The golden key to open mystery boxes of SMARCA4-deficient undifferentiated thoracic tumor: focusing immunotherapy, tumor microenvironment and epigenetic regulation

Abstract

SMARCA4-deficient undifferentiated thoracic tumor is extremely invasive. This tumor with poor prognosis is easily confused with SMARCA4-deficent non-small cell lung cancer or sarcoma. Standard and efficient treatment has not been established. In this review, we summarized the etiology, pathogenesis and diagnosis, reviewed current and proposed innovative strategies for treatment and improving prognosis. Immunotherapy, targeting tumor microenvironment and epigenetic regulator have improved the prognosis of cancer patients. We summarized clinicopathological features and immunotherapy strategies and analyzed the progression-free survival (PFS) and overall survival (OS) of patients with SMARCA4-UT who received immune checkpoint inhibitors (ICIs). In addition, we proposed the feasibility of epigenetic regulation in the treatment of SMARCA4-UT. To our knowledge, this is the first review that aims to explore innovative strategies for targeting tumor microenvironment and epigenetic regulation and identify potential benefit population for immunotherapy to improve the prognosis.

A case of surgically treated non-metastatic SMARCA4-deficient undifferentiated thoracic tumor: a case report and literature review

“…Sanger sequencing, although accurate and low-throughput, is expensive and time-consuming for large-scale sequencing. Therefore, a combined approach using both immunohistochemistry and NGS is recommended for diagnosing SMARCA4-UT, with Sanger sequencing as a verification tool if needed ( 1 ).…”

“…Moreover, CD34, Sox2, and Syn are frequently expressed in SMARCA4-UT cells ( 16 , 17 ). Therefore, for a young male heavy smoker presenting with a large undifferentiated or poorly differentiated chest tumor, clinicians should consider the possibility of SMARCA4-UT ( 1 ).…”

“…Radical surgery is the preferred method for treating malignant tumors; however, SMARCA4-UT often shows local invasion and distant metastasis, making only a few early stage patients eligible for surgery. Although initial surgery has been reported to extend overall survival (OS), the benefits may not be significant, and rapid tumor recurrence post-surgery is common ( 1 ). In the present case, adjuvant therapy was recommended based on the postoperative clinical staging, but the patient declined further treatment.…”

“…For instance, the 6-month non-progression rate was 40% in patients with TLS-positive SMARCA4-UT, as opposed to only 4.2% in all patients ( 7 ). Patients who receive first-line ICI therapy generally exhibit longer median OS and progression-free survival compared to those who receive ICI therapy in later lines or not at all ( 1 ). Some cases have demonstrated the effectiveness of immunotherapy as a neoadjuvant treatment, resulting in radical tumor resection and a complete pathological response ( 20 ).…”

“…SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT) is a rare malignant tumor characterized by inactivation of the SMARCA4 gene and the presence of undifferentiated or rhabdoid morphology in the tissue. Previously known as SMARCA4-deficient thoracic sarcoma ( 1 ), SMARCA4-UT is associated with smoking and displays unique clinical and pathological features ( 2 ). The World Health Organization categorizes SMARCA4-UT in the other lung epithelial tumors’ group ( 3 ).…”