NRF2 mRNA Expression Signature Associated with Regional Nodal Recurrence in Early-stage Non-small Cell Lung Cancer (NSCLC)

Abstract

Lung stereotactic body radiation therapy (SBRT) achieves high local control in the treatment of early-stage non-small cell lung cancer (NSCLC). Nevertheless, up to 15-20% of patients may have regional nodal or distant recurrence after treatment. Molecular profiling may allow for personalized identification of patients at highest risk for recurrence. To this end, we conducted a transcriptomic analysis of lung SBRT samples with focus on the NRF2 pathway, which is involved in antioxidant regulation and has been associated with recurrence and survival in a variety of cancers. We studied the association of a NRF2 pathway mRNA expression profile with recurrence and survival. We identified patients with T1-3N0 NSCLC treated with SBRT at our institution. We isolated total RNA from formalin fixed paraffin embedded pretreatment tumor biopsy samples using an RNA Purification kit. Expression of mRNAs was analyzed using an assay. We used a published 20-mRNA risk score based on NRF2 pathway genes and dichotomized patients into high- and low-NRF2 groups using the median risk score value of the dataset. Kaplan-Meier analysis was used to study the association of the high NRF2 score with recurrence and survival. Cox proportional hazards multivariable analysis was used to account for histology, age, T-stage, and ECOG performance status. We identified 92 patients treated with lung SBRT with available mRNA data. There were no significant differences in age, sex, race, performance status, T-stage, histology, biologically effective dose, or central vs peripheral tumor location between high NRF2 (n = 46) and low NRF2 (n = 46) cohorts. There was significantly worse regional nodal recurrence in high- vs low-NRF2 patients (HR = 1.69; 95% CI 10.13 – 25.8; p = 0.035). There was no statistically significant difference in local recurrence (HR = 1.78; 95% CI 0.42 – 7.56; p = 0.43), distant recurrence (HR = 1.19; 95% CI 0.74 – 1.93; p = 0.48), or overall survival (HR = 1.67; 95% CI -.88 – 3.15; p = 0.12). On multivariable analysis, the association of high NRF2 score with regional nodal recurrence persisted (HR = 4.5; 95% CI 1.02 – 26.6; p = 0.046). There was no significant association of histology, age, T-stage, or ECOG performance status with regional nodal recurrence on multivariable analysis. We validated a published NRF2 mRNA expression signature, and found a high NRF2 signature was associated with regional nodal recurrence in patients with early-stage NSCLC treated with lung SBRT. This risk score may help to identify patients who would benefit from more aggressive mediastinal staging. These findings should be validated in an independent cohort.