Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

Takada, Kohichi; Sugita, Shintaro; Murase, Kazuyuki; Kikuchi, Tomoki; Oomori, Ginji; Itô, Ryo; Hayasaka, Naotaka; Miyanishi, Koji; Iyama, Satoshi; Ikeda, Hiroshi; Kobune, Masayoshi; Emori, Makoto; Kato, Junji; Hasegawa, Tadashi

doi:10.1111/1759-7714.13215

Cited by 83 publications

(79 citation statements)

References 14 publications

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“…Notably, recognition of these uncommon WHO types based on morphology alone is challenging; undifferentiated carcinoma can be misinterpreted as the poorly cohesive type, and adenocarcinoma with enteroblastic differentiation can be misinterpreted as the tubular type 15,16 . These types of gastric cancers are also enriched for PD‐L1 expression in comparison with other types 17‐20 . On the basis of our findings, when these morphologies are encountered, NGS and PD‐L1 tumor testing should be recommended.…”

Section: Discussionmentioning

confidence: 84%

Morphologic and molecular analysis of early‐onset gastric cancer

Setia

Wang

Lager

et al. 2020

Cancer

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BACKGROUND: Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. METHODS: Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from nextgeneration sequencing data. RESULTS: A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. CONCLUSIONS: Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers. Cancer 2021;127:103-114.

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Section: Discussionmentioning

confidence: 84%

Morphologic and molecular analysis of early‐onset gastric cancer

Setia

Wang

Lager

et al. 2020

Cancer

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“…Both cases presented as large necrotic mediastinal masses in middle-aged males, and we emphasize that the presence of rhabdoid phenotype cells in aspirates or effusions in such patients should raise suspicion for SMARCA4-dTS and prompt testing for BRG1 and BRM protein loss – both when occurring together are highly specific for SMARCA4-dTS among all other tumours that may enter the differential diagnoses [7]. Recent reports on the use of immunotherapy for PDL1-expressing SMARCA4-dTS are encouraging [13], and in one of our SMARCA4-dTSs (case 4) that showed a 100% tumour proportion score for PD-L1, immunotherapy using pembrolizumab and ipilimumab produced a partial response, with the patient being alive 22 months after diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Cytology of SMARCA4-Deficient Thoracic Neoplasms: Comparative Analysis of SMARCA4-Deficient Non-Small Cell Lung Carcinomas and SMARCA4-Deficient Thoracic Sarcomas

et al. 2020

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Introduction: Inactivating mutations of the SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or loss of the BRG1 (brahma-related gene 1) protein defines SMARCA4-deficient thoracic sarcoma (SMARCA4-dTS), an aggressive neoplasm with a usually fatal outcome. Similar SMARCA4 mutations/BRG1 loss is also seen in a subset of non-small cell lung carcinomas (NSCLCs; SMARCA4-dNSCLCs) that lack alterations in currently targetable oncogenic drivers, that is, EGFR, ALK, and ROS1. There is limited knowledge on the cytomorphological features of these SMARCA4-deficient thoracic neoplasms. Methods: We retrospectively analysed the cytology of 2 cases each of SMARCA4-dNSCLC and SMARCA4-dTS to understand their cytomorphological overlap, if any, and identify features that would prompt testing for BRG1 loss. Results: All 4 patients were males presenting with advanced disease, with a mean age of 41.5 years (SMARCA4-dTS) and 58.5 years (SMARCA4-dNSCLC) at presentation. The cytology of the 2 SMARCA4-dTSs was strikingly similar, showing predominantly singly dispersed rhabdoid phenotype tumour cells with perinuclear cytoplasmic condensations in an inflammatory or necrotic background. The cytology raised suspicion for a wide range of differentials, including melanoma, high-grade lymphoma, germ cell tumour, undifferentiated carcinoma, and undifferentiated sarcoma. SMARCA4-dNSCLCs, on the other hand, were recognizable as poorly differentiated (adeno)carcinomas and were easily distinguished from SMARCA4-dTSs, with both cases showing cohesive clusters of frequently large tumour cells with abundant pale cytoplasm. Conclusion: A diagnosis of SMARCA4-dTS is possible on cytology with appropriate ancillary testing and a high index of suspicion. The cytology of SMARCA4-dNSCLCs does not overlap with SMARCA4-dTS; rather, it resembles that of any poorly differentiated (adeno)carcinoma in the limited numbers analysed in this study.

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“…Specifically, a patient diagnosed with SMARCA4-DTC showed a partial response with only one dose of Pembrolizumab. Sixty percent of the tumor cells expressed programmed cell death ligand-1 protein [ 21 ]. A patient with SMARCA4-deficient lung adenocarcinoma exhibiting a high tumor mutation burden was successfully treated with nivolumab [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Undifferentiated colonic neoplasm with SMARCA4 germline gene mutation and loss of SMARCA4 protein expression: a case report and literature review

et al. 2021

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Background Nonsense mutation or inactivation of SMARCA4 (BRG1) is associated with a monomorphic undifferentiated histological appearance in tumors at different sites. The association between SMARCA4 alteration and undifferentiated colonic carcinoma needs to be further elucidated. Methods A 61-year-old male patient presented to the hospital with intermittent epigastric pain in the right upper abdomen and abdominal distension. The enhanced computed tomography detected a mass in the hepatic flexure of the colon and multiple liver metastases. Results The right hemicolectomy contained a 4.5-cm undifferentiated malignancy with cells arranged in sheets, abundant necrosis, and areas showing rhabdoid morphology. The immunohistochemistry result showed that these tumor cells were focally positive for cytokeratin (CK), CK8, and CK18; however, diffusely positive for vimentin, P53, Fli-1, and SALL-4. Notably, tumor cells showed a heterogeneous loss of SMARCA4 expression pattern and intact SMARCB1 expression. Next-generation sequencing showed a germline SMARCA4 c.3277C>T(p.R1093*)mutation, somatic APC mutation, and no abnormal SMARCB1 gene. The tumor exhibited microsatellite stability, negative PD-L1 expression, and few infiltrating CD8 + T cells. The patient died a month later after surgery. Conclusions We presented a rare case of undifferentiated colonic neoplasm with loss of SMARCA4 protein expression and germline SMARCA4 mutation. Moreover, the role of SMARCA4 alterations in tumor diagnosis and treatment was also summarized.

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Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

Cited by 83 publications

References 14 publications

Morphologic and molecular analysis of early‐onset gastric cancer

Morphologic and molecular analysis of early‐onset gastric cancer

Cytology of SMARCA4-Deficient Thoracic Neoplasms: Comparative Analysis of SMARCA4-Deficient Non-Small Cell Lung Carcinomas and SMARCA4-Deficient Thoracic Sarcomas

Undifferentiated colonic neoplasm with SMARCA4 germline gene mutation and loss of SMARCA4 protein expression: a case report and literature review

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