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

Abstract

Background: Intratumoral heterogeneity has been suggested to be an important resistant mechanism of treatment failure. We hypothesized that radiologic images could be an alternative or surrogate method for tumor heterogeneity identification. Hence, heterogeneity textural parameters on pretreatment PET/CT were tested for the predictive value of target therapy. Material and Methods: Recurred or metastatic NSCLC subjects with an activating EGFR mutation treated with either gefitinib or erlotinib were reviewed. An exploratory (n=161) and validation (n=21) data sets were used and selected 8 parameters were applied for survival analysis. The optimal cutoff value was determined by the recursive partitioning method, and predictive value was calculated by Harrells C-index. Results: Univariate analysis revealed that all 8 parameters showed an increased hazard ratio (HR) for progression free survival (PFS). The highest HR was 6.41 (95% CI 2.80-14.68) with co-occurrence (Co) entropy. Adjusted for initial stage, performance status (PS), and metabolic volume, increased risk remained present (aHR: 4.86, 95%CI 1.97-11.98). Textural parameters were found to have incremental predictive value of early EGFR tyrosine kinase inhibitor (TKI) failure compared to that of the base model with stage and PS (C-index 0.596 vs. 0.662, P=0.024, by Co entropy). Conclusions: Heterogeneity textural parameters acquired from pretreatment PET/CT are high predictive factors for PFS of EGFR TKI in EGFR mutant 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.