Abstract
BackgroundIntrinsic resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC) patients with an activating mutation in the epidermal growth factor receptor (EGFR). We investigated co-occurring genetic alterations in circulating tumor DNA (ctDNA) as predictive markers of clinical response to first-line erlotinib. MethodsPretreatment plasma samples were collected from 76 patients with EGFR-mutated, advanced-stage NSCLC treated with first-line erlotinib. We isolated ctDNA from plasma for next-generation sequencing. ResultsCo-occurring oncogenic drivers were detected in 21% of pretreatment samples and correlated with decreased progression-free survival (PFS) (6.9 months vs 14.4 months; hazard ratio [HR], 2.088; 95% confidence interval [CI], 0.8119-5.370; P = .0355). Concurrent MET amplification was identified in 9 samples (12%), predicting inferior PFS (5.5 months vs 14.4 months; HR, 4.750; 95% CI, 0.5923-38.10; P = .0007) and overall survival (7.6 months vs 28.3 months; HR, 3.952; 95% CI, 0.8441-18.50; P = .0005). Co-occurring non-MET-amplification oncogenic alterations showed a tendency for shorter PFS (9.9 months vs 14.4 months; HR, 1.199; 95% CI, 0.3373-4.265; P = .7586). Clearing EGFR-mutated ctDNA during erlotinib treatment is a positive predictor of clinical outcomes. Among patients who cleared the EGFR mutation, 12% had a co-occurring oncogenic driver, with a tendency toward inferior PFS (8.7 months vs 16.1 months; HR, 1.703; 95% CI, 0.5347-5.424; P = .2508). ConclusionCo-occurring MET amplification in pretreatment ctDNA samples predict inferior clinical response to first-line erlotinib in advanced-stage, EGFR-mutated NSCLC patients. Co-occurring oncogenic alterations were associated with inferior response and may be potential predictors of clinical outcome.
Highlights
Activating mutations in the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers in non-small cell lung cancer (NSCLC)
Pretreatment circulating tumor DNA (ctDNA) Profiling To investigate possible markers of intrinsic resistance to erlotinib, we evaluated the genomic profile of pretreatment ctDNA samples from patients treated with first line erlotinib
We demonstrate that co-occurring oncogenic drivers are present in patients with advanced-stage, EGFR-mutated NSCLC and that the presence of a co-occurring genetic alterations is associated with a shorter progression-free survival (PFS) during erlotinib treatment
Summary
Activating mutations in the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers in non-small cell lung cancer (NSCLC). The mutations confer sensitivity to EGFR targeting tyrosine kinase inhibitors (TKIs).[1,2,3] EGFR TKIs induce a dramatic tumor response in approximately 70% of patients with EGFRmutated NSCLC.[4,5,6] a subset of 20% to 30% of these patients have no or a limited response, despite an activating EGFR mutation. Markers of intrinsic resistance to TKIs are lacking. Cooccurring genetic alterations could play an important role in treatment response and, provide information on the genes
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