The spatiotemporal evolution of early-stage non-small-cell lung cancer.

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8539 Background: Lung cancer is a genetically heterogeneous disease. The genomic basis of tumorigenesis and cancer cell spread, as well as intratumor heterogeneity (ITH) and subclonal evolutionary patterns might correlate with patients’ clinical outcomes. In this prospective study, we aimed to investigate such associations through comprehensive spatiotemporal genomic profiling in early-stage non-small cell lung cancers (NSCLCs). Methods: We performed deep targeted sequencing (GeneseeqPrime, 425 genes) of 503 primary tumor regions and 141 metastatic lymph node tumors from surgery and 378 longitudinal plasma biopsies (pre- and post-operation) across 128 Stage I-III NSCLC patients. ITH and phylogenetic tree for each patient were analyzed and correlated with clinical outcomes. Longitudinal and phylogenetic ctDNA analyses were further performed. Results: Spatial ITH varied among patients and was associated with clinical phenotypes. Geographical stratification of clonal structure, with localized confinement of subclones, was linked with slower tumor progression. In contrast, early expansion of subclones to multiregions was associated with rapid tumor growth and lymph node metastases. EGFR and TP53 mutations were nearly always clonal, whereas subclonal mutations in PI3K, WNT and TGF-beta pathway that occurred later in evolution were found in more than 50% of the patients. By tracking these phylogenetic events, we identified five evolutionary subtypes with distinct clinical outcomes, including a rare subtype characterized by independent origin of multiple EGFR driver mutations. ctDNA profiling could capture the spatial ITH to a certain extent with additional unique signatures. Further longitudinal and phylogenetic ctDNA analyses indicated early detection of relapse and adjuvant chemotherapy resistance. Conclusions: ITH is a key factor associated with clinical outcomes of early-stage NSCLC patients, which show diverse evolutionary subtypes underpinning the disease progression such as lymph metastasis and relapse. ctDNA sequencing can be used to capture spatial ITH, predict recurrence and track drug resistance.