Figure 3: Pathogenic KEAP1/NFE2L2 mutations but not passenger mutations or expression analysis predict local recurrence after radiotherapy.

(A) Incidence of local recurrence after CRT or SABR in patients with KEAP1/NFE2L2 mutations stratified by functional classification. (B) Tumor volumes for patients with pathogenic KEAP1/NFE2L2 mutations (K/N^MUT). For patients who did not develop local recurrence (LR) the volume of the largest lesion is shown (*P=0.03). (C) Incidence of local recurrence in patients with pathogenic KEAP1/NFE2L2 mutations stratified by radiotherapy type. (D) Overall survival of patients in the SABR cohort stratified by presence or absence of pathogenic KEAP1/NFE2L2 mutations (WT, wild-type). (E) Overall survival of stage I-II patients from the TCGA lung adenocarcinoma and squamous cell cohorts who were treated with RT and not surgery, stratified by presence or absence of KEAP1/NFE2L2 mutations. (F) RNA-seq analysis of tumor cells from FFPE tumor biopsies of patients in the CRT and SABR cohorts (n=41). CIBERSORTx was used to deconvolve tumor cell expression (26). The heatmap depicts single sample gene set enrichment analysis (ssGSEA) scores of a previously defined NFE2L2 target gene expression signature (NFE2L2 sig.) and expression of the individual signature genes (27). (G) NFE2L2 target gene ssGSEA scores in tumor biopsies from patients in the CRT and SABR cohorts stratified by the presence or absence of pathogenic KEAP1/NFE2L2 mutations. (H) Incidence of local recurrence after CRT or SABR stratified by ssGSEA scores for NFE2L2 signature. Legend is same as in F. Stratification threshold was obtained by choosing the highest significance value by log-rank for LR based on 1,000 re-sampling iterations (I) Overall survival of patients from the TCGA lung adenocarcinoma and squamous cell cohorts who were treated with RT and not surgery, stratified by ssGSEA scores for NFE2L2 signature. The optimal cutpoint identified in H was used.