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

Hyeon Gyu Kang; Jiwon Koh; Tae Min Kim; Doo Hee Han; Tae-Bin Won; Dong-Wan Kim; Dong-Young Kim; Bhumsuk Keam

doi:10.4143/crt.2023.1308

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Case Report Molecular and Treatment Characteristics of SMARCB1 or SMARCA4-Deficient Undifferentiated Tumor: Retrospective Case Series: Hyeon Gyu Kang¹, Jiwon Koh², Tae Min Kim³, Doo Hee Han⁴, Tae-Bin Won⁴, Dong-Wan Kim³, Dong-Young Kim⁴, Bhumsuk Keam^3,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2024;56(3):967-971.
DOI: https://doi.org/10.4143/crt.2023.1308
Published online: February 13, 2024

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: December 11, 2023 • Accepted: February 9, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor has aggressive nature with a poor prognosis. Patients with this disease were diagnosed by immunohistochemistry or next-generation sequencing. Those who were able to receive a surgery tended to be cured, while the others treated with chemotherapy, radiation therapy, or immune checkpoint inhibitor were often insensitive to these therapies. However, one having CD274 (PD-L1) amplification showed the response to immune checkpoint inhibitor and a good prognosis. We believed that this report could provide promising information for determining the optimal treatment option.
Key words: SMARCB1, SMARCA4, Undifferentiated tumor

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).

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.

NOTES

Ethical Statement

The study protocol was approved by the Institutional Review Board of Seoul National University Hospital (approval number: H-2307-026-1446) and was conducted in accordance with the Principles of the Declaration of Helsinki. Informed consents were waived from IRB, because this study was retrospective analysis with minimal risk.

Author Contributions

Conceived and designed the analysis: Kang HG, Keam B.

Collected the data: Kang HG, Koh J, Kim TM, Han DH, Won TB, Kim DW, Kim DY, Keam B.

Contributed data or analysis tools: Kang HG, Keam B.

Performed the analysis: Kang HG, Keam B.

Wrote the paper: Kang HG, Koh J, Kim TM, Han DH, Won TB, Kim DW, Kim DY, Keam B.

Conflicts of Interest

The authors certified that they have no conflict of interest (COI) directly related to this report. Broad information about their COI is presented.

BK received research funding from MSD, AstraZeneca, and Ono Pharmaceutical Co., Ltd., and has served as an advisor for Handok, NeoImmuneTec, Trialinformatics and ImmuneOncia outside of the current work.

TMK received consulting or advisory from Amgen, AstraZeneca/MedImmune, Bayer, Boryung, Hanmi, IMBDx, Inc., Janssen, Novartis, Regeneron, Roche/Genentech, Samsung Bioepis, Sanofi, and Takeda outside of the current work.

DWK received clinical trial research funding from Alpha Biopharma, Amgen, Astrazeneca/Medimmune, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi-Sankyo, GSK, Hanmi, Janssen, Merck, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan outside of the current work.

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).

Table 1.

