PMC9727108_01
(A-F) CT scan showed the changes in the lung mass in the patient PRE- and POST-treatment (G) The CT scan revealed an atrial filling defect. (H,I) MRI and PET-CT showed no metastasis in brain and bone.
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Chest computed tomography (CT) revealed a soft tissue mass measuring 49 mm * 70 mm in the lower lobe and hilum of the right lung, enlargement with lymph nodes in the right hilum, and irregular thickening of the right pleura with pleural effusion (Figure 1A). CT showed a filling defect in the left atrium, which was considered to be the formation of a vascular tumor thrombus (Figure 1G). No metastases of the brain or bone were found by magnetic resonance imaging (MRI) (Figure 1H) or positron emission tomography-computed tomography (PET-CT) (Figure 1I). BID) as first-line targeted therapy for approximately 2.5 months, beginning on 30 October 2018. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, progressive disease (PD) was diagnosed according to chest CT (Figure 1B), and the patient was switched to ceritinib (150 mg, QD) for nearly 2 months. However, the chest CT assessment indicated PD after ceritinib (Figure 1C), the patient subsequently underwent chemotherapy. Afterward, due to the progression of the tumor during treatment (Figure 1D), the patient underwent a rebiopsy and NGS analysis on 24 July 2019, and the result still showed EML4-ALK fusion and the F1174L-cis-S1189C mutation (Figures 2F, 3C,D). One month later, chest CT showed that the tumor was smaller (Figure 1E). However, his condition deteriorated again during alectinib therapy in the second month (Figure 1F), and the patient ultimately passed away in October 2019.
(A) Hematoxylin-eosin staining (HE) (B-E) Immunohistochemistry analysis revealed immunoreactivity to CK (B), TTF-1 (C), Ki-67 (D), and ALK-D5F3 (E). (F) The rebiopsy analysis revealed immunoreactivity to ALK-D5F3 (F).
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TTF-1, and Ki-67 was positive (Figures 2A-E). The presence of EML4-ALK gene fusion and an ALK exon 23 F1174L and S1189C mutation was identified by targeted next-generation sequencing (Figures 3A,B; Supplementary Methods). Afterward, due to the progression of the tumor during treatment (Figure 1D), the patient underwent a rebiopsy and NGS analysis on 24 July 2019, and the result still showed EML4-ALK fusion and the F1174L-cis-S1189C mutation (Figures 2F, 3C,D).
NGS analyses before and after therapy. NGS analysis before crizotinib treatment revealed the presence of the ALK fusion (A) plus the F1174L-cis-S1189C mutation (B). NGS analysis after crizotinib and ceritinib treatment revealed the presence of the ALK fusion (C) plus the F1174L-cis-S1189C mutation (D). (E) ALK structure retrieved from PDB 2XP2. In silico mutagenesis of human ALK binding to three ALK inhibitor complexes (PDB ID: 2XP2, PDB ID: 4MKC, and PDB ID: 3AOX) was used to predict the variable influence on protein stability. The dStability and relative thermostability of the mutation with respect to the wild-type protein are shown in the table.
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TTF-1, and Ki-67 was positive (Figures 2A-E). The presence of EML4-ALK gene fusion and an ALK exon 23 F1174L and S1189C mutation was identified by targeted next-generation sequencing (Figures 3A,B; Supplementary Methods). Afterward, due to the progression of the tumor during treatment (Figure 1D), the patient underwent a rebiopsy and NGS analysis on 24 July 2019, and the result still showed EML4-ALK fusion and the F1174L-cis-S1189C mutation (Figures 2F, 3C,D).