Diagnostics of EGFR-mutant disease: biomarkers with significant clinical implications
The clinical relevance of additional genetic alterations in advanced EGFR-mutant NSCLC is not clear. Blakely et al. hypothesised that co-occurring genomic alterations in cancer-related genes can cooperate with the mutant EGFR to drive de-novo resistance to EGFR TKI treatments . The investigators performed targeted exome sequencing of plasma cell-free DNA (cfDNA) in 86 samples collected from 81 patients with known clinical history. They found alterations in multiple concurrent oncogenic pathways, including TP53, WNT, PI3K and MYC, and in cell-cycle genes (e.g., CDK4/6, Cyclin D/E), which appeared to function collaboratively in tumour progression and drug resistance. Co-occurring aberrations were more frequently observed in EGFR-TKI nonresponders and they increased with each line of therapy. A proposed new model of EGFR-mutant NSCLC pathogenesis that arises from these findings suggests that TP53, RTK and RAS-MAPK are the most commonly coaltered functional genes. Alterations in cell-cycle genes showed the strongest correlations with non-response to EGFR TKI treatments, which warrants further investigation. As the authors noted, these findings call for re-evaluation of the prevailing paradigm of monogenicbased molecular stratification to monotherapy, and they highlight an alternative model of genetic collectives as a determinant of lung cancer progression and therapy resistance.