Genomic heterogeneity affects response to targeted agents. Liquid biopsy is a promising approach to detect genetic mutations in circulating cellfree DNA (cfDNA) and allows the tracking of treatment-induced genetic evolution in metastatic colorectal cancer (mCRC) patients.
Longitudinal plasma samples (n = 92) were collected from 15 mCRC patients receiving cetuximab contained regimen therapy. KRAS, NRAS, BRAF and PIK3CA mutational status relevant to cetuximab resistance were monitored by next-generation sequencing in plasma, which could be reflected by variant allele frequency (VAF). We also included 11 healthy controls to differentiate total cfDNA levels from mCRC patients.
Of these 15 mCRC patients, baseline plasmas were collected in 8 patients. The average cfDNA level in treatment naive patients was significantly higher than healthy cohort (p = 0.0004). Moreover, cfDNA levels correlate with the tumor burden before systemic therapy (R2=0.544). Dynamics of KRAS/NRAS/BRAF/PIK3CA VAF mirrored disease evolution, showing the same trend with partial response, disease progression and relapse. In addition, KRAS/NRAS/BRAF/PIK3CA VAF gradually declined upon cetuximab withdrawal for more than 2 months, and partial response was again achieved when cetuximab was re-used on 1 patient. This provided a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.
Dynamic monitoring of KRAS/NRAS/BRAF/PIK3CA mutations in cfDNA is feasible and appears to be useful in early detection of drug resistance to cetuximab in mCRC patients.
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