared to those with G12C or G12V (HR 0.94 p=0.77) or G12D or G12S (HR 1.39 p=0.48) or WT, but the differences were not significant (comparison of 4 HRs p=0.76). Conclusions: In this study, patients with KRAS codon 13 mutations had significantly poorer outcomes with ACT. These results require further confirmation and should be interpreted with caution in view of the small number of patients with codon 13 mutations. Supported by unrestricted grants from Sanofi Aventis and LNCC.