| Summary: | <i>KRAS</i> mutations are found in approximately one third of non-small cell lung cancer (NSCLC) patients. In this study, we aim to investigate whether <i>KRAS</i> G12/G13 mutant allele fraction (MAF) in cell-free DNA (cfDNA) can provide meaningful prognostic information in NSCLC. Multiplex droplet-digital PCR was used to quantitatively assess <i>KRAS</i> G12/G13 MAF in cfDNA from 114 pre-treated advanced disease NSCLC patients. In 14 patients, changes in <i>KRAS</i> G12/G13 MAF were longitudinally monitored during treatment. Plasma <i>KRAS</i> G12/G13 status was associated with poor patients’ outcome in terms of progression-free survival (PFS) (<i>p</i> < 0.001) and overall survival (OS) (<i>p</i> < 0.001). In multivariate analysis, the detection of plasma <i>KRAS</i> mutations was an independent predictor of adverse PFS (HR = 3.12; <i>p</i> < 0.001) and OS (HR = 2.53; <i>p</i> = 0.002). <i>KRAS</i> G12/G13 MAF at first treatment evaluation (T1) was higher (<i>p</i> = 0.013) among patients experiencing progressive disease compared to those with disease control, and increased <i>KRAS</i> MAF at T1 was associated (<i>p</i> = 0.005) with shorter PFS. On the contrary, no association was observed between tissue <i>KRAS</i> mutation status and patients’ prognosis. Our results show that ddPCR-based detection of <i>KRAS</i> G12/G13 mutations in plasma could serve as an independent biomarker of unfavorable prognosis in NSCLC patients. Changes in <i>KRAS</i> MAF can provide valuable information for monitoring patient outcome during treatment.
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