Intratumoral heterogeneity characterized by pretreatment PET in non-small cell lung cancer patients predicts progression-free survival on EGFR tyrosine kinase inhibitor

Intratumoral heterogeneity has been suggested to be an important resistance mechanism leading to treatment failure. We hypothesized that radiologic images could be an alternative method for identification of tumor heterogeneity. We tested heterogeneity textural parameters on pretreatment FDG-PET/CT in order to assess the predictive value of target therapy. Recurred or metastatic non-small cell lung cancer (NSCLC) subjects with an activating EGFR mutation treated with either gefitinib or erlotinib were reviewed. An exploratory data set (n = 161) and a validation data set (n = 21) were evaluated, and eight parameters were selected for survival analysis. The optimal cutoff value was determined by the recursive partitioning method, and the predictive value was calculated using Harrell's C-index. Univariate analysis revealed that all eight parameters showed an increased hazard ratio (HR) for progression- free survival (PFS). The highest HR was 6.41 (P< 0.01) with co-occurrence (Co) entropy. Increased risk remained present after adjusting for initial stage, performance status (PS), and metabolic volume (MV) (aHR: 4.86, P< 0.01). Textural parameters were found to have an incremental predictive value of early EGFR tyrosine kinase inhibitor (TKI) failure compared to that of the base model of the stage and PS (C-index 0.596 vs. 0.662, P = 0.02, by Co entropy). Heterogeneity textural parameters acquired from pretreatment FDG-PET/CT are highly predictive factors for PFS of EGFR TKI in EGFR-mutated NSCLC patients. These parameters are easily applicable to the identification of a subpopulation at increased risk of early EGFR TKI failure. Correlation to genomic alteration should be determined in future studies.