Response to Crizotinib in a Patient with Metastatic Lung Spindle Cell Carcinoma Harboring TPM3-ROS1 Fusion
Lung spindle cell carcinoma (SpCC), a rare histological subtype of sarcomatoid carcinoma, is characterized by malignant spindle-shaped tumor cells with aggressive clinical behavior. Due to its rarity, limited data exist on the molecular profile and targeted therapy options for this malignancy. This case report highlights the clinical course of a patient with metastatic lung SpCC harboring a TPM3-ROS1 fusion who demonstrated a sustained response to crizotinib, a tyrosine kinase inhibitor (TKI) targeting ROS1.
Clinical Presentation and Diagnostic Workup
A 72-year-old Chinese male, a non-smoker with no family history of cancer, presented with progressive cough, dyspnea, and intermittent fever. Initial imaging studies revealed a right upper lobe lung mass (18 × 15 mm) with mediastinal lymphadenopathy, pleural invasion, left adrenal gland metastasis, and a right cerebellar hemisphere lesion [Figure 1A–C]. A CT-guided core needle biopsy of the lung mass confirmed spindle-shaped tumor cells with necrosis and lymphocytic infiltration [Figure 1D–E]. Immunohistochemical staining showed positivity for pan-cytokeratin AE1/AE3, vimentin, thyroid transcription factor 1 (TTF-1), and a high Ki-67 index (70%), while markers for smooth muscle actin, desmin, ALK, and others were negative. Tumor cells were also identified in pleural effusion cytology [Figure 1F], confirming stage IV SpCC (ECOG performance score: 3).
Molecular Profiling and Treatment Initiation
Plasma circulating tumor DNA (ctDNA) and tissue biopsy analyses via next-generation sequencing (NGS) identified a TPM3-ROS1 fusion (exon 7 of TPM3 fused to exon 31 of ROS1) with an allele frequency of 37.9%. No ALK rearrangements or other actionable mutations (e.g., EGFR, KRAS, BRAF) were detected. Based on the presence of the ROS1 fusion, the patient was started on crizotinib (250 mg twice daily) in December 2017.
Treatment Response and Disease Course
Within one month of crizotinib therapy, the patient experienced significant symptomatic improvement. Follow-up imaging at four months revealed a partial response (PR) in the lung primary lesion, mediastinal lymph nodes, and left adrenal metastasis, with near-complete resolution of pleural effusion [Figure 1G–I]. However, at six months, mild progression of the cerebellar metastasis and elevated serum carcinoembryonic antigen (CEA) were noted. Whole-brain radiotherapy and bevacizumab (750 mg every 3 weeks) were added to address intracranial progression and prevent systemic relapse. The patient achieved PR for brain lesions and maintained stable lung disease for 13 months on crizotinib. By the 13-month follow-up, a slight elevation in cytokeratin fragment 21-1 (CYFRA 21-1) prompted a repeat ctDNA analysis, which showed no resistance mutations (e.g., ROS1 G2032R) or new genomic alterations. The patient subsequently enrolled in a clinical trial for lorlatinib, a third-generation ALK/ROS1 TKI, with ongoing evaluation of efficacy.
Molecular and Therapeutic Implications
The TPM3-ROS1 fusion drives oncogenesis by constitutively activating ROS1 tyrosine kinase signaling, promoting cell proliferation and survival. TPM3, an actin-binding protein, may enhance tumor invasiveness through cytoskeletal remodeling. In non-small cell lung cancer (NSCLC), ROS1 fusions occur in 1–2% of cases, with CD74-ROS1 being the most common variant. While ROS1 fusions are well-characterized in NSCLC, this case represents the first documented instance in lung SpCC, expanding the molecular spectrum of this rare carcinoma.
Crizotinib, a first-generation ALK/ROS1/MET inhibitor, has demonstrated robust efficacy in ROS1-rearranged NSCLC, with objective response rates (ORR) of 72% and median progression-free survival (mPFS) of 19.2 months. The sustained response in this patient aligns with these findings, underscoring the potential utility of crizotinib in ROS1-positive SpCC. However, intracranial progression—attributed to poor blood-brain barrier penetration of crizotinib—highlights the need for adjunctive therapies like radiotherapy or next-generation TKIs with enhanced CNS activity.
Resistance Mechanisms and Future Directions
Acquired resistance to crizotinib in ROS1-driven cancers often involves kinase domain mutations (e.g., G2032R) or bypass signaling pathways. In this case, the absence of resistance mutations on liquid biopsy suggests alternative mechanisms, such as tumor heterogeneity or ctDNA detection limitations. Lorlatinib, a brain-penetrant TKI, may overcome resistance in crizotinib-refractory cases, though clinical data remain preliminary.
Conclusion
This case illustrates the importance of comprehensive molecular profiling in rare malignancies like lung SpCC. The identification of a TPM3-ROS1 fusion enabled targeted therapy with crizotinib, resulting in prolonged disease control and improved quality of life. While intracranial progression necessitated multimodal management, the systemic response underscores the relevance of ROS1-directed therapy in SpCC. Future studies should explore the prevalence of ROS1 fusions in sarcomatoid carcinomas and evaluate next-generation TKIs to address resistance and CNS dissemination.
doi.org/10.1097/CM9.0000000000000556
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