2023 World Conference on Lung Cancer (Posters)-P1.21. DOT1L Mutations as a Potential Predictor for Immune Checkpoint Inhibitor Efficacy in Non-Small-Cell Lung Cancer

P1.21. DOT1L Mutations as a Potential Predictor for Immune Checkpoint Inhibitor Efficacy in Non-Small-Cell Lung Cancer - PDF(Abstract)

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A study presented at the World Conference on Lung Cancer in 2023 explored the potential of DOT1L mutations as a predictive biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC). The researchers characterized the frequency and genomic characteristics of DOT1L mutations in a cohort of 393 treatment-naïve stage III/IV NSCLC patients using targeted next-generation sequencing. They then evaluated the association between these mutations and the prognosis of NSCLC patients receiving ICI treatments using three independent external cohorts.<br /><br />The results showed that DOT1L mutations were found in approximately 3.6% of baseline NSCLC cases and were significantly associated with male patients. They were also mutually exclusive with EGFR-sensitizing mutations. Pathway-level analysis indicated that DOT1L mutations were likely co-occurring with oncogenic alterations in key signaling pathways.<br /><br />Importantly, DOT1L mutations were significantly enriched in NSCLC patients who had a durable clinical benefit and a better overall response rate to ICI treatments. The median progression-free survival of DOT1L-mutated patients receiving ICIs was significantly longer than that of DOT1L-wildtype patients. In patients with solid tumors treated with ICIs, DOT1L-mutated patients also showed a trend towards prolonged overall survival.<br /><br />Furthermore, DOT1L-mutated patients had a higher proportion of activated neutrophil infiltration and lower expression of genes involved in neutrophil migration and chemotaxis. Gene set enrichment analysis suggested that DOT1L-mutated NSCLC was significantly enriched in the cell cycle and PI3K-AKT-mTOR signaling pathways but downregulated in the inflammatory response.<br /><br />Overall, the findings suggest that baseline mutations in the uncommon gene DOT1L may be associated with higher levels of tumor mutational burden and chromosomal instability. These mutations could potentially serve as a biomarker for identifying patients with locally advanced NSCLC who may benefit from ICI treatments.

Asset Subtitle

Yang Shao

Meta Tag

Speaker Yang Shao

Topic Pathology & Biomarkers: Biomarkers for Immuno-oncology

Keywords

DOT1L mutations

predictive biomarker

immune checkpoint inhibitors

non-small-cell lung cancer

genomic characteristics

prognosis

oncogenic alterations

durable clinical benefit

neutrophil infiltration

tumor mutational burden