Abstract
KRAS mutations are found in approximately one third of non-small cell lung cancer (NSCLC) patients. In this study, we aim to investigate whether KRAS 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 KRAS G12/G13 MAF in cfDNA from 114 pre-treated advanced disease NSCLC patients. In 14 patients, changes in KRAS G12/G13 MAF were longitudinally monitored during treatment. Plasma KRAS G12/G13 status was associated with poor patients’ outcome in terms of progression-free survival (PFS) (p < 0.001) and overall survival (OS) (p < 0.001). In multivariate analysis, the detection of plasma KRAS mutations was an independent predictor of adverse PFS (HR = 3.12; p < 0.001) and OS (HR = 2.53; p = 0.002). KRAS G12/G13 MAF at first treatment evaluation (T1) was higher (p = 0.013) among patients experiencing progressive disease compared to those with disease control, and increased KRAS MAF at T1 was associated (p = 0.005) with shorter PFS. On the contrary, no association was observed between tissue KRAS mutation status and patients’ prognosis. Our results show that ddPCR-based detection of KRAS G12/G13 mutations in plasma could serve as an independent biomarker of unfavorable prognosis in NSCLC patients. Changes in KRAS MAF can provide valuable information for monitoring patient outcome during treatment.
Highlights
In advanced non-small cell lung cancer (NSCLC), treatment paradigms have shifted from histology-based to genotype-based approaches [1]
The frequency of detection of specific Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations among mutated samples was as follows: G12C, 45.71% (N = 16/35); G12D, 28.57% (N = 10/35), G12V, 14.29% (N = 5/35), G13D, 5.71% (N = 2/35), G12S, 2.86% (N = 1/35) and G12A, 2.86% (N = 1/35). These mutations are all included in the droplet digital PCR (ddPCR) KRAS G12/G13 multiplex kit used for plasma-based analyses
Of the 96 NSCLC sample pairs analyzed, we found that 18 patients (18.75%) were positively concordant; that is, KRAS G12/G13 mutations were detected in both cell-free DNA (cfDNA) by ddPCR and in tumor tissues via Sanger sequencing
Summary
In advanced NSCLC, treatment paradigms have shifted from histology-based to genotype-based approaches [1]. Cells 2020, 9, 2514; doi:10.3390/cells9112514 www.mdpi.com/journal/cells (BRAF) prior to the initiation of first-line treatment in NSCLC [2]. Beyond these biomarkers, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, and the KRAS G12C point mutation, will likely soon be approved as biomarkers for the selection of patients eligible for treatment with direct inhibitors such as AMG510 [3]. KRAS mutations, and in particular single amino acid substitutions in codon 12 (e.g., G12C, G12V, and G12D) are the most prevalent gain-of-function alterations found in 20–40% of lung adenocarcinomas [4] These oncogenic mutations, hold the KRAS oncoprotein in a constitutively active state and are associated with the development and progression of several cancers, including. The prognostic and predictive value of KRAS mutations in NSCLC is still not well established [6,7]
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