Methylation–based liquid biopsy facilitates early detection of small cell transformation in ALK-rearranged non–small cell lung cancer

Histologic transformation from non–small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of resistance in anaplastic lymphoma kinase (ALK)–rearranged disease. Diagnosis is traditionally dependent on tissue biopsy, which may be limited by lesion accessibility and low disease burden. We report a case of ALK-rearranged lung adenocarcinoma that underwent small cell transformation, in which methylation-based circulating cell-free DNA (cfDNA) analysis detected a small cell lung cancer signature 5 months prior to tissue confirmation. Serial liquid biopsies demonstrated dynamic changes in tumor fraction and histologic composition that correlated with response to chemoradiation and continuation of ALK-directed therapy. This case highlights the potential utility of methylation-based liquid biopsy for early detection and longitudinal monitoring of histologic transformation in oncogene-driven NSCLC.