First Case of A859T Epidermal Growth Factor Receptor Mutation Responding to Erlotinib

Abstract

A 59-year-old smoker consulted for a pulmonary nodule. Computed tomography (CT) scan lung biopsy diagnosed a non-small cell lung cancer (NSCLC) of adenocarcinoma subtype. Positron emission tomography demonstrated a left adrenal metastasis. First-line chemotherapy with a combination of pemetrexed and carboplatin was performed. After four cycles, a partial response was observed according to RECIST 1.1 criteria. During the same period, epidermal growth factor receptor (EGFR) mutations were characterized according to a sensitive method based on high-performance liquid chromatography and sequencing (Figures 1A, B). The rare mutation A859T was observed. Erlotinib was introduced after a wash-out period of 4 weeks. Tolerance was excellent. Eight weeks later, CT scan demonstrated a partial response (criteria RECIST 1.1 = − 41%). Maximal standard uptakes of 18F-fluorodeoxyglucose (FDG) showed a reduction for primary and secondary tumors, 3.9 to 1.0 and 2.9 to 2.3, respectively (Figure 2). The radiographic response was confirmed with a CT scan 3 months later. To date, the duration of response is 3 months.FIGURE 2Computed tomography and positron emission tomography scans and fused images before and 8 weeks after erlotinib.View Large Image Figure ViewerDownload (PPT) Activating EGFR mutations are predictive responses for the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The most frequent deletions and mutations, located in exon 19 and 21, are observed from 10% in Caucasian populations1Rosell R Moran T Queralt C et al.Screening for epidermal growth factor receptor mutations in lung cancer.N Engl J Med. 2009; 361: 958-967Crossref PubMed Scopus (1901) Google Scholar up to 40 to 60% in female, nonsmoking Asian populations.2Mok TS Wu YL Thongprasert S et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (6514) Google Scholar Alongside the most frequent activating EGFR mutations, many other less frequent mutations have been described.3Avizienyte E Ward RA Garner AP Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations.Biochem J. 2008; 415: 197-206Crossref PubMed Scopus (73) Google Scholar In general, little is known about the sensitivity or the lack of sensitivity to TKIs in humans. A859T EGFR mutation has already been reported twice and has been associated with the absence of sensitivity to gefitinib.4Han SW Kim TY Hwang PG et al.Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib.J Clin Oncol. 2005; 23: 2493-2501Crossref PubMed Scopus (715) Google Scholar, 5Cappuzzo F Bemis L Varella-Garcia M HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer.N Engl J Med. 2006; 354: 2619-2621Crossref PubMed Scopus (183) Google Scholar Functional analysis of A859T EGFR mutation exposed to erlotinib based on a cellular assay concluded that this variant could be a silent polymorphism.6de Gunst MM Gallegos-Ruiz MI Giaccone G et al.Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain.Mol Cancer. 2007; 6: 56Crossref PubMed Scopus (19) Google Scholar To the contrary of all these published data, our case supports the evidence of a therapeutic effect of erlotinib in a NSCLC patient bearing A859T EGFR mutation. The proofs are a tumor size reduction and a decrease of the FDG maximal uptake after 8 weeks of treatment and confirmed 3 months later. Although the follow-up of our case is limited, our observation seems similar to patients with TKI-sensitive adenocarcinomas harboring a frequent EGFR mutation: significant shrinking tumor size after TKI introduction, long period of stable disease, and good tolerance. For all the reasons, we consider that A859T EGFR mutation could be an activating mutation-associated response to erlotinib. Because of the lack of a reliable tool to predict EGFR mutation sensitivity of current TKIs, we recommend that physicians test both/several TKIs for every NSCLC patient harboring a rare/new EGFR mutation.