Abstract
IntroductionEpidermal growth factor receptor (EGFR) 19del and L858R mutation are known as “common mutations” in non-small cell lung cancer (NSCLC) and predict sensitivities to EGFR tyrosine kinase inhibitors (TKIs), whereas 20ins and T790M mutations confer drug-resistance to EGFR-TKIs. The role of the remaining uncommon EGFR mutations remains elusive.MethodsWe retrospectively screened a group of NSCLC patients with uncommon EGFR mutations other than 20ins and T790M. The mutation patterns, use of different generations of EGFR-TKIs, and concurrent genetic alterations were analyzed. Meanwhile, a cohort of patients with single 19del or L858R were included for comparison.ResultsA total of 180/1,300 (13.8%) patients were identified. There were 102 patients with advanced or recurrent NSCLC that received first-line therapy of gefitinib/erlotinib/icotinib and afatinib and were eligible for analysis. The therapeutic outcomes among patients with common mutations (EGFRcm, n = 97), uncommon mutation plus common mutations (EGFRum+EGFRcm, n = 52), complex uncommon mutations (complex EGFRum, n = 22), and single uncommon mutations (single EGFRum, n = 28) were significantly different (ORRs: 76.3%, 61.5%, 54.5%, and 50.0%, respectively, p = 0.023; and mPFS: 13.3, 14.7, 8.1, and 6.0 months, respectively, p = 0.004). Afatinib showed superior efficacy over gefitinib/erlotinib/icotinib in EGFRcm (ORR: 81.0% vs. 75.0%, p = 0.773; mPFS: 19.1 vs. 12.0m, p = 0.036), EGFRum+EGFRcm (ORR: 100% vs. 54.5%, p = 0.017; mPFS: NE vs. 13.6m, p = 0.032), and single EGFRum (ORR: 78.6% vs. 21.4%, p = 0.007; mPFS: 10.1 vs. 3.0m, p = 0.025) groups. Comprehensive genomic profiling by Next Generation Sequencing encompassing multiple cancer-related genes was performed on 51/102 patients; the mPFS of patients without co-mutation (n = 16) and with co-mutations of tumor-suppressor genes (n = 31) and driver oncogenes (n = 4) were 31.1, 9.2, and 12.4 months, respectively (p = 0.046). TP53 mutation was the most common co-alteration and showed significantly shorter mPFS than TP53 wild-type patients (7.0 vs. 31.1m, p < 0.001). Multivariate analysis revealed that concurrent 19del/L858R and tumor-suppressor gene alterations independently predicted better and worse prognosis in patients with uncommon mutations, respectively.ConclusionsUncommon EGFR mutations constitute a highly heterogeneous subgroup of NSCLC that confer different sensitivities to EGFR-TKIs with regard to the mutation patterns. Afatinib may be a better choice for most uncommon EGFR mutations. Concurrent 19del/L858R and tumor-suppressor gene alterations, especially TP53, can be established as prognostic biomarkers.
Highlights
Epidermal growth factor receptor (EGFR) 19del and L858R mutation are known as “common mutations” in non-small cell lung cancer (NSCLC) and predict sensitivities to EGFR tyrosine kinase inhibitors (TKIs), whereas 20ins and T790M mutations confer drug-resistance to EGFR-TKIs
There were 180 (13.8%) patients identified with uncommon EGFR mutations other than 20ins and T790M, including 79 (44%) patients with a coexisting common EGFR mutation (19del or L858R), 39 (22%) patients with complex uncommon EGFR mutations, and 62 (34%) patients with single uncommon EGFR mutations such as G719X (n = 9, 5%), L861Q (n = 16, 9%), S768I (n = 4, 2%), and other single uncommon mutations (n = 33, 18%) (Supplementary Figure 1)
TP53 was the most frequently identified co-occurring genomic alteration; we further investigated the role of TP53 mutation in patients with uncommon EGFR mutations and found that TP53 mutated (TP53-MUT) patients had a significantly shorter mPFS than those of TP53 wild-type (TP53-WT)
Summary
Epidermal growth factor receptor (EGFR) 19del and L858R mutation are known as “common mutations” in non-small cell lung cancer (NSCLC) and predict sensitivities to EGFR tyrosine kinase inhibitors (TKIs), whereas 20ins and T790M mutations confer drug-resistance to EGFR-TKIs. The role of the remaining uncommon EGFR mutations remains elusive. EGFR mutations other than 19del and L858R are known as “uncommon mutations”, which can occur alone or coexisted with other EGFR mutations (termed “complex mutations”) [4, 5]. These uncommon mutations constitute a highly heterogeneous group with varied responses to EGFR-TKIs which have not been fully elucidated. Evidence on the clinical responses of other uncommon EGFR mutations remains elusive
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