Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer (NSCLC) patients.

Abstract

e21080 Background: The prognostic and predictive role of KRAS mutations and gene copy number aberrations (CNA) in early stage NSCLC is unclear. In this study, we characterize the prognostic effect of KRAS mutation status and concomitant CN gain in early stage NSCLC, and determine the ability to predict survival benefit from adjuvant chemotherapy. We hypothesize that concomitant KRAS mutations and CN gain will be prognostic of worse survival compared to KRAS mutations alone. Methods: Clinical and genomic data from The LACE (Lung Adjuvant Cisplatin Evaluation)-BIO consortium was utilized. CNA were categorized as Gain or Neutral (Neut)/Loss; mutation status was defined as wild type (WT) or mutant (MUT). WT+Neut/Loss (reference), WT+Gain, MUT+Gain and MUT+Neut/Loss groups were compared in all patients and the adenocarcinoma subgroup. Primary endpoint was lung-cancer-specific survival (LCSS); secondary endpoints were DFS and OS. Survival curves were assessed using Kaplan-Meier and log-rank tests. Concomitant KRAS CNA and mutation status was correlated to endpoints using a Cox proportional hazards model stratified by trial and adjusted for treatment, age, gender, histology, WHO performance status, surgery type, tumor and nodal stage. A treatment-by-variable interaction was added to evaluate predictive effect. Results: 946 (399 adenocarcinoma) patients had complete KRAS mutation, CNA and clinical data: 41 (30) MUT+Gain, 145 (99) MUT+Neut/Loss, 125 (16) WT+Gain, 635 (254) WT+Neut/Loss. There was a negative prognostic effect of KRAS MUT+Neut/Loss for LCSS (HR = 1.32 [1.01-1.71]) on univariable analysis, and to a lesser extent after adjusting for covariates (HR = 1.28 [0.97-1.68]). A similar non-significant trend was observed in KRAS MUT+Gain patients for LCSS (HR = 1.34 [0.83-2.17]), DFS (HR = 1.34 [0.86-2.09]) and OS (HR = 1.59 [0.99-2.54]). There was no significant predictive effect in the overall population; however, a potential predictive effect of KRAS for OS was seen in the adenocarcinoma subgroup (interaction p = 0.046). KRAS MUT+Gain was associated with a beneficial effect of chemotherapy on DFS (HR = 0.33 [0.11-0.99], p = 0.048), with a non-significant trend also seen for LCSS (HR = 0.41 [0.13-1.33]) and OS (HR = 0.40 [0.13-1.26]). Conclusions: A small prognostic effect of KRAS mutation was identified for LCSS. A potential predictive effect of concomitant KRAS mutation status and CNA was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require further validation.