Dataset Information

Partial response to pralsetinib in an advanced pulmonary sarcomatoid carcinoma patient harboring a KIF5B-RET rearrangement: a case report.

ABSTRACT:

Background

Pulmonary sarcomatoid carcinoma (PSC) is a rare and unconventional non-small-cell lung cancer (NSCLC) that appears to be aggressive, with a poor prognosis and response to conventional treatment. Approximately 30% of PSCs have potentially targetable genomic alterations, but few studies have involved RET gene fusions, and corresponding targeted therapies are lacking.

Case presentation

In this report, we describe a patient with PSC harboring a KIF5B-RET gene fusion who was initially diagnosed with stage IVb lung cancer. Due to the poor performance status, the patient was unable to tolerate any radiotherapy or chemotherapy. Based on the next-generation sequencing (NGS) result of RET gene fusion, the patient was treated with pralsetinib. Two months after the treatment, the patient achieved a partial response.

Conclusions

Our case indicates that RET is one of the main driver oncogenes of PSC and provides useful information for precise RET inhibitor administration in the future. Thus, the use of comprehensive genomic profiling may provide important treatment options for PSC.

SUBMITTER: Wu Y

PROVIDER: S-EPMC9724403 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Partial response to pralsetinib in an advanced pulmonary sarcomatoid carcinoma patient harboring a KIF5B-RET rearrangement: a case report.

Wu Ying Y Yan Zhecheng Z Pan Juan J Chang Xiaona X Huang Bo B Luo Danju D Meng Rui R Shi Heshui H Fan Jun J Nie Xiu X

World journal of surgical oncology 20221206 1

<h4>Background</h4>Pulmonary sarcomatoid carcinoma (PSC) is a rare and unconventional non-small-cell lung cancer (NSCLC) that appears to be aggressive, with a poor prognosis and response to conventional treatment. Approximately 30% of PSCs have potentially targetable genomic alterations, but few studies have involved RET gene fusions, and corresponding targeted therapies are lacking.<h4>Case presentation</h4>In this report, we describe a patient with PSC harboring a KIF5B-RET gene fusion who was ...[more]

PMID: 36471407

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Project description:BackgroundPulmonary sarcomatoid carcinoma (PSC) is a rare disease which is highly malignant with a poor prognosis. PSC is highly resistant to chemotherapy and radiotherapy and is prone to recurrence even after surgery. Most of what is known about PSC comes from limited single-center, retrospective studies. There is still no standard international clinical guideline for PSC. Limited case reports have shown that PSC patients with driver gene mutations and high programmed death-ligand 1 (PD-L1) expression have good responses to molecular targeted therapy and immune checkpoint inhibitor (ICI) immunotherapy, respectively. Therefore, current first-line chemotherapy, targeted therapy and immunotherapy play a leading role in the diagnosis and treatment of advanced PSC patients.Case descriptionWe report a 42-year-old male who was diagnosed with PSC [stage IVB (T4N2M1)] and treated at our department (Department of Radiation Oncology, The Affiliated Hospital of Soochow University). The initial computed tomography (CT) scan of the chest showed a large mass (159 mm × 112 mm) which on needle biopsy showed sarcomatoid carcinoma histology. The patient received 8 cycles of abraxane plus cisplatin chemotherapy combined with anlotinib and immunotherapy, followed by immunotherapy and anlotinib for >1 year. Finally, the local tumor was well controlled, and no obvious drug-related adverse reactions were observed. The large lesions in the lung remained in complete response for >24 months.ConclusionsTo our knowledge, this is the first reported case of an advanced PSC patient showing a good response to the treatment consisting of anlotinib combined with sintilimab and platinum-doublet chemotherapy. This case suggests that chemotherapy combined with antiangiogenic therapy and immunotherapy may benefit patients with advanced PSC. Long-term immunotherapy and anlotinib maintenance therapy has been safe and effective in our case. However, randomized controlled clinical studies are needed to confirm the efficacy and safety of these treatment options.

Project description:KIF5B-RET gene rearrangement occurs in ~1% of lung adenocarcinomas. Recently, targeted agents that inhibit RET phosphorylation have been evaluated in several clinical studies; however, little is known about the role of this gene fusion in driving lung cancer. Immunohistochemistry was used to evaluate the expression of the FOXA2 protein in tumor tissues of patients with lung adenocarcinoma. KIF5B-RET fusion cells proliferated in a cohesive form and grew tightly packed with variable-sized colonies. The expression of RET and its downstream signaling molecules, including p-BRAF, p-ERK, and p-AKT, increased. In KIF5B-RET fusion cells, the intracellular expression of p-ERK was higher in the cytoplasm than in the nucleus. Two transcription factors, STAT5A and FOXA2, exhibiting significantly different expressions at the mRNA level, were finally selected. p-STAT5A was highly expressed in the nucleus and cytoplasm, whereas the expression of the FOXA2 protein was lower; however, it was much higher in the nucleus than in the cytoplasm. Compared with the expression of FOXA2 in the RET rearrangement-wild NSCLC (45.0%), high expression (3+) were observed in most RET rearrangement NSCLCs (94.4%). Meanwhile, KIF5B-RET fusion cells began to increase belatedly from day 7 and only doubled on day 9 in 2D cell culture. However, tumors in mice injected with KIF5B-RET fusion cells began to rapidly increase from day 26. In cell cycle analyses, the KIF5B-RET fusion cells in G0/G1 were increased on day 4 (50.3 ± 2.6%) compared with the empty cells (39.3 ± 5.2%; P = 0.096). Cyclin D1 and E2 expressions were reduced, whereas CDK2 expression slightly increased. pRb and p21 expression was diminished compared with the empty cells, TGF-β1 mRNA was highly expressed, and the proteins were accumulated mostly in the nucleus. Twist mRNA and protein expression was increased, whereas Snail mRNA and protein expression was decreased. Particularly, in KIF5B-RET fusion cells treated with FOXA2 siRNA, the expression of TGF-β 1 mRNA was remarkably reduced but Twist1 and Snail mRNA were increased. Our data suggest that cell proliferation and invasiveness in KIF5B-RET fusion cells are regulated by the upregulation of STAT5A and FOXA2 through the continuous activation of multiple RET downstream signal cascades, including the ERK and AKT signaling pathways. We found that TGF-β1 mRNA, where significant increments were observed in KIF5B-RET fusion cells, is regulated at the transcriptional level by FOXA2.

Dataset Information

Partial response to pralsetinib in an advanced pulmonary sarcomatoid carcinoma patient harboring a KIF5B-RET rearrangement: a case report.

Background

Case presentation

Conclusions

Publications

Partial response to pralsetinib in an advanced pulmonary sarcomatoid carcinoma patient harboring a KIF5B-RET rearrangement: a case report.

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