Clinical features and prognosis of SMARCA4-deficient thoracic undifferentiated tumors: a single-center, retrospective clinical study

doi:10.3877/cma.j.issn.1674-6902.2024.04.005

Abstract

Abstract:

Objective

SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) present a class of rare malignant tumors with high aggressiveness and poor prognosis, which have poor response to traditional chemotherapy. Currently, there are no specific treatment guidelines for SMARCA4-UT, but some patients have been shown to benefit from immunotherapy. This study intends to retrospectively analyze the clinical features and prognostic factors of SMARCA4-UT in the real world.

Methods

The clinical data of 48 patients with SMARCA4-UT treated in the First Affiliated Hospital of Army Military Medical University from March 2021 to June 2023 were retrospectively analyzed, including 40 patients with advanced stage and 8 patients with early and middle stage. 5 cases were treated with surgery, 22 cases with chemotherapy alone, 5 cases with chemotherapy combined with immunization, 7 cases with chemotherapy combined with anti-tumor angiogenesis, 2 cases with chemotherapy combined with anti-tumor angiogenesis and immunotherapy, and 7 cases were untreated. Immunohistochemistry and second-generation sequencing were used to analyze the clinicopathological and genetic characteristics of patients, observe the efficacy of different treatment methods, and analyze the relationship between clinical characteristics and prognosis.

Results

PFS and OS of chemotherapy combined with immunotherapy were superior to chemotherapy alone and chemotherapy combined with anti-tumor angiogenesis therapy, among which EP chemotherapy combined with Tislelizumab could be the preferred treatment for SMARCA4-UT patients. Liver metastasis and ≥3 metastatic sites are both influential factors for PFS and OS. Patients with STK11 and KEAP1 mutations have poor overall prognosis, but immunotherapy can still prolong OS in these patients. End of follow-up date, 3 cases (60.00%) death in surgery group, 16 cases(72.73%) death in chemotherapy group, 3 cases (60.00%)death in chemotherapy combined with immunization, 5 cases (71.43%)death in chemotherapy combined with anti-tumor angiogenesis group, no case (0.00%)death in chemotherapy combined with anti-tumor angiogenesis and immunotherapy group, 7 cases(100.00%) deaths in untreated group.

Conclusion

The efficacy of first-line immunocheckpoint inhibitor combined with chemotherapy in advanced SMARCA4-UT patients may be better than that of chemotherapy alone, among which EP regimen may be a potential better chemotherapy choice. STK11 and KEAP1 gene mutations may be markers of poor prognosis in SMARCA4-UT patients.

Key words: SMARCA4-deficient undifferentiated tumors, Clinical features, Immunization, Predictive factors

Pan Yang, Xiaohan Huang, Caixia Deng, Lihang Zhou, Xiangdong Zhou, Hu Luo. Clinical features and prognosis of SMARCA4-deficient thoracic undifferentiated tumors: a single-center, retrospective clinical study[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2024, 17(04): 529-534.

