Treatment of Thoracic SMARCA4-Deficient Undifferentiated Tumors: Where We Are and Where We Will Go

Abstract

Recently, the fifth edition of the WHO classification recognized the thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) as a separate entity from conventional non-small cell lung cancer with SMARCA4 deficiency because of the different clinicopathological characteristics of these two diseases. SMARCA4-UT mainly occurs in young to middle-aged adults and involves a large mass compressing the tissues surrounding the mediastinum and lung parenchyma. Unfortunately, SMARCA4-UT shows a high probability of recurrence after upfront surgery as well as radiotherapy resistance; moreover, chemotherapy has low efficacy. Moreover, given the recent classification of SMARCA4-UT, no data concerning specific clinical trials are currently available. However, several case reports show immunotherapy efficacy in patients with this disease not only in a metastatic setting but also in a neoadjuvant manner, supporting the development of clinical trials. In addition, preclinical data and initial clinical experiences suggest that inhibiting pathways such as CDK4/6, AURKA, ATR, and EZH2 may be a promising therapeutic approach to SMARCA4-UT.

A Rare Case of Thoracic SMARCA4-Deficient Undifferentiated Tumor With Diffuse Brain Metastasis

“…The above findings confirm the diagnosis of SMARCA4-UT, given the poorly differentiated morphology and the lack of expression of BRG1. Positive expression of SOX2 and synaptophysin are common findings of this tumor and support the diagnosis [ 2 , 8 , 10 ].…”

“…Other findings that support this diagnosis include loss of BRM, negative claudin-4, and positive expression of SOX2, CD34, and SALL4 [ 2 - 3 , 9 ]. Synaptophysin is also commonly found to be positive in these tumors in up to 70% of cases [ 8 , 10 ]. The SMARCA4 gene located on chromosome 19p encodes the BRG1 protein, one of the two mutually exclusive catalytic subunits of the mammalian SWI/SNF ATP-dependent chromatin remodeling complex [ 12 ].…”

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

“…The most commonly mutated genes in SMARCA4-UT were TP53 , STK11 , KEAP1 , and KRAS ( 24 ). Although ALK mutations have been reported in some cases, EGFR mutations typically observed in NSCLC have not been reported in SMARCA4-UT ( 5 ). Currently, there are no highly effective targeted drugs available.…”

“…Typically diagnosed at advanced stages, SMARCA4-UT often extensively involves thoracic structures and metastasizes to the lymph nodes, bones, and adrenal glands ( 2 , 4 ). Although radiotherapy and chemotherapy have limited efficacy, immunotherapy is effective in these patients ( 5 – 8 ). However, the lack of definitive treatment guidelines and scarcity of reported cases, especially those suitable for surgery, pose challenges in the diagnosis and management of SMARCA4-UT.…”

Successful treatment with tislelizumab plus chemotherapy for SMARCA4-deficient undifferentiated tumor: a case report

“…SMARCA4-dUT was initially defined as SMARCA4-dTS, originally discovered in 2015 by Le Loarer et al (11) by RNA sequencing of unclassified sarcomas, and subsequently classified as a new type of undifferentiated lung malignancy of pulmonary epithelial origin. Thoracic SMARCA4-dUT exhibits consistent immunohistochemical loss of both SMARCA4 and SMARCA2 (12). In addition, this tumor frequently displays the robust expression of one or more stem cell markers, such as SOX2, CD34, and SALL4, which can facilitate the differential diagnosis of SMARCA4-deficient non-small cell lung cancer (NSCLC) (SMARCA4-dNSCLC), typically negative for these markers (13,14).…”