The epidermal growth factor receptor (EGFR) is a membrane-bound protein with an intracellular tyrosine kinase (TK) domain. When activated, it triggers a signalling pathway that leads to several cell proliferation signals (1). Findings in the last decade showed that mutations in this TK domain could lead to a permanent activation of this pathway. Several specific TK inhibitors, usable as therapeutic agents, have been developed and have dramatically modified management and prognosis of lung cancer in advanced stage. Most EGFR mutations are located in exons 18–21 of the TK domain, and around 85% of them are in exons 19 and 21 (2). However, minor mutations are associated with resistance to TKI therapy and have been reported in about 50% of patients with disease progression (3, 4).
In a multicentre observational study by the French ERMETIC-IFCT network, 10,117 non-small cell lung cancer samples, collected between 2008 and 2011, were tested for EGFR mutations. Rare EGFR mutations were defined as mutations at exon 18 and/or 20; complex mutations were defined as mutations at more than one exon. There were 9070 (90%) EGFR wild-type and 1047 (10%) EGFR-mutated samples. Among mutated tumours, 102 (10%) were with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations.
French National Cancer Institute required to collect clinical data for testing as well, such as demographic information, clinical staging, and tumour histology. Never smokers were defined as <100 cigarettes in life time. It also established requirements for clinical information on patient follow-up under treatment, including response to treatment and survival.
All patients with rare EGFR mutations were Caucasian, none had received EGFR-TKI before DNA sequencing. The majority of patients, 46 (62%) were smokers, among them there were 27 former and 19 current smokers comparing to 26 never smokers. Mostly men, 14 in total (50%) showed single exon 18 mutations and 23 women (61%) showed single exon 20 mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (p < 0.001).
Median overall survival (OS) in metastatic disease was worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; HR for death 0.27, 95% CI 0.08–0.87, p = 0.03). Fifty patients had been known to be treated with EGFR-TKI (40 with erlotinib, 9 with gefitinib, and 1 with gefinitib following by erlotinib). The best response was assessable in 47 patients, with partial responses in 7 patients (15%), stable disease in 15 cases (32%), and progressive disease in 25 (53%). A disease control rate (DCR) was 47%.
Primary resistance to EGFR TKI was suggested in 22 patients with PFS under 3 months (48%). Overall response rate and DCR under EGFR-TKI appeared not different between exon 18 in 1 patient (7%) and 5 patients (34%) and exon 20 in 2 patients (8%) and 11 patients (44%), but higher for complex mutations in 4 patients (57%) and 6 patients (86%) compared with single exon 18 or exon 20 mutations (p = 0.004 and p = 0.03, respectively). Median OS for EGFR-TKI was better for patients with exon 18 (22 months, 95% CI 1–44) than for patients with exon 20 mutations (9.5 months, 95% CI 4–15) .
Rare EGFR mutations are heterogeneous and require novel targeted therapeutic approaches, which are possible if the mutations are searched for, and if the variant is documented.
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- Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007; (3):169-81.
- Riely GJ, Politi KA, Miller VA, et al. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006;12(24):7232-41.
- Hirsch FR, Bunn PA Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009; 10(5):432-3.
- Beau-Faller M, Prim N, Ruppert AM, et al. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol. 2014; 25(1):126-31.
- Do we need to test all NSCLC patients for rare EGFR mutations?
- In case of EGFR exon 20 mutation, is chemotherapy more beneficial than TK inhibitors?
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.