Plasma EGFR mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer

Abstract

Background: Activated epidermal growth factor receptor (EGFR) mutation is the main pathogenic cause of non-small cell lung cancer (NSCLC) in Asia. However, the impact of plasma EGFR mutation abundance, especially of the ultra-low abundance of EGFR mutation detected by highly sensitive techniques on clinical outcomes of first-line EGFR tyrosine kinase inhibitors (TKIs) for advanced NSCLC patients remains unclear.Methods: We qualitatively detected baseline EGFR status of NSCLC tissues using amplification-refractory mutation system and quantified the plasma abundance of EGFR mutations through next-generation sequencing (NGS). Every 8-12 weeks, we performed dynamic detection of plasma mutation abundance and imaging evaluation. We analyzed the association between plasma abundance of EGFR sensitizing mutations, tumor size, tumor shrinkage percentage, concomitant TP53 mutations, and clinical response to TKIs.Results: This prospective study enrolled 135 patients with advanced NSCLC. The objective response rate (ORR) and disease control rate (DCR) for EGFR mutation-positive patients were 50.0% and 87.0%, respectively. When the cutoff value of plasma EGFR mutation abundance was 0.1%, the ORRs of TKItreated patients were significantly different (60.0% for the >0.1% group vs. 21.4% for the ≤0.1% group, P=0.028). Median progression-free survival (PFS) was significantly longer for participants with a mutation abundance above 0.1% compared to those with a 0.01-0.1% abundance (log rank, P=0.0115). There was no significant association between plasma abundance of EGFR sensitizing mutations and tumor size, tumor shrinkage percentage, or concomitant TP53 mutations. Cox multivariate analysis demonstrated that plasma mutation abundance was an independent predictive factor for PFS [hazard ratio (HR) 2.41, 95% confidence interval (CI): 1.12-5.20; P=0.025]. We identified 11 participants with the acquired T790M resistance mutation according to serial dynamic plasma samples.Conclusions: Liquid biopsy screening based on highly sensitive NGS is reliable for detecting drug

Concurrent TP53 mutations predict a poor prognosis of EGFR‑mutant NSCLCs treated with TKIs: An updated systematic review and meta‑analysis

“…In addition, a retrospective study by Tan et al ( 40 ) demonstrated that the co-existence of uncommon EGFR mutations and TP53 mutations is associated with a shorter PFS. By contrast, Canale et al ( 41 ) observed significantly shorter PFS and OS times in the subgroup of TKI-treated patients with EGFR exon 19 deletion compared with those without this deletion, whilst Wang et al ( 42 ) identified no significant difference in PFS between patients with EGFR exon 19 deletion and EGFR L585R mutations. Such evidence is not sufficient to completely clarify the intrinsic association between TP53 mutations and EGFR -TKI efficacy.…”

A Novel KIF5B-EGFR Fusion Variant in Non-Small-Cell Lung Cancer and Response to Afatinib: A Case Report

“…Previous study has shown that highly abundant EGFR mutations in pretreatment blood samples predicted longer PFS on EGFR-TKIs in advanced NSCLC patients. 23 More studies are needed to establish the efficacy of osimertinib for NSCLC patients with EGFR fusions in either first- or second-line treatment. Interestingly, histology on biopsies revealed the gradual development of SCC transformation.…”

Can Liquid Biopsy Based on ctDNA/cfDNA Replace Tissue Biopsy for the Precision Treatment of EGFR-Mutated NSCLC?

“…Table 1 presents data on the association between plasma ctDNA/cfDNA EGFR mutations and the efficacy and prognosis of targeted therapy in NSCLC patients [ 28 , 30 , 31 , 32 , 33 , 34 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. The BENEFIT trial prospectively demonstrated the feasibility of using liquid biopsy to guide the efficacy of first-line EGFR-TKI therapy for the first time.…”

“…The median PFS was also significantly longer in patients with a plasma EGFR mutation abundance of >0.1% compared to that of patients with a plasma EGFR mutation abundance of 0.01–0.1% ( p = 0.0115). Additionally, one Cox multivariate analysis indicated that mutation abundance in plasma was an independent predictor of PFS (HR = 2.41, 95% CI = 1.12–5.20; p = 0.025) [ 55 ]. In another study, researchers used a modified semi-quantitative method (reformed-superARMS) based on ΔCt values that were generated during polymerase chain reaction (PCR) assays to investigate the impact of different baseline ctDNA EGFR mutation levels and changes in ctDNA EGFR mutations with reformed-superARMS on the outcomes and prognoses of patients receiving targeted therapy.…”