Prognostic value of EGFR and KRAS in circulating tumor DNA in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis

EGFR (exon 19 and exon 21) mutations in patients with advanced non-small cell lung cancer (NSCLC) treated by EGFR-TKIs are associated with a better survival; while KRAS mutations predict a worse prognosis. However, there are divergent findings regarding the prognostic value of EGFR and KRAS mutations in circulating tumor DNA (ctDNA). We aimed to summarize the evidence for the use of circulating EGFR and KRAS mutations as prognostic factors in advanced NSCLC patients. We searched the network databases for studies reporting progression-free survival (PFS) and overall survival (OS) stratified by EGFR or KRAS mutations in ctDNA in advanced NSCLC patients. Thirteen studies enrolling 2,293 patients were reviewed. Correlation of circulating EGFR or KRAS mutations with patients’ prognosis was assessed by meta-analysis. The pooled analyses showed that EGFR mutations in ctDNA significantly prolong PFS (HR=0.64,95% CI 0.51-0.81, I2=0%, p=0.0002), namely, in patients treated by EGFR-TKIs. There is a trend to have a prolonged OS for advanced NSCLC patients with circulating EGFR mutations who were treated by EGFR-TKIs (HR=0.79, 95% CI 0.52-1.21, I2=0, p=0.28). KRAS mutations detected in ctDNA predict a worse PFS (HR=1.83, 95% CI 1.40-2.40, p<0.0001) and OS (HR=2.07, 95% CI 1.54-2.78, p<0.00001) in advanced NSCLC patients treated by chemotherapy. Sensitivity analyses and subgroup analyses demonstrated the stability of our conclusion. Our analysis showed that EGFR mutations in ctDNA predicted a better PFS, in particular in advanced NSCLC patients treated by EGFR-TKIs. KRAS mutations in ctDNA indicated a worse PFS and OS in patients treated by chemotherapy.