Coexistence of Tyrosine Kinase Inhibitor-Sensitizing and Resistant EGFR Mutations in an Untreated Lung Adenocarcinoma Patient and Response to Erlotinib
Authors: Gagan Mathur, Deqin Ma
Journal: Journal of Thoracic Oncology (2014)

A 50-year-old asian man with a remote history of light smoking (half a pack per day × 4 years) presented to the orthopedic clinic with several months of progressively worsening right hip pain. A radiograph showed a lytic lesion in the right acetabulum with soft-tissue involvement. Computed topography (CT)-guided biopsy revealed a moderately differentiated adenocarcinoma, positive for TTF-1 and CK7 and negative for CK20 by immunohistochemistry. CT scan revealed a 10 mm irregular nodule in the apex of the left lung with hilar and mediastinal lymphadenopathy. The patient was diagnosed with metastatic lung adenocarcinoma and staged as IVB. EGFR mutation analysis was performed using massively parallel sequencing using the Ion AmpliSeq Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, CA). A compound heterozygous mutation in exon 19 (c.2240T>C, p.L747S and c.2246_2260de15, p.A750_K754del) was identified (Fig. 1) and the result was confirmed by Sanger sequencing (Fig. 2). The two mutations were also found to be allelic as shown in Figure 1. Given the positive family history of lung cancer (father; no detailed information available), EGFR mutation analysis was performed on the patient’s peripheral blood to rule out a germline mutation. No mutation was found. The patient was treated with Erlotinib, 150 mg/d, in conjunction with palliative radiation therapy directed to his right acetabulum. He developed non-itching rashes on his nose and forehead and had loose stools, but otherwise tolerated the therapy. Follow-up chest CT after 2 months of Erlotinib showed interval decrease in the size of the lung nodule (Fig. 3), but slight increase in the size of a mediastinal lymph node. At 6-month follow-up, CT showed no interval tumor growth and radiograph showed improvement of the hip lesion. The patient had almost no hip pain, his energy level had increased, and he was able to go back to work full time.FIGURE 2Identification of EGFR exon 19 compound mutation by Sanger sequencing. Exons18-21 of the EGFR gene was polymerase chain reaction amplified and Sanger sequencing was performed. The hollow arrow indicates the c.2240T>C point mutation and the solid arrow marks the beginning of the15 base-pair deletion (c.2246_2260de15).View Large Image Figure ViewerDownload Hi-res image Download (PPT)FIGURE 3Computed Tomography images of the initial presentation (A) and 2 months post-Erlotinib treatment (B) of the lung nodule.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Compound mutations comprise up to 14% of mutations identified in the tyrosine kinase domain (exons 18–21) of the EGFR gene.1Kobayashi S Canepa HM Bailey AS et al.Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors.J Thorac Oncol. 2013; 8: 45-51Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar More than one-third of the compound mutations found before therapy involve one of five amino acids: E709, G719, S768, T790, and L858.2Chen Z Feng J Saldivar JS Gu D Bockholt A Sommer SS EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids.Oncogene. 2008; 27: 4336-4343Crossref PubMed Scopus (64) Google Scholar Exon 19 deletions are less frequently found in compound mutations in untreated patients.3Kobayashi S Boggon TJ Dayaram T et al.EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.N Engl J Med. 2005; 352: 786-792Crossref PubMed Scopus (3476) Google Scholar The p.L747S mutation is also rare with only seven cases being reported in the COSMIC database (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic). The compound p.L747S and p.A750_K754del mutation was only reported in one case in the literature, in a 73-year-old asian woman with unknown smoking status or therapy information.2Chen Z Feng J Saldivar JS Gu D Bockholt A Sommer SS EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids.Oncogene. 2008; 27: 4336-4343Crossref PubMed Scopus (64) Google Scholar Exon 19 deletions are known to be associated with sensitivity to tyrosine kinase inhibitor (TKI) and tumors harboring p.L747S mutation are TKI resistant.4Yamaguchi F Fukuchi K Yamazaki Y et al.Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases.Oncol Lett. 2014; 7: 357-360Crossref PubMed Scopus (28) Google Scholar We are reporting for the first time the Erlotinib response in a TKI-naive patient with a compound TKI-resistant and sensitive mutation. The patient is currently in remission and still receiving Erlotinib therapy. It should be noted that cells carrying p.L747S mutation may become predominate after initial TKI response because of clonal selection of tumor cells carrying this p.L747S-resistant mutation. The authors thank Dr. Michael Gailey for critically reviewing this manuscript.