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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3182a471e0
Case Report

An Uncommon Insertion Mutation in Exon 19 of EGFR Showed Stable Disease after TKI Treatment

Chan, Anthony W.H. FRCPA*; Tong, Joanna H.M. PhD*; Lo, Sing-Hung FRCR; To, Ka Fai FRCPA*

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*Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong; and Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong.

Disclosure: The authors declare no conflict of interest.

Address correspondence to: Ka Fai To, FRCPA, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong. E-mail: kfto@cuhk.edu.hk

In October 2010, a 55-year-old Chinese woman presented with a T3N3M1a (stage IV) adenocarcinoma of left lung. She had left apical main tumor with carcinomatosis of both lungs, and metastatic lymphadenopathies of left hilar, right paratracheal, right supraclavicular, aortopulmonary, and subcarinal lymph nodes. She presented with a Karnofsky performance score of 80% and an Eastern Cooperative Oncology Group performance score of 1, and had never smoked.

Molecular analysis was performed on a formalin-fixed and paraffin-embedded tissue derived by bronchoscopic transbronchial biopsy. Tumor cells were isolated from paraffin tissue by manual microdissection. Mutations in exons 18, 19, 20, and 21 of epidermal growth factor receptor (EGFR) gene were analyzed by polymerase chain reaction direct sequencing. An insertion mutation in exon 19 was identified: c.2232insTAAAATTCCCGTCGCTAT (c.2214_2231dup) p.K745_E746insIPVAIK (Fig. 1).

FIGURE 1.
FIGURE 1.
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Despite uncertain clinical response of this mutation at time of diagnosis, the patient preferred tyrosine kinase inhibitor (TKI) treatment over conventional chemotherapy, after detailed discussion with the oncologist. Erlotinib 150 mg once daily was initiated in December 2010. Patient’s symptoms improved after 3 weeks of treatment, and serial chest radiographic findings revealed a stable disease according to Response Evaluation Criteria in Solid Tumors criteria in a treatment period of 18 months (Fig. 2A–C). She did not suffer from any significant erlotinib toxicity except grade 1 rash. Clinical and radiological disease progression was revealed after 18 months of erlotinib (Fig. 2D). She was switched to two courses of gemcitabine–carboplatin, and then a course of pemetrexed–carboplatin, but no clinical response was found. She finally succumbed at 24 months after initial diagnosis of pulmonary adenocarcinoma.

FIGURE 2.
FIGURE 2.
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Insertion mutation in exon 19 of EGFR is an uncommon event representing about 2% and 1% of all exon 19 mutations and all activation mutations in non–small-cell carcinoma of lung, respectively.1 Patients with pulmonary non–small-cell carcinoma harboring insertion mutation in exon 19 are sensitive to EGFR-TKI.1 In our local series of 2018 cases of pulmonary adenocarcinoma in Hong Kong, 860 cases (42.6%) harbor EGFR activation mutation and three of these (0.35%) have K745_E746insIPVAIK mutation in exon 19. Nucleosides 2212 to 2234 of exon 19 are the insertion mutation hotspots, and duplication of 18 nucleotides at position 2214 to 2231 (K745_E746insIPVAIK) comprises 41.1% of all described insertion mutations in exon 19.1,2 We observed a stable disease in a patient with stage IV pulmonary adenocarcinoma, which harbored K745_E746insIPVAIK mutation in exon 19, under an 18-month treatment of EGFR-TKI. This case further supports the responsiveness to TKI in pulmonary adenocarcinoma with uncommon exon 19 insertion mutations.

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REFERENCES

1. He M, Capelletti M, Nafa K, et al. EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma. Clin Cancer Res. 2012; 18:1790–1797

2. Otto C, Csanadi A, Fisch P, Werner M, Kayser G. Molecular modeling and description of a newly characterized activating mutation of the EGFR gene in non-small cell lung cancer. Diagn Pathol. 2012; 7:146

Copyright © 2013 by the International Association for the Study of Lung Cancer

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