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

Patient No.	Age (yr)/Sex	Diagnosis	Initial stage	IHC	Variant gene	Variant type	Variant detail	Tier	MSI	TMB_alpha	Treatment summary	CT regimen	BR	Clinical course	OS
1	47/ F	ON→SNC	pT4bNxM0	BRG1(–)	SMARCA4	SNV	Q915*	Not reported			Surgery+PO CCRT	Cisplatin	(–)	NED	10.4+
					SMARCA4	CNV	CN 1 copy
					TET2	SNV	R1451fs
2	50/M	ON→SNC	pTxN2bM0	BRG1(–)			NGS not conducted				Surgery+PORT	(–)	(–)	NED	5.6+
3	77/M	SNC	pT2N0M0	INI-1(–)			NGS not conducted				Surgery+PORT	(–)	(–)	NED	19.2+
4	76/M	SNC	cT3aN0M0	INI-1(–)			NGS not conducted				IC+dCCRT	DP	PR	CR	11.4+
4	76/M	SNC	cT3aN0M0	INI-1(–)			NGS not conducted				IC+dCCRT	Cisplatin	CR	CR	11.4+
5	86/M	SNC	cT4bN0M0	INI-1(–)	SMARCB1	CNV	CN 1 copy	D	MSS	2.13	pRT	(–)	PD	Death	10.4
6	68/M	SNC	cT4aN0M0	INI-1(–)	SMARCB1	CNV	CN 0 copy	C	MSS	7.46	IC+dCCRT	DPF	PD	AWD	3.6+
6	68/M	SNC	cT4aN0M0	P40(–)	SMARCB1	CNV	CN 0 copy	C	MSS	7.46	IC+dCCRT	Cisplatin	SD	AWD	3.6+
7	74/M	TUT	cT4N2M0/1	BRG1(–)			NGS not conducted				pCT+ICI	TC	PD	Death	3.3
				P40(–)								Pembro	PD
				PD-L1(90%)
8	52/M	TUT	cT4N2M1	BRG1(–)	SMARCA4	SNV	V318fs	D	MSS	5.33	pCT	TC	PD	death	3.4
				P40(–)	ARID1A	SNV	D179Y	C
					ARID1B	SNV	M510V	C
					POLE	SNV	Q714Q	C
					NRAS	SNV	Q61L	C
					DNMT3A	SNV	R882H	D
					TP53	SNV	Q204*	D
9	72/M	TUT	cT4N3M0	P40(–)	SMARCA4	SNV	R704fs	D	MSS	8.52	dCCRT+ICI	TC durva	PR	AWD	17.0+
				PD-L1(90%)	ARID1B	SNV	Q124_Q131del	C					PR
					ARID1B	SNV	T1586M	C
					SMARCA2	SNV	R1089Q	C
					POLE	SNV	I1144V	C
					CTNNB1	SNV	D32A	D
					TP53	SNV	R335fs	D
					CD274	CNV	CN 6 copy	D
					FGFR1	CNV	CN 6 copy	D
					JAK2	CNV	CN 7 copy	D
					PDCD1LG2	CNV	CN 6 copy	D

AWD, alive with disease; BR, best response; CN, copy number; CNV, copy number variant; CR, complete response; CT, chemotherapy; dCCRT, definitive concurrent chemoradiation therapy; del, deletion; DP, docetaxel+cisplatin; DPF, docetaxel+cisplatin+5-FU; durva, durvalumab; fs, frame shift; IC, induction chemotherapy; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; MSI, microsatellite instability; MSS, microsatellite stability; NED, no evidence of disease; NGS, next-generation sequencing; ON, olfactory neuroblastoma; OS, overall survival; pCT, palliative chemotherapy; PD, progression of disease; PD-L1, programmed death-ligand 1; pembro, pembrolizumab; PO CCRT, post-operative concurrent chemoradiation therapy; PORT, post-operative radiation therapy; PR, partial response; pRT, palliative radiation therapy; SD, stable disease; SNC, sinonasal carcinoma; SNV, single nucleotide variant; TC, paclitaxel+carboplatin; TMB, tumor mutation burden; TUT, thoracic undifferentiated tumor.

REFERENCES

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4. Contrera KJ, Shakibai N, Su SY, Gule-Monroe MK, Roberts D, Brahimaj B, et al. Impact of clinical factors and treatments on SMARCB1 (INI-1)-deficient sinonasal carcinoma. Otolaryngol Head Neck Surg. 2023;169:435–40. Article PubMed PDF
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7. Wang R, Wang L, Fang J, Zhong Q, Hou L, Ma H, et al. Clinical diagnosis and treatment analyses on SMARCB1 (integrase interactor 1)-deficient sinonasal carcinoma: case series with systematic review of the literature. World Neurosurg. 2022;161:e229–43. Article PubMed
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11. Takada K, Sugita S, Murase K, Kikuchi T, Oomori G, Ito R, et al. Exceptionally rapid response to pembrolizumab in a SMARCA4-deficient thoracic sarcoma overexpressing PD-L1: a case report. Thorac Cancer. 2019;10:2312–5. Article PubMed PMC PDF
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Molecular and Treatment Characteristics of SMARCB1 or SMARCA4-Deficient Undifferentiated Tumor: Retrospective Case Series

