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

Abstract

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.

Keywords: EGFR; KRAS; NSCLC; meta-analysis; prognosis.

Figure 1. PRISMA 2009 Flow Diagram

PRISMA flow diagram for study selection.

Figure 2. Our judgements about each risk of bias item of included studies

Red circles represent studies with high risk of bias; Green circles represent studies with low risk of bias, yellow circles represent studies with uncertain risk of bias.

Figure 3. Meta-analysis of the prognosis of circulating EGFR mutations for PFS

A. Forest plots of HR and 95% CI in advanced NSCLC patients. Patients with circulating EGFR mutations had a better PFS (HR = 0.64, 95% CI 0.51-0.81); B. results of sensitive analysis showed that there was no “dominant” study driving the results of the meta-analysis; C. forest plots of HR and 95% CI in advanced NSCLC patients treated by EGFR-TKIs. Circulating EGFR mutations indicated a better PFS among patients who were treated by EGFR-TKIs (HR = 0.64, 95% CI 0.51-0.81).

Figure 4. Meta-analysis of the prognosis of circulating EGFR mutations for OS

A. Forest plots of HR and 95% CI in advanced NSCLC patients. Only marginally statistically significant OS (HR = 0.77, 95% CI 0.54-1.10) was observed between NSCLC patients with and without circulating EGFR mutations; B. results of sensitive analysis showed that there was no “dominant” study driving the results of the meta-analysis; C. forest plots of HR and 95% CI in advanced NSCLC patients treated by EGFR-TKIs, there was no statistical significance between patients with and without circulating EGFR mutations (HR = 0.79, 95% CI 0.52-1.21, p = 0.15).

Figure 5. Meta-analysis of the prognosis of circulating KRAS mutations for PFS

A. Forest plots of HR and 95% CI in advanced NSCLC patients. The pooled analysis showed that circulating KRAS mutations were associated with a worse PFS (HR = 1.83, 95% CI 1.40-2.40); B. forest plots of HR and 95% CI in advanced NSCLC patients treated with chemotherapy. Circulating KRAS mutations were associated with a shorter PFS among patients treated by chemotherapy (HR = 1.81, 95% CI 1.38-2.38); C. Subgroup analyses on the basis of detection matrix (serum vs plasma) indicates no statistical significance between these KRAS mutations detected in serum and KRAS mutations detected in plasma regarding PFS (p = 0.43).

Figure 6. Meta-analysis of the prognosis of circulating KRAS mutations for OS

A. Forest plots of HR and 95% CI in advanced NSCLC patients; patients with circulating KRAS mutations had a worse OS (HR = 2.07, 95% CI 1.54-2.78) B. forest plots of HR and 95% CI in advanced NSCLC patients treated with chemotherapy; circulating KRAS mutations were associated with a worse OS among patients treated by chemotherapy (HR = 2.03, 95% CI 1.29-3.19) C. subgroup analysis in advanced NSCLC patients on the basis of detecting matrix (serum vs. plasma). The subgroup difference was not significant (p = 0.43).