Two Patients Having NSCLC With Novel Duplication Mutation in Their EGFR Gene (p.I740_K745dupIPVAIK) and Their Response to Osimertinib

Previously, scientists have reported patients with NSCLC with insertion or deletion mutation in exon 19 of EGFR gene.1Peiyi X. Enjie L. Pan L. Wencai L. Guozhong J. A case of primary resistance to gefitinib due to novel deletion-insertion mutation of EGFR exon 19 in NSCLC.J Thorac Oncol. 2019; 14: e117-e119Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 2Silvia L.M. Roberta M. Daniele C. et al.Acquired BRAF G469A mutation as a resistance mechanism to first-line osimertinib treatment in NSCLC cell lines harboring an EGFR exon 19 deletion.Target Oncol. 2019; 14: 619-626Crossref PubMed Scopus (26) Google Scholar, 3van Kempen L.C. Wang H. Aguirre M.L. et al.Afatinib in osimertinib-resistant EGFR ex19del/T790M/P794L mutated NSCLC.J Thorac Oncol. 2018; 13: e161-e163Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 4Ancevski H.K. Friedland D.M. Villaruz L.C. Burns T.F. First-line osimertinib in patients with treatment-naive somatic or germline EGFR T790M-mutant metastatic NSCLC.J Thorac Oncol. 2018; 13: e3-e5Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Here, we report two patients with NSCLC with a novel duplication mutation in their EGFR gene who responded well to osimertinib. A 67-year-old woman who never smoked presented with convulsion and numbness to our hospital. The plain magnetic resonance imaging (MRI) scan of the brain revealed some nodules over her right parietal lobe, and these nodules were suspected to be a metastatic tumor. The patient then had a thoracic computed tomography (CT) scan, which revealed a tumor with peripheral obstructive inflammation in the inferior lobe of the left lung and multiple swollen lymph nodes in the mediastinum. Lung biopsy and immunohistochemistry staining were performed, which indicated NSCLC. Taking all the results together, this patient was diagnosed with NSCLC (cT1cN2M1b stage IVA) with brain metastasis. Next-generation sequencing indicated a rare duplication mutation in EGFR gene exon 19 (p.I740_K745dupIPVAIK) (Figs. 1A). The patient did not have an operation, but instead was started on osimertinib treatment. After 8 weeks, brain MRI showed disappearance of nodules, and thoracic CT scan showed diminished tumor and shrunken lymph nodes in the left lung (Fig. 1B). Another 59-year-old female patient visited our orthopedics department for paroxysmal dull pain in the lumbosacral region. The MRI indicated multiple focuses of bone destruction and multiple enhanced focuses in cerebral hemisphere surface and subcortical areas, which were suspected to be metastatic tumors. The thoracic CT showed a tumor in the dorsal inferior region of the right lung, and the tumor cells had metastasized to the right pleura and several lymph nodes of the mediastinum. Similarly, the percutaneous biopsy and immunohistochemistry staining indicated NSCLC, and next-generation sequencing revealed a duplication in EGFR gene exon 19 (p.I740_K745dupIPVAIK) and a splicing mutation in TP53 gene exon 3 (Figs. 2A). This patient was ultimately diagnosed with NSCLC stage IV and 1 week later received palliative radiotherapy to the bone for 15 days. On the fifth day of radiotherapy, the patient started osimertinib treatment together with bevacizumab. Four weeks after treatment, the tumor in the inferior dorsal aspect of the lung and lymph nodes in the mediastinum shrank, and the brain metastases disappeared (Fig. 2B). To the best of our knowledge, the two cases reported in this article were the first with duplication mutation (p.I740_K745dupIPVAIK) in the EGFR exon 19 region. Our report provides a feasible therapy for some patients who harbor a rare EGFR mutation such as duplication in exon 19. However, the effect of osimertinib to EGFR 19 duplication, especially its side effect, should be further investigated in subsequent studies. This work was supported by the National Natural Science Foundation of China [grant number 81960571] and the Project of Department of Jiangxi Province Science and Technology Plan [grant number 20192ACB70013]. The authors thank Berry Oncology Corporation for genetic analysis of the patient’s tumor sample.