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Cfdna Changes for Monitoring of Targeted Therapy in a Primary EGFR Mutation Lung Adenocarcinoma

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Cfdna Changes for Monitoring of Targeted Therapy in a Primary EGFR Mutation Lung Adenocarcinoma 810 Letter to the Editor cfDNA changes for monitoring of targeted therapy in a primary EGFR mutation lung adenocarcinoma Qiong He1,2,3#, Xian Zhu4#, Xun Shi1,2,3, Chen Lin1,2,3, Yin Jin1,2,3, Junrong Yan5, Jiachen He5, Xinmin Yu1,2,3 1Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou 310022, China; 2Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou 310022, China; 3Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China; 4Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310022, China; 5Nanjing Geneseeq Technology Inc., Nanjing 210032, China #These two authors contributed equally to this work. Correspondence to: Xinmin Yu. Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou 310022, China. Email: [email protected]. Provenance and peer review: This article was a free submission to the editorial office,Translational Lung Cancer Research. This article did not undergo external peer review. Submitted Feb 27, 2020. Accepted for publication Apr 22, 2020. doi: 10.21037/tlcr-20-442 View this article at: http://dx.doi.org/10.21037/tlcr-20-442 EGFR-TKI treatments are recommended to be used in 20.2%; tissue 87%), while no T790M mutation by next non-small cell lung carcinomas with sensitizing mutations, generation sequencing (NGS) assay. NGS also detected and acquired resistance still is a vital issue for the treatment. TP53 mutation (level: plasma 1.7%; tissue 32.8%), and More than 50% of resistance develops EGFR T790M (1-3). amplification of EGFR (6.3-fold in tissue) and KRAS Besides, MET amplification has been described as a (2.1-fold in tissue). She was switched to palliative chemotherapy resistance mechanism in 5% to 20% of patients treated with single pemetrexed due to a patient’s score of ECOG with first/second generation and up to 30% with third- performance status is two and fear of chemotherapy. generation (osimertinib) TKIs (4). Here We report a Unfortunately, she developed progression as she was rare case of later T790M mutation that occurred with completing four cycles of chemotherapy, and then switched a secondary MET amplification after first line icotinib to third-line chemotherapy with single docetaxel. Also, she treatment in EGFR-mutated lung adenocarcinoma. The was undergoing disease progression with a left lung and emergence of two resistance mechanisms after EGFR-TKI mediastinal adenopathy, accompany with new malignant may be challenging for successful treatment. pleural effusions (PE). Molecular analysis by NGS was The patient was a 65-year-old female never-smoker who again performed and revealed persistent EGFR 19del (level: presented with intermittent chest pain and was found to Plasma 27.9%; PE 84.8%), TP53 mutation (level: Plasma have bilateral lung infiltrates with a maximum of a 6×5 cm 1.9%; PE 74.3%), MET and EGFR amplification (2.9- and left lower lobe mass and mediastinal adenopathy. CT- 3.9-fold in PE). The patient’s clinical condition rapidly guided lung biopsy showed lung adenocarcinoma positive switched to a performance status of 4 when coming back for an EGFR exon 19del mutation by direct sequencing. in 2018-8. The patient developed respiratory failure with Then she was started on induction icotinib (150 mg tid PO). assisted oxygen requirement, and fourth-line joint therapy Image scans after four weeks showed partial response (PR) with crizotinib (200 mg bid PO) and icotinib (150 mg of the lung mass. After a progression-free survival (PFS) of tid PO) was urgently initiated. The patient’s symptoms ~12 months, she experienced progressive disease (PD) with significantly improved within three days. Restaging new lung metastasis. Liquid biopsy and CT-guided lung re- scans obtained after one month of crizotinib and icotinib biopsy revealed newly acquired MET amplification (2-fold joint therapy showed marked pulmonary improvement in Tissue) conjunction with EGFR 19del (level: plasma and resolution of PE. Seven months after treatment, © Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020;9(3):807-810 | http://dx.doi.org/10.21037/tlcr-20-442 808 He et al. cfDNA changes monitor EGFR-targeted therapy in lung adenocarcinoma A B C Dynamic changes in plasma Dynamic changes in PE 30 100 8 95 25 90 7 85 20 80 6 75 15 70 5 65 10 60 5 4 4 1 CNV ratio 3 3 2 MAF of mutation (%) 2 MAF of mutation (%) 0 1 1 0 −1 −1 0 Dec-17 Jul-18 Mar-19 Sep-19 Jan-20 Jul-18 Nov-19 Jan-20 Jul-18 Nov-19 Jan-20 Resistance Resistance Resistance Resislance Resistance Resistance Resistance Resistance Resistance Resistance Resistance to Ico to PEM & to Ico & to Osimer to Osimer to PEM & to Osimer to Osimer to PEM & to Osimer to Osimer DOC Crizo & Anlo DOC & Anlo DOC & Anlo EGFR 19Del EGFR T790M TP53 R282W EGFR 19Del EGFR T790M TP53 R282W EGFR MET KRAS Figure 1 Dynamic changes of genetic alterations in plasma over the course of the patient’s treatment (A). Dynamic changes of genetic