Hypoxic Gene Expression Signature as a Predictor of Recurrence and Mortality in Early-Stage Non-Small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy

PURPOSE Recurrence occurs in 20%-30% of early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). Hypoxia in the tumor microenvironment drives radiation resistance, immune evasion, and tumor progression. Biomarkers measuring hypoxia may be useful for prognostication of NSCLC treated with SBRT. We investigate an RNA-based approach to measure tumor hypoxia and associate these molecular biomarkers with clinical outcomes after SBRT. METHODS We included patients with T1-3N0 NSCLC treated with SBRT. RNA isolated from formalin-fixed paraffin-embedded tumor biopsy specimens (pretreatment) was analyzed using the Clariom-D assay. Hypoxia scores were derived using three well-established gene signatures measuring hypoxia and risk scores were median-dichotomized. Kaplan-Meier and Cox proportional hazards were used to study the association between high hypoxia scores and tumor recurrence and survival. RESULTS We included 92 patients treated between 2008 and 2018 with a median follow-up of 23.9 months. All three signatures were associated with squamous histology (P < .001) and clinical outcomes, with the Lane signature serving as the most prognostic of disease recurrence and mortality. On multivariable analysis, the Lane signature was associated with worse local recurrence (hazard ratio [HR], 13.36 [95% CI, 1.09 to 163.94]; P = .043), distant recurrence (HR, 2.15 [95% CI, 1.25 to 3.70]; P = .005), disease-free survival (HR, 3.68 [95% CI, 1.41 to 9.58]; P = .008), and overall mortality (HR, 2.91 [95% CI, 1.41 to 9.58]; P = .009). No significant difference was seen in regional nodal recurrence (P = .277). CONCLUSION We demonstrate squamous histology is associated with RNA-based hypoxic gene signatures, and that the Lane RNA-based hypoxia signature is highly prognostic of disease progression and mortality in NSCLC treated with SBRT, which merits prospective validation.