SMARCA4-deficient epithelioid sarcoma revealed by comprehensive genomic profiling, leading to a notable response by...

A 50-year-old man presented with a bulky mass in the left thigh and was referred to our department. He showed an impaired Eastern Cooperative Oncology Group performance status of 3 due to swelling of the left thigh and pain. Imaging analysis revealed a large mass measuring 16 cm in the left thigh and right forearm, along with the bilateral adrenal gland, right lung, right axillary lymph nodes, liver, and left femur. Despite additional tests, including pathological examination, the primary origin of the tumors could not be identified. Because of the rapid tumor progression, he was placed on nivolumab (NIVO; 240 mg/body, every 2 weeks) monotherapy based on the diagnosis of cancer of unknown primary, unfavorable type. Simultaneous comprehensive genomic profiling (CGP) test revealed a high tumor mutation burden (15.69 Muts/Mb) and a truncating mutation of SMARCA4, along with loss of BRG1 expression detected by additional immunohistochemical (IHC) analysis. Based on the predominance of soft tissue in the lesion, histological and IHC findings, and genomic phenotype, the patient was finally re-diagnosed with SMARCA4-deficient, SMARCB1/INI-1-preserved epithelioid sarcoma (ES). He showed a dramatic improvement in physical and laboratory findings at 5 weeks after the initial NIVO dose. Although he experienced immune-related adverse events, such as liver dysfunction, colitis and relative adrenal failure, and severe sepsis due to pulmonary cyst infection, he was able to overcome these complications. By the 12th dose of NIVO (13 months after the initial treatment), he has exhibited a positive response to NIVO without any additional complications. Among SMARCA4-deficient tumors, there have been multiple reports on the sensitivity of SMARCA4-deficient thoracic tumors to immune checkpoint inhibitors (ICIs), including PD-1 blockade agents. This case indicates that SMARCA4-deficient SMARCB1/INI-1-preserved ES may share molecular pathological characteristics with SMARCA4-deficient thoracic tumors, given their similar sensitivity to ICIs. In addition, CGP may play an important role in hypothesizing the primary site of tumors and guiding treatment selection for rare cancers, as in the present case, which lacks established treatment options. Further data accumulation is essential to validate this approach.