Cancer Res Treat. 2024;56(3):967-971. Published online February 13, 2024

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

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Abstract
Introduction
Case Report
Discussion
NOTES
REFERENCES

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

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).

Fig. 1.

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

Patient No.	Age (yr)/Sex	Diagnosis	Initial stage	IHC	Variant gene	Variant type	Variant detail	Tier	MSI	TMB_alpha	Treatment summary	CT regimen	BR	Clinical course	OS
1	47/ F	ON→SNC	pT4bNxM0	BRG1(–)	SMARCA4	SNV	Q915*	Not reported			Surgery+PO CCRT	Cisplatin	(–)	NED	10.4+
					SMARCA4	CNV	CN 1 copy
					TET2	SNV	R1451fs
2	50/M	ON→SNC	pTxN2bM0	BRG1(–)			NGS not conducted				Surgery+PORT	(–)	(–)	NED	5.6+
3	77/M	SNC	pT2N0M0	INI-1(–)			NGS not conducted				Surgery+PORT	(–)	(–)	NED	19.2+
4	76/M	SNC	cT3aN0M0	INI-1(–)			NGS not conducted				IC+dCCRT	DP	PR	CR	11.4+
4	76/M	SNC	cT3aN0M0	INI-1(–)			NGS not conducted				IC+dCCRT	Cisplatin	CR	CR	11.4+
5	86/M	SNC	cT4bN0M0	INI-1(–)	SMARCB1	CNV	CN 1 copy	D	MSS	2.13	pRT	(–)	PD	Death	10.4
6	68/M	SNC	cT4aN0M0	INI-1(–)	SMARCB1	CNV	CN 0 copy	C	MSS	7.46	IC+dCCRT	DPF	PD	AWD	3.6+
6	68/M	SNC	cT4aN0M0	P40(–)	SMARCB1	CNV	CN 0 copy	C	MSS	7.46	IC+dCCRT	Cisplatin	SD	AWD	3.6+
7	74/M	TUT	cT4N2M0/1	BRG1(–)			NGS not conducted				pCT+ICI	TC	PD	Death	3.3
				P40(–)								Pembro	PD
				PD-L1(90%)
8	52/M	TUT	cT4N2M1	BRG1(–)	SMARCA4	SNV	V318fs	D	MSS	5.33	pCT	TC	PD	death	3.4
				P40(–)	ARID1A	SNV	D179Y	C
					ARID1B	SNV	M510V	C
					POLE	SNV	Q714Q	C
					NRAS	SNV	Q61L	C
					DNMT3A	SNV	R882H	D
					TP53	SNV	Q204*	D
9	72/M	TUT	cT4N3M0	P40(–)	SMARCA4	SNV	R704fs	D	MSS	8.52	dCCRT+ICI	TC durva	PR	AWD	17.0+
				PD-L1(90%)	ARID1B	SNV	Q124_Q131del	C					PR
					ARID1B	SNV	T1586M	C
					SMARCA2	SNV	R1089Q	C
					POLE	SNV	I1144V	C
					CTNNB1	SNV	D32A	D
					TP53	SNV	R335fs	D
					CD274	CNV	CN 6 copy	D
					FGFR1	CNV	CN 6 copy	D
					JAK2	CNV	CN 7 copy	D
					PDCD1LG2	CNV	CN 6 copy	D

Table 1. Clinicopathological features of patients with SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor including next-generation sequencing data