alterations in PE (B). PE amplification copy evolution. PE, pleural effusion. she developed new chest wall pain and dyspnea. Repeat by MET amplification after resistance to third-generation scans showed multiple new lung lesions and progressive (osimertinib) in NSCLC EGFR-mutated patient. What’ osseous metastases. Plasma NGS detected original EGFR more, several studies report MET amplification, sometimes 19del (level: plasma 15.1%), TP53 (level: plasma 0.9) co-occur with EGFR T790M as molecular mechanisms and newly acquired EGFR T790M (level: plasma 2.6%). of resistance to EGFR TKIs (5,6). However, we are Then, the patient was then treated with osimertinib and reporting a rare case of a patient with EGFR-mutated lung experienced significant improvement in dyspnea and pain, adenocarcinoma who had an excellent initial response to and CT scan after 1-month osimertinib therapy showed a icotinib, with a MET amplification detected by liquid biopsy dramatic tumor response. However, after approximately when first acquired resistance occurred, and the patient seven months of therapy, the patient was admitted to the showed clear clinical and radiographic response to the hospital with further dyspnea and malaise. Imaging showed combination therapy with crizotinib and icotinib, followed progressive lung metastases and increasing pleural effusion. by progression, at which time plasma cell-free DNA analysis NGS revealed variational EGFR 19del (level: PE 76.6%), identified acquired EGFR T790M mutation that was not EGFR T790M (level: PE 0.1%), TP53 mutation (level: detected at the time of the first acquired resistance diagnosis. 93.9%), MET and EGFR amplification (2.9- and 6.0-fold After ~seven months of PFS of osimertinib treatment, the in PE). Then, the patient was suggested to take Anlotinib, patient developed drug-resistance, meantime liquid biopsy an antivascular drug, combined with osimertinib, and she analysis identified clearance of EGFR T790M mutation and experienced ~three months of stable disease (SD) until reappearance of MET amplification in liquid (PE) biopsy 2020-1. The patient developed worsening respiratory failure (Figure 2). Efforts have been made to interrogate mechanism with continuously assisted 3 L/min oxygen requirement of targeted therapy in a primary EGFR mutation lung when returned to the clinic in 2020-1, re-test by NGS adenocarcinoma. Analysis of EGFR on DNA from MET revealed persistence of EGFR19del (level Plasma 20.5%; PE amplification clones revealed that both shared a common 66%), EGFR T790M (level Plasma 0.7%; PE not detected), tumor origin, supporting the heterogeneous scenario of TP53 mutation (level Plasma 2.5%; PE 70%), MET and acquired mechanisms of resistance (7). In addition, our group EGFR amplification (4.0- and 3.0-fold in PE) (Figure 1). previous research found clonal evolution analyses suggest that The patient clinical condition rapidly worsened due to the composition and relationship among resistant subclones, respiratory failure, and she died a few days later. particularly relationship with T790M subclone, help to better EGFR T790M accounts for more than 50% mechanism understand the drug-resistant mechanism to TKIs (8). of first-generation TKI resistance, MET amplification Our case shows that combination therapy with icotinib accounts for 5% to 20% resistance mechanism in patients and crizotinib can be safe and effective in patients with EGFR treated with first generation. Generally speaking, EGFR mutation and MET amplification detected by cfDNA as an T790M mutations are firstly reported when drug resistance acquired resistance mechanism. Also, the case highlights occurs after first-generation EGFR-TKI (icotinib), followed the reliable utility of noninvasive liquid biopsy assays into © Translational Lung Cancer Research. All rights reserved. Transl Lung Cancer Res 2020;9(3):807-810 | http://dx.doi.org/10.21037/tlcr-20-442 Translational Lung Cancer Research, Vol 9, No 3 June 2020 809 A Plasma: Plasma (09/2019): EGFR 19Del, Lung re-biopsy & Plasma: PE & Plasma: EGFR 19Del, T790M T790M EGFR 19Del EGFR 19Del Plasma: PE (11/2019): PE: Lung biopsy: Lung re-biopsy: PE: EGFR 19Del EGFR 19Del, T790M EGFR 19Del, EGFR 19Del EGFR, MET, KRAS Amp EGFR, MET Amp Plasma: EGFR, MET, KRAS Amp EGFR, MET Amp PR PR PR SD PEM × 4 cycles & Osimer + Ico Ico + Crizo Osimer DOC × 4 cycles Anlo Decease 08/2018 11/2019 PFS 12 months 7 months PFS 8 months PFS 7 months PFS 3 months 12/2016 12/2017 07/2018 03/2019 09/2019 09/2019 Diagnosis PD PD PD PD PD Lung metastasis Malignant PE New lung lesion & Lung metastases & Respiratory failure Osseous metastasis Increasing PE B 12/2016 01/2017 12/2017 Diagnosis One month after Icotinib PD on Icotinib 04/2018 07/2018 09/2018 PD on PEM PD on DOC, before lcotinib + Crizotinib One month after lcotinib + Crizotinib initiation 03/2019 05/2019 11/2019 PD on Icotinib + Crizotinib, before Osimertinib One month after Osimertinib initiation PD on Osimertinib, before Osimertinib + Anlotinib Figure 2 The course of the disease with treatment history, driver mutations (A), and CT images (B).
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