Detecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling

Histologic transformation to small cell lung cancer (SCLC) is an increasingly common resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR mutant lung adenocarcinoma (LUAD) that is underdiagnosed in clinical practice due to the requirement for tissue biopsy. Early and accurate detection of transformed (t)SCLC has important prognostic and therapeutic implications. To address this unmet need, we first comprehensively profiled the epigenomes of metastatic lung tumors finding widespread epigenomic reprogramming during histologic transformation from LUAD to SCLC. We then utilized a novel approach for epigenomic profiling of cell-free DNA, which discriminated patients with EGFR mutant tSCLC from patients with EGFR mutant LUAD with greater than 90% accuracy. This first demonstration of the ability to accurately, and non-invasively, detect small cell transformation in patients with EGFR mutant LUAD through epigenomic cfDNA profiling is a critical step towards a new paradigm of diagnostic and therapeutic precision for patients with advanced lung cancer.