EGFR variant allele frequency predicts EGFR-TKI efficacy in lung adenocarcinoma: a multicenter study

Abstract

Background: Although lung adenocarcinoma (LADC) with sensitizing mutations of the epidermal growth factor receptor (EGFR) is highly sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), in most cases disease progression inevitably occurs. Our aim was to investigate the predictive and prognostic significance of adjusted tumoral EGFR variant allele frequency (EGFR-aVAF) in the above setting.

Methods: Eighty-nine Caucasian advanced-stage LADC patients with known exon-specific EGFR mutations undergoing EGFR-TKI treatment were included. The correlations of EGFR-aVAF with clinicopathological variables including progression-free and overall survival (PFS and OS, respectively) were retrospectively analyzed.

Results: Of 89 EGFR-mutant LADC patients, 46 (51.7%) had exon 19 deletion, while 41 (46.1%) and 2 (2.2%) patients had exon 21- and exon 18-point mutations, respectively. Tumoral EGFR-aVAF was significantly higher in patients harboring EGFR exon 19 mutations than in those with exon 21-mutant tumors (P<0.001). Notably, patients with EGFR exon 19 mutant tumors demonstrated significantly improved PFS (P=0.003) and OS (P=0.02) compared to patients with exon 21 mutations. Irrespective of specific exon mutations, a statistically significant positive linear correlation was found between EGFR-aVAF of tumoral tissue and PFS (r=0.319; P=0.002). High (≥70%) EGFR-aVAF was an independent predictor of longer PFS [vs. low (<70%) EGFR-aVAF; median PFSs were 52 vs. 26 weeks, respectively; P<0.001]. Additionally, patients with high EGFR-aVAF also had significantly improved OS than those with low EGFR-aVAF (P=0.011).

Conclusions: Our study suggests that high (≥70%) EGFR-aVAF of tumoral tissue predicts benefit from EGFR-TKI treatment in advanced LADC and, moreover, that exon 19 EGFR mutation is associated with high EGFR-aVAF and improved survival outcomes.

Keywords: Epidermal growth factor receptor mutation (EGFR mutation); lung adenocarcinoma (LADC); variant allele frequency (VAF).

Figure 1

EGFR-aVAF of tumoral tissue in LADC patients. (A) Bar chart illustrating the distribution of all included LADC patients (n=89), according to tumoral EGFR-aVAF irrespective of specific exon mutations. (B) Distribution of LADC patients diagnosed with EGFR exon 19 and exon 21 mutations (n=46 and n=41, respectively). EGFR, epidermal growth factor receptor; EGFR-aVAF, adjusted EGFR variant allele frequency; LADC, lung adenocarcinoma.

Figure 2

Kaplan-Meier plots for PFS and OS in patients with LADC according to specific EGFR exon mutations and therapeutic approaches. (A) LADC patients with tumors harboring EGFR exon 21 mutations had significantly shorter median PFS than those with exon 19 mutations (median PFSs were 25 vs. 44 weeks, respectively; P=0.003, log-rank test). (B) EGFR exon 21 mutation was also associated with significantly shorter OS in these patients (vs. EGFR exon 19 mutations, median OSs were 57 vs. 76 weeks, respectively; P=0.02, log-rank test). (C) No significant differences in PFS have been observed in patients treated with gefitinib vs. erlotinib (median PFSs were 37 vs. 40 weeks, respectively; P=0.654, log-rank test). (D) Similarly, the OS also did not differ significantly between the patients treated with gefitinib vs. erlotinib (median OSs were 68 vs. 87 weeks, respectively; P=0.665, log-rank test). PFS, progression-free survival; OS, overall survival; LADC, lung adenocarcinoma; EGFR, epidermal growth factor receptor.

Figure 3

Scatter plots and Kaplan-Meier estimates for PFS and OS in LADC patients according to EGFR-aVAF. (A) Scatter plot showing significant positive linear correlation between tumoral EGFR-aVAF and PFS (r=0.319; P=0.002, Spearman’s correlation) (each dot represents a single patient, and the dashed line shows the linear trendline). (B) Statistically non-significant, although clinically notable correlation was found between EGFR-VAF and OS (r=0.208; P=0.061, Spearman’s correlation). (C) Patients with tumoral EGFR-aVAF ≥70% had significantly longer PFS than those in the EGFR-aVAF low (<70%) group (median PFSs were 52 vs. 26 weeks, respectively; P<0.001, log-rank test). (D) Similarly, the median OS was also significantly increased in patients with high (≥70%) EGFR-aVAF [vs. those with low (<70%) EGFR-aVAF, median OSs were 94 vs. 57 weeks, respectively; P=0.011, log-rank test]. PFS, progression-free survival; OS, overall survival; LADC, lung adenocarcinoma; EGFR, epidermal growth factor receptor; EGFR-aVAF, adjusted EGFR variant allele frequency.