Identication of A Novel FRK-ROS1 Fusion Variant in Advanced Non-Small Cell Lung Cancer with Brain Metastases and Remarkable Response to Crizotinib

ROS1-rearranged non-small cell lung cancer (NSCLC) is a subset of NSCLC patients with unique malignant behavior and clinical course. Crizotinib, a multi-targeted ALK/ROS1/MET tyrosine kinase inhibitor (TKI), has promising signicant activity in NSCLC with ROS1-rearrangement. The next-generation sequencing (NGS) is commonly used to identify the “druggable” genetic alterations in clinical practice. We identied a novel ROS1 fusion variant (FRK-ROS1) in a de novo stage IV NSCLC patient by NGS testing. This novel ROS1-rearrangement is generated by the fusion FRK to ROS1. The patient was remarkably responsive to crizotinib including the brain metastasis. A 29-year-old male never-smoker with chief complaints of back pain with a lumpy and aky soft tissue mass in the upper right lobe of the lung and diffuse ground-glass shadow in both lungs e IV (cT 4 N 3 M 1b ). A CT-guided biopsy revealed the predominant adenocarcinoma and partial mucinous adenocarcinoma. By using next-generation sequencing (NGS) assay, we found that the tumor had FRK-ROS1 fusion rather than other actionable mutations. In that case, the patient took the rst-line crizotinib and experienced a remarkable tumor response to it and tolerance well until written. FRK-ROS1 is a novel ROS1 fusion variant in NSCLC identied by NGS testing and the rst-line crizotinib showed excellent performance in all lesions including the brain metastasis.

predominant adenocarcinoma and partial mucinous adenocarcinoma. By using next-generation sequencing (NGS) assay, we found that the tumor had FRK-ROS1 fusion rather than other actionable mutations. In that case, the patient took the rst-line crizotinib and experienced a remarkable tumor response to it and tolerance well until written. FRK-ROS1 is a novel ROS1 fusion variant in NSCLC identi ed by NGS testing and the rst-line crizotinib showed excellent performance in all lesions including the brain metastasis.

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Nowadays, ROS1 rearrangement represented a unique pattern in about 1%-2% of patients with NSCLC [1]. Crizotinib, a tyrosine kinase inhibitor targeting ROS1, ALK, and MET, has become the standard rst-line therapy in this population [5]. Other ROS1 targeted drugs are emerging but varying levels of effectiveness, such as entrectinib, lorlatinib, ceritinib, TPX-0005, DS-6051b, and cabozantinib [6][7][8][9][10][11]. However, brain metastasis has been found not very sensitive to crizotinib treatment probably due to its poor penetration of the blood-brain barrier (BBB) [12][13]. Here, we reported FRK-ROS1 fusion as a novel ROS1 fusion variant in non-small lung cancer (NSCLC). Meanwhile, the excellent well-control of all lesions including BM by crizotinib and the response lasted at least 8.0 months in this de novo stage IV NSCLC patient with ROS1 fusion.
The patient is a 29-year-old male never-smoker with chief complaints of back pain for 3 days and cough for 1 day charged in hospital on Sep 20th, 2019. No family history of cancer or any other special disease has been tract. Physical examination revealed the reduced respiratory sound of the right lung. The levels of serum tumor markers of CEA and NSE were elevated to 25.46 ng/ml and 18.56 ng/ml, respectively.
Chest computed tomography (CT) revealed a lumpy and aky soft tissue mass in the upper right lobe of the lung and diffuse ground-glass shadow in both lungs ( Figure 1A). MR-PET found the suspicious pulmonary lesion as above, multiple metastatic lesions in the lungs, and lumbar spine. A CT-guided biopsy revealed the predominant adenocarcinoma and partial mucinous adenocarcinoma ( Figure 2). The contrast-enhanced MR images depicted a metastatic lesion in his left frontal lobe. No evidence of the super cial lymphadenopathy or adrenal glands metastasis by ultrasound examination. The primary tumor tissue biopsy has been delivered for NGS testing that the FRK-ROS1 fusion and abnormal alterations of CDKN2A, CDKN2B, and BCL2L11 were found (Figure 3). The initial diagnosis was stage IV (cT 4 N 3 M 1b ) NSCLC with multiple metastases in the lungs, brain, lymph nodes, and lumbar spines. This patient was treated with crizotinib (250 mg/twice daily) as rst-line therapy from Oct 8th, 2019 until now (July 2020). After administration of crizotinib for 1.0 month, his primary tumor achieved partial response (PR) con rmed by CT scans ( Figure 1B)

according to Response Evaluation Criteria in Solid Tumors
(RECIST) standard (version 1.1) [14]. Of note, the BM lesion was also detected remarkably shrink just after 2.0 months of crizotinib treatment and BM is controlled until now without radiation intervention.
Meanwhile, he tolerated crizotinib well and no severe adverse event has been reported, including abnormal hepatic and renal dysfunction, visual disorders, gastrointestinal disturbances, cardiac and endocrine abnormalities. Until recently, his disease has no clinical sign of progress and remained as PR for almost 8.0 months and tolerated well with crizotinib as the rst-line therapy.
In patients with NSCLC, ROS1 fusion is featured by mutually exclusive to ALK-rearranged and patients tend to be younger, never-smokers, and histology of adenocarcinoma [2]. Identi cation of the fusion partners to ROS1 is the key to locating NSCLC patients for effective target therapy. More than 50 fusion partners have been reported for ROS1 in NSCLC, including CD74, EZR, SLC34A2, GOPC, TMEM106B, ADGRG6, and others [16][17][18]. The protein encoded by the FRK gene belongs to the tyrosine kinase receptor family of protein kinases which is a nuclear protein [2]. Functionally FRK has played a role as a tumor suppressor by negatively regulating cell proliferation and positively regulating PTEN protein stability [19]. So far, the FRK-ROS1 fusion has not been reported in NSCLC but as the potential oncogenic activating the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway causing the occurrence of the in ammatory hepatocellular adenomas (IHCAs) [20].
About 60-80% of advanced ROS1 fusion NSCLC patients respond to crizotinib as the rst-line therapy [20], but 23.3% of patients will develop brain metastasis as the most frequent site of initial crizotinib failure [12,21]. The mechanism of crizotinib resistance in BM is considered as the poor penetration of crizotinib into the central nervous system [13]. By now, some of ROS1 fusion targeted drugs may have shown intracranial activities, such as entrectinib, lorlatinib, and repotrectinib (TPX-0005) [22]. One recent study compared the crizotinib or pemetrexed-based chemotherapy in ROS1 fusion NSCLC patients with BM and chemotherapy seemed to have better BM control than crizotinib for unknown reason [20]. Active surveillance of brain imaging during crizotinib treatment and exploration of next-generation ROS1 inhibitors featured by higher BBB penetration is warranted.
Altogether, this case provided the clinical evidence for FRK-ROS1 as a novel ROS1 fusion variant with a remarkable response to crizotinib in de novo advanced ROS1 fusion patients with brain metastasis. Figure 1 Computed tomography (CT) scans show: before crizotinib therapy (A); CT of the chest showed partial response after one months of crizotinib (B).