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References 30

1	Arnaud O, Le Loarer F, Tirode F. BAFfling pathologies: Alterations of BAF complexes in cancer[J]. Cancer Lett, 2018, 419: 266-279.
2	Nambirajan A, Jain D. Recent updates in thoracic SMARCA4-deficient undifferentiated tumor[J]. Semin Diagn Pathol, 2021, 38(5): 83-89.
3	Nambirajan A, Singh V, Bhardwaj N, et al. SMARCA4/BRG1-deficient non-small cell lung carcinomas: a case series and review of the literature[J]. Arch Pathol Lab Med, 2021, 145(1): 90-98.
4	Schoenfeld AJ, Bandlamudi C, Lavery JA, et al. The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer[J]. Clin Cancer Res, 2020, 26(21): 5701-5708.
5	Gupta M, Concepcion CP, Fahey CG, et al. BRG1 loss predisposes lung cancers to replicative stress and ATR dependency[J]. Cancer Res, 2020, 80(18): 3841-3854.
6	Perret R, Chalabreysse L, Watson S, et al. SMARCA4-deficient thoracic sarcomas: Clinicopathologic study of 30 cases with an emphasis on their nosology and differential diagnoses[J]. Am J Surg Pathol, 2019, 43(4): 455-465.
7	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
8	Lamberti G, Spurr LF, Li Y, et al. Clinicopathological and genomic correlates of programmed cell death ligand 1 (PD-L1) expression in nonsquamous non-small-cell lung cancer[J]. Ann Oncol, 2020, 31(6): 807-814.
9	Henon C, Blay JY, Massard C, et al. Long lasting major response to pembrolizumab in a thoracic malignant rhabdoid-like SMARCA4-deficient tumor[J]. Ann Oncol, 2019, 30(8): 1401-1403.
10	Naito T, Umemura S, Nakamura H, et al. Successful treatment with nivolumab for SMARCA4-deficient non-small cell lung carcinoma with a high tumor mutation burden: A case report[J]. Thorac Cancer, 2019, 10(5): 1285-1288.
11	Yang P, Xiong F, Lin Y, et al. Effectiveness of tislelizumab when combined with etoposide and carboplatin in patients with SMARCA4-deficient undifferentiated thoracic tumor: A case report[J]. Transl Cancer Res, 2023, 12(4): 1041-1048.
12	Naito T, Udagawa H, Umemura S, et al. Non-small cell lung cancer with loss of expression of the SWI/SNF complex is associated with aggressive clinicopathological features, PD-L1-positive status, and high tumor mutation burden[J]. Lung Cancer, 2019, 138: 35-42.
13	Dagogo-Jack I, Schrock AB, Kem M, et al. Clinicopathologic Characteristics of BRG1-Deficient NSCLC[J]. J Thorac Oncol, 2020, 15(5): 766-776.
14	Luo J, Ding B, Campisi A, et al. Molecular, clinicopathological characteristics and surgical results of resectable SMARCA4-deficient thoracic tumors[J]. J Cancer Res Clin Oncol, 2023, 149(8): 4455-4463.
15	Yoshida A, Kobayashi E, Kubo T, et al. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities[J]. Mod Pathol, 2017, 30(6): 797-809.
16	Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma[J]. Nature, 2014, 511(7511): 543-550.
17	Chiba Y, Kawanami T, Yamasaki K, et al. Hyper-progressive disease after immune checkpoint inhibitor in SMARCA4-deficient small-cell lung carcinoma[J]. Respirol Case Rep, 2020, 8(8): e00667.
18	Dong ZY, Zhong WZ, Zhang XC, et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma[J]. Clin Cancer Res, 2017, 23(12): 3012-3024.
19	Saleh MM, Scheffler M, Merkelbach-Bruse S, et al. Comprehensive analysis of TP53 and KEAP1 mutations and their impact on survival in localized-and advanced-stage NSCLC[J]. J Thorac Oncol, 2022, 17(1): 76-88.
20	Zheng D, Wang R, Zhang Y, et al. The prevalence and prognostic significance of KRAS mutation subtypes in lung adenocarcinomas from Chinese populations[J]. Onco Targets Ther, 2016, 9: 833-843.
21	Liu SY, Sun H, Zhou JY, et al. Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients[J]. Biomark Res, 2020, 8: 22.
22	Negrao MV, Skoulidis F, Montesion M, et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer[J]. J Immunother Cancer, 2021, 9(8): e002891.
23	Liu C, Zheng S, Jin R, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity[J]. Cancer Lett, 2020, 470: 95-105.
24	Alessi JV, Ricciuti B, Spurr LF, et al. SMARCA4 and other SWItch/sucrose nonfermentable family genomic alterations in NSCLC: Clinicopathologic characteristics and outcomes to immune checkpoint inhibition[J]. J Thorac Oncol, 2021, 16(7): 1176-1187.
25	Shang X, Li Z, Sun J, et al. Survival analysis for non-squamous NSCLC patients harbored STK11 or KEAP1 mutation receiving atezolizumab[J]. Lung Cancer, 2021, 154: 105-112.
26	Hiraoka K, Miyamoto M, Cho Y, et al. Concurrent infiltration by CD8＋ T cells and CD4＋ T cells is a favourable prognostic factor in non-small-cell lung carcinoma[J]. Br J Cancer, 2006, 94(2): 275-280.
27	Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy[J]. Nat Rev Cancer, 2019, 19(9): 495-509.
28	Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma[J]. Cancer Discov, 2018, 8(7): 822-835.
29	Simon PC, Parul D, Radu D, et al. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort[J]. ESMO Open, 2020, 5(2): e000706.
30	Xu X, Yang Y, Liu X, et al. NFE2L2/KEAP1 mutations correlate with higher tumor mutational burden value/PD-L1 expression and potentiate improved clinical outcome with immunotherapy[J]. Oncologist, 2020, 25(6): e955-e963.

序号	cTNM	(y)pTNM	基因分型	新辅助治疗	辅助治疗	PFS	OS	结局
例1	T1cN0M0	T0N0M0	未知	TP(3cycle)	否	5.5/NA	5.5/NA	生存
例2	T2bN0M0	T2bN0M0	SMARCA4、STK11、TP53^a	否	否	7.0	9.8	死亡
例3	T2aN0M0	T2aN0M0	未知	否	否	10.6	13.7	死亡
例4	T1cN3M0	T1aN0M0	未知	TP-P(4 cycle)	TP-P(2 cycle)	22.1/NA	22.1/NA	生存
例5	T4N0M0	T4N0M0	未知	否	否	2.3	12.6	死亡

序号	cTNM	(y)pTNM	基因分型	新辅助治疗	辅助治疗	PFS	OS	结局
例1	T1cN0M0	T0N0M0	未知	TP(3cycle)	否	5.5/NA	5.5/NA	生存
例2	T2bN0M0	T2bN0M0	SMARCA4、STK11、TP53^a	否	否	7.0	9.8	死亡
例3	T2aN0M0	T2aN0M0	未知	否	否	10.6	13.7	死亡
例4	T1cN3M0	T1aN0M0	未知	TP-P(4 cycle)	TP-P(2 cycle)	22.1/NA	22.1/NA	生存
例5	T4N0M0	T4N0M0	未知	否	否	2.3	12.6	死亡

序号	分　期	基因检测	治疗方案	PFS	OS
例1	T4N0M0 ⅢA期	AMRS-PCR方法：(－)	一线：TP方案化疗7周期，PR 二线：EP联合替雷利珠单抗3周期，替雷利珠维持至今，PR	12个月	28.8个月
例2	T4N2M0 ⅢB期	PD-L1(22C3)(－) NGS方法：TP53错义突变、KEAP1错义突变，TMB 15.95/Mb	一线：TP4周期＋安罗替尼2周期，SD 二线：EP＋替雷利珠单抗4周期，随后替雷利珠单抗维持，PR	3.6个月	28.7个月

序号	分　期	基因检测	治疗方案	PFS	OS
例1	T4N0M0 ⅢA期	AMRS-PCR方法：(－)	一线：TP方案化疗7周期，PR 二线：EP联合替雷利珠单抗3周期，替雷利珠维持至今，PR	12个月	28.8个月
例2	T4N2M0 ⅢB期	PD-L1(22C3)(－) NGS方法：TP53错义突变、KEAP1错义突变，TMB 15.95/Mb	一线：TP4周期＋安罗替尼2周期，SD 二线：EP＋替雷利珠单抗4周期，随后替雷利珠单抗维持，PR	3.6个月	28.7个月

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