ALK and ROS1 Double-Rearranged Lung Squamous Cell Carcinoma Responding to Crizotinib Treatment: A Case Report Qiong Li, MD, Jian Wu, MD, PhD, Li-Xu Yan,

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ALK and ROS1 Double-Rearranged Lung Squamous Cell Carcinoma Responding to Crizotinib Treatment: A Case Report Qiong Li, MD, Jian Wu, MD, PhD, Li-Xu Yan, MD, PhD, Jun-Wei Huang, MD, Zhou Zhang, PhD, Jin-E Zhang, MD, Xing-Lin Gao, MD, PhD, Ze-Ru Luo, MD, Jing Liu, PhD, Shi-Fang Yang, MD, PhD, Yan-Hui Liu, MD, PhD Journal of Thoracic Oncology Volume 12, Issue 12, Pages e193-e197 (December 2017) DOI: 10.1016/j.jtho.2017.08.021 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Histopathological and immunohistological findings of the primary lung (A–C) and metastatic pleural (D and E) tumor tissue samples. (A and D) Hematoxylin and eosin staining showed a moderately differentiated squamous cell carcinoma (original magnification, ×400). (B, C, E, and F) Immunostaining for p63 and anaplastic lymphoma kinase. (B and E) The tumor was strongly positive for p63 (N/A rabbit immunoglobulin G [Biocare Medical, Concord, CA]) (400X). (C and F) ALK receptor tyrosine kinase gene (ALK) rearrangement was suggested by positive immunostaining using ALK (D5F3) CDx assay (Ventana Medical Systems, Tucson, AZ) (original magnification, ×400). Expression of CK5/6 and p40 and no expression of thyroid transcription factor-1, napsin A, or neuroendocrine markers was observed (staining not shown). Journal of Thoracic Oncology 2017 12, e193-e197DOI: (10.1016/j.jtho.2017.08.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Next-generation sequencing (NGS) findings of testing of the primary lung and metastatic pleural tumor tissue samples. (A) The Integrative Genomics Viewer screenshots show that chimeric reads by NGS indicate ALK receptor tyrosine kinase gene (ALK) and ROS1 double rearrangement. ROS1 genes were rearranged with two partners, with 5′ of ROS1 joined to 16 kilobases upstream of regulatory factor X6 gene (RFX6) and 3′ of ROS1 joined to 4 kilobases downstream of G protein–coupled receptor class C group 6 member A gene (GPRC6A). (B) Comparison of NGS mutation profiling between the primary and the metastastic tumor. The percentages represent the mutation allele fraction. EML4, echinoderm microtubule associated protein like 4 gene; AF, allele fraction; CN, copy number; PTEN, phosphatase and tensin homolog gene; STAG2, stromal antigen 2 gene; CTNNA1, catenin alpha 1 gene; ARID2, AT-rich interaction domain 2 gene; FANC1, Fanconi anemia complementation group 1 gene; MYC, v-myc avian myelocytomatosis viral oncogene homolog gene; NFE2L2, nuclear factor erythroid 2, like 2 gene; EMSY, EMSY, BRCA interacting transcriptional repressor gene; PMS2, PMS1 homolog 2, mismatch repair system component gene; DAXX, death domain associated protein gene; PALB2, partner and localizer of BRCA2 gene. Journal of Thoracic Oncology 2017 12, e193-e197DOI: (10.1016/j.jtho.2017.08.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 The dynamic evolution of the patient's primary lung tumor (A₁–E₁) and metastases (A₂–E₂) after crizotinib treatment. (A) The baseline chest computed tomography (CT) scan (November 5, 2015) showing a 6×7 cm mass in the inferior lingular segment of the left upper lobe of the lung (A₁), and showing pleural tumors in the lower lobe of the lung and small pleural effusion (A₂). (B) Positron emission tomography/CT scan after 5 weeks of crizotinib treatment (December 18, 2015). The lesion of the primary lung tumor was obviously smaller (from 6×7 cm to 2.6×2.4 cm), and there was a distinct reduction in radiopharmaceutical uptake (maximum standardized uptake decreased from 21.7 to 2.0) compared with on October 3, 2015 (B₁). The left pleural lesions disappeared and left pleura radiopharmaceutical uptake was completely absent (B₂). (C) Chest CT scan after 3 months of crizotinib treatment (February 18, 2016). The primary tumor continued to decrease (C₁). Multiple nodules occurred in the pleura of left lower lobe of the lung, with the largest one at 20×22 mm (C₂). (D) Chest CT scan after 5 months of crizotinib treatment (April 19, 2016). No obvious change in the primary tumor compared with on February 18, 2016 (D₁). Multiple nodules in the pleura of the left lower lobe progressed, with the largest one at 46×32 mm (D₂). (E) Chest CT scan before death (September 22, 2016): No change in the primary tumor (E₁). Extensive metastases including pleural and liver tumor lesions occurred in the patient (E₂). Journal of Thoracic Oncology 2017 12, e193-e197DOI: (10.1016/j.jtho.2017.08.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 The clinical course of the diagnosis and treatment of the patient. On October 31, 2015, the patient's positron emission tomography/CT scan suggested a left lung tumor and left pleural metastases; On November 5, 2015, she underwent CT-guided lung biopsy. On November 11, 2015, she started crizotinib treatment. On December 18, 2015 (after 5 weeks of crizotinib treatment), positron emission tomography/CT showed a dramatic reduction in the size and the radiopharmaceutical uptake in the mass, disappearance of the pleural metastases, and partial disappearance of the mediastinal lymph nodes. On April 22, 2016, she underwent a second biopsy of the pleural metastasis in the posterior basal segment of the left lower lobe. On April 26, 2016, she underwent an ablation of the left lower pleural metastases. On May 26, 2016, she switched to gemcitabine plus paclitaxel chemotherapy for two cycles in the local hospital and died on September 30, 2016. PR, partial response; PD, progressive disease. Journal of Thoracic Oncology 2017 12, e193-e197DOI: (10.1016/j.jtho.2017.08.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions