A Novel Radio-Genomics Biomarker for Precision Epidermal Growth Factor Receptor Mutation Targeting Therapy in Non-Small Cell Lung Cancer

Background: Newer generation tyrosine kinase inhibitors (TKI) are becoming more effective against cancers exhibiting certain driver mutations⁠, with those relating to epidermal growth factor receptor (EGFR) being the mostly commonly targeted in non-small cell lung cancer (NSCLC). Treatment decision is currently guided by tissue sampling and genetic testing⁠, an invasive process limited by patient tolerance, procedural complications, tumour heterogeneity and mutation evolution. Co-mutational status of EGFR with other target mutations can affect treatment response and is associated with worse patient outcomes. Exclusive EGFR mutation, where other common actionable mutations are negative, forms a favourable treatment scenario supporting first line EGFR-TKI use. Methods: We developed a radiomics signature, EGFR-RPV, to predict for exclusive EGFR mutational status, based on NSCLC patients (n = 304, age: 67.6 ± 10.7, male: female [M:F] = 174:130) who underwent CT scans and tissue sampling with genetic testing at our multi-centre institution between February 2012 and July 2018, and tested on an independent testing cohort of 51 patients (Age: 69.6 ± 8.1, M: F = 35:16); and conducted enrichment analysis of their paired RNA transcriptomics readouts. Results: EGFR-RPV predicted exclusive EGFR mutation to an accuracy of 0.77, 95% CI: 0.66–0.88 and 0.71, 95% CI: 0.54-0.89 in the internal and external testing sets, respectively. EGFR-RPV also achieved patient prognostic stratification (hazard ratio 2.15, 95% CI 1.50-3.08). We discovered the enrichment of FAM190A and CBMO1 genes in exclusive EGFR positive cases, concordant with their known regulatory roles in cancer cell division and conversion of beta-carotene into vitamin A, respectively. Conclusion: EGFR-RPV enables non-invasive prediction of exclusive EGFR mutations in NSCLC, with a potential to guide first-line EGFR-TKI use