A PI3Kinase/Akt/mTOR Gene Expression Signature Predicts for Recurrence in Early-Stage Non-Small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy

Abstract

Listen

Translate article

<h3>Purpose/Objective(s)</h3> Stereotactic body radiation therapy (SBRT) has emerged as an effective alternative to surgery in the treatment of early-stage non-small cell lung cancer (NSCLC). Despite this, disease progression occurs in over 20-30% of patients. Previous work established AKT/mTOR signaling as a pathway modulating response to radiation for NSCLC. In this study, we sought to validate a previously published mRNA signature that measures PI3K/Akt/mTOR pathway activation and measure its association with clinical outcomes in patients with early-stage NSCLC treated with SBRT. <h3>Materials/Methods</h3> We queried our institutional dataset for patients with T1-3N0 NSCLC treated with SBRT. RNA of formalin fixed paraffin embedded biopsy specimens (pre-therapy) was isolated and mRNA expression was analyzed using the Clariom D^TM assay. We derived a t score, defined as the two-sided t statistic comparing the average of the PI3K-induced genes with that of repressed genes within each tumor after centering log-transformed values on the median across samples. Cox proportional hazards was performed to account for age, sex, ECOG performance status, biological effective dose, and histology. <h3>Results</h3> We identified 92 patients with NSCLC treated between 2008 and 2018 with available gene expression and dichotomized patients by their median PI3K pathway score (<i>Table 1</i>). Median follow up was 24.0 months. Higher PI3k score was associated with worse progression-free survival (PFS) (HR= 3.98; 95% CI 1.57–10.09; p=0.0035) and local recurrence (LR) (HR= 11.72; 95% CI 1.40–98.0; p=0.023). There was no significant association with overall survival (p=0.49), regional nodal recurrence (p=0.15), or distant recurrence (p=0.85). On multivariable analysis, PI3K score remained independently associated with worse PFS (HR= 3.03; 95% CI 1.13–8.13; p=0.028) and LR (HR= 17.15; 95% CI 1.50–195.59; p=0.022). Worse performance status (HR= 2.58; 95% CI 1.06–6.27) and younger age (HR= 0.94; 95% CI 0.88–0.999) were also associated with worse PFS. <h3>Conclusion</h3> Our findings demonstrate that degree of PI3K pathway activation is associated with PFS and LR after SBRT for early-stage NSCLC. This requires validation in an independent dataset but may be useful in prognostication or in selecting patients for treatment intensification.