Potential Role of Lymphocyte CD44 in Determining Treatment Selection Between Stereotactic Body Radiation Therapy and Surgery for Early-Stage Non-Small Cell Lung Cancer

Abstract

Background: Stereotactic body radiotherapy (SBRT) versus surgery for operable early-stage non-small-cell lung cancer (ES-NSCLC) remains highly debated. Herein, we utilized spatial proteomics to identify whether any molecular biomarker(s) associate with the efficacy of either modality, in efforts to optimize treatment selection between surgery or SBRT for this population. Methods: We evaluated biopsy tissue samples from 44 ES-NSCLC patients treated with first-line SBRT (cohort 1) by GeoMx Digital Spatial Profiling (DSP) with a panel of 70 proteins in five spatial molecular compartments: tumor (panCK+), leukocyte (CD45+), lymphocyte (CD3+), macrophage (CD68+), and stroma (α-SMA+). To validate the findings in cohort 1, biopsy samples from 52 ES-NSCLC patients who received SBRT (cohort 2) and 62 ES-NSCLC patients who underwent surgery (cohort 3) were collected and analyzed by multiplex immunofluorescence (mIF). Results: In cohort 1, higher CD44 expression in the lymphocyte compartment was associated with poorer recurrence-free survival (RFS) (DSP: P<0.001; mIF: P<0.001) and higher recurrence rate (DSP: P=0.001; mIF: P=0.004). mIF data from cohort 2 validated these findings (P<0.05 for all). From cohort 3, higher lymphocyte CD44 predicted higher RFS after surgery (P=0.003). Inter-modality comparisons demonstrated that SBRT was associated with significantly higher RFS over surgery in CD44-low patients (P<0.001), but surgery was superior to SBRT in CD44-high cases (P=0.016). Conclusions: Lymphocyte CD44 may not only be a predictor of SBRT efficacy in this population, but also an important biomarker (pending validation by large prospective data) that could better sharpen selection for SBRT vs. surgery in ES-NSCLC.