Molecular and Treatment Characteristics of SMARCB1 or SMARCA4-Deficient Undifferentiated Tumor: Retrospective Case Series

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Cancer Res Treat. 2024;56(3):967-971

Publication date (electronic) : 2024 February 13

doi : https://doi.org/10.4143/crt.2023.1308

Hyeon Gyu Kang¹, Jiwon Koh², Tae Min Kim³, Doo Hee Han⁴, Tae-Bin Won⁴, Dong-Wan Kim³, Dong-Young Kim⁴, Bhumsuk Keam^,3

¹Seoul National University College of Medicine, Seoul, Korea

²Department of Pathology, Seoul National University Hospital, Seoul, Korea

³Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

⁴Department of Otorhinolaryngology, Seoul National University Hospital, Seoul, Korea

Correspondence: Bhumsuk Keam, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: 82-2-2072-7215 Fax: 82-2-2072-7379 E-mail: bhumsuk@snu.ac.kr

Received 2023 December 11; Accepted 2024 February 9.

Abstract

Introduction

The SWI/SNF chromatin remodeling complexes regulate DNA transcription and have roles in DNA-damage repair. They act as tumor suppression genes due to their ability to suppress the development of certain cancers when functioning properly, as mutations in these complexes can contribute to cancer initiation and progression [1]. The loss of SMARCB1 or SMARCA4 subunits of SWI/SNF complexes, found in rare cases of sinonasal or thoracic cancer, has been recognized as a significant finding that makes the nature of this cancer more aggressive and the prognosis worse. Early detection and initiation of induction chemotherapy may help improve the prognosis [2,3]. Various regimens of chemotherapy and multimodality treatments are being explored. However, the absence of a standard therapy regimen remains a challenge [4,5]. Furthermore, the impact of genetic variants in cancer cells on therapy outcomes is not well known. Here, we reported our cases of SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor with next-generation sequencing (NGS) data. The objective of this study was to investigate potential directions for optimizing treatment and improving the prognosis of this challenging disease.

Case Report

Six patients with SMARCB1 or SMARCA4-deficient sinonasal carcinoma and three patients with SMARCA4-deficient thoracic undifferentiated tumor were diagnosed from 2021 to 2023. Detailed clinicopathologic features were summarized in Table 1. The deficiency of SMARCB1 or SMARCA4 was defined by NGS or immunohistochemistry (IHC) of SMARCB1 (INI-1) or SMARCA4 (BRG1) loss. Patient 1, 2, and 3 received a surgery. For the unresectable cases, definitive concurrent chemoradiotherapy with or without induction chemotherapy was done. In the case of patient 4 and 6, cisplatin treatment suppressed the disease progression. Patient 1 and 2 who had been diagnosed as olfactory neuroblastoma got the revision of the diagnosis after IHC revealing BRG1 loss. NGS was conducted in five patients. Patient 9, who exhibited CD274 gene amplification and was associated with a programmed death-ligand 1 (PD-L1) IHC positivity (22C3, Tumor Proportion Score 90%), experienced a favorable prognosis when treated with an immune checkpoint inhibitor (ICI), durvalumab. This CD274-amplified patient showed partial response and progression free survival of more than 17 months (Fig. 1).

Table 1.

Clinicopathological features of patients with SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor including next-generation sequencing data

Fig. 1.

Clinical response to durvalumab in CD274-amplified patient with SMARCA4-deficient thoracic undifferentiated tumor. Initial computed tomography (CT) image before therapy (A). CT image after concurrent chemoradiation (B). Follow-up CT image after treating with consolidation durvalumab 13 cycles (C).

Discussion

In our case series, SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor presented the advanced stage when initially diagnosed, and showed the rapid progression leading to a poor prognosis. However, some patients, especially with CD274 (PD-L1) amplification, showed a good response to ICI, suggesting that ICI could be a treatment option for this rare disease. We could diagnose the deficiency of SMARCB1 or SMARCA4 using NGS or IHC of INI-1 or BRG1.

When the patients were diagnosed as locally advanced setting, multi-disciplinary treatments including surgery, radiation therapy, chemotherapy and ICI were important. Within this group, a subset of patients achieved no evidence of disease. Although another case series reported that patients with SMARCA4-deficient sinonasal carcinoma experienced poor outcomes following surgery [6], our patients who underwent upfront surgery displayed a favorable prognosis compared to others. Adjuvant radiation therapy after surgery potentially contributed to improved overall survival [7].

Taxane in combination with platinum was the preferred regimen in our case series, similar to the major treatment option for sinonasal malignancies in other studies [8]. Some studies demonstrated the resistance to chemotherapy and radiation therapy, especially the ineffectiveness of platinum therapy for SMARCA4-deficient undifferentiated tumor [9,10]. In our case series, several patients showed the insensitivity to these therapies, while a subset of the patients exhibited clinical responses. Additionally, we observed promising effects of ICI in some cases [11-13], with two patients receiving this therapy displaying contrasting responses. In NGS findings, most patients showed negative microsatellite instability and low tumor mutation burden, indicating a lower likelihood of responding to ICI. However, one patient exhibited CD274 amplification with PD-L1 overexpression and displayed the response to ICI. Notably, CD274 amplification in cancer cells might indicate the sensitivity to ICI, making this finding significant for guiding therapeutic planning and potentially leading to a more favorable prognosis [14,15].

Nevertheless, given the limited sample size of our report and the lack of data such as NGS study only conducted on a subset of the patients, it is essential to conduct further in-depth studies with a larger sample size to validate and elucidate the nature of this rare disease fully.

In conclusion, due to the potential implications of SMARCB1 or SMARCA4 loss in sinonasal or thoracic cancer, it is crucial to gain a comprehensive understanding of the underlying pathophysiology and consider prompt evaluation using IHC or NGS techniques. NGS, in particular, allows for the identification of several key gene variations, such as PD-L1 amplification, which can significantly impact the efficacy of the therapy. This knowledge can aid in tailoring the most optimal treatment regimen for each patient, ultimately leading to improved therapeutic outcomes.

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