Recent updates in thoracic SMARCA4-deficient undifferentiated tumor

Nambirajan, Aruna; Jain, Deepali

doi:10.1053/j.semdp.2021.06.001

Cited by 51 publications

(81 citation statements)

References 46 publications

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“…The thoracic SMARCA4-DUT is known to localize mainly at the mediastinum, and it can arise at the pulmonary hilum, lung, and/or pleura with or without chest wall invasion. Young to middle aged adults (27-90 years) with preponderance to the male sex and a smoking history are commonly affected [27]. An average of 10% of never smokers can also be victims of this aggressive high-grade tumor.…”

Section: Clinicopathological Features Of Smarca4-deficient Thoracic Cancersmentioning

confidence: 99%

Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

Armon

Hofman

Ilié

2021

Cells

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Lung cancers are ranked third among the cancer incidence in France in the year 2020, with adenocarcinomas being the commonest sub-type out of ~85% of non-small cell lung carcinomas. The constant evolution of molecular genotyping, which is used for the management of lung adenocarcinomas, has led to the current focus on tumor suppressor genes, specifically the loss of function mutation in the SMARCA4 gene. SMARCA4-deficient adenocarcinomas are preponderant in younger aged male smokers with a predominant solid morphology. The importance of identifying SMARCA4-deficient adenocarcinomas has gained interest for lung cancer management due to its aggressive behavior at diagnosis with vascular invasion and metastasis to the pleura seen upon presentation in most cases. These patients have poor clinical outcome with short overall survival rates, regardless of the stage of disease. The detection of SMARCA4 deficiency is possible in most pathology labs with the advent of sensitive and specific immunohistochemical antibodies. The gene mutations can be detected together with other established lung cancer molecular markers based on the current next generation sequencing panels. Sequencing will also allow the identification of associated gene mutations, notably KRAS, KEAP1, and STK11, which have an impact on the overall survival and progression-free survival of the patients. Predictive data on the treatment with anti-PD-L1 are currently uncertain in this high tumor mutational burden cancer, which warrants more groundwork. Identification of target drugs is also still in pre-clinical testing. Thus, it is paramount to identify the SMARCA4-deficient adenocarcinoma, as it carries worse repercussions on patient survival, despite having an exceptionally low prevalence. Herein, we discuss the pathophysiology of SMARCA4, the clinicopathological consequences, and different detection methods, highlighting the perspectives and challenges in the assessment of SMARCA4 deficiency for the management of non-small cell lung cancer patients. This is imperative, as the contemporary shift on identifying biomarkers associated with tumor suppressor genes such as SMARCA4 are trending; hence, awareness of pathologists and clinicians is needed for the SMARCA4-dNSCLC entity with close follow-up on new management strategies to overcome the poor possibilities of survival in such patients.

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Section: Clinicopathological Features Of Smarca4-deficient Thoracic Cancersmentioning

confidence: 99%

Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

Armon

Hofman

Ilié

2021

Cells

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“…For the second gene ( SMARCA4 ), we found no previous associations with sorafenib efficacy in the literature. However, molecular function of this gene product is ATP-dependent chromatin remodeling and overall transcriptional activation, and SMARCA4 mutations are linked with many cancers ( Fountzilas et al, 2021 ; Nambirajan and Jain, 2021 ; Pastorczak et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Gene Expression-Based Signature Can Predict Sorafenib Response in Kidney Cancer

Gudkov

Shirokorad

Kashintsev

et al. 2022

Front. Mol. Biosci.

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Sorafenib is a tyrosine kinase inhibitory drug with multiple molecular specificities that is approved for clinical use in second-line treatments of metastatic and advanced renal cell carcinomas (RCCs). However, only 10–40% of RCC patients respond on sorafenib-containing therapies, and personalization of its prescription may help in finding an adequate balance of clinical efficiency, cost-effectiveness, and side effects. We investigated whether expression levels of known molecular targets of sorafenib in RCC can serve as prognostic biomarker of treatment response. We used Illumina microarrays to profile RNA expression in pre-treatment formalin-fixed paraffin-embedded (FFPE) samples of 22 metastatic or advanced RCC cases with known responses on next-line sorafenib monotherapy. Among them, nine patients showed partial response (PR), three patients—stable disease (SD), and 10 patients—progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. We then classified PR + SD patients as “responders” and PD patients as “poor responders”. We found that gene signature including eight sorafenib target genes was congruent with the drug response characteristics and enabled high-quality separation of the responders and poor responders [area under a receiver operating characteristic curve (AUC) 0.89]. We validated these findings on another set of 13 experimental annotated FFPE RCC samples (for 2 PR, 1 SD, and 10 PD patients) that were profiled by RNA sequencing and observed AUC 0.97 for 8-gene signature as the response classifier. We further validated these results in a series of qRT-PCR experiments on the third experimental set of 12 annotated RCC biosamples (for 4 PR, 3 SD, and 5 PD patients), where 8-gene signature showed AUC 0.83.

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“…There has been an important change in terminology since the ‘sarcoma’ classification was dropped in favor of ‘thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT)’, which is newly classified in the fifth edition of the WHO classification of thoracic tumors (2021) ( 1 ). It was classified as a subtype of undifferentiated lung cancer of pulmonary epithelial origin ( 10 ). These tumors mostly occur in the fourth and fifth decades of life; moreover, there is a strong connection with smoking history (only 10% of the cases are reported in non-smokers).…”

Section: Discussionmentioning

confidence: 99%

Case report: A rapid response to immunotherapy in a thoracic SMARCA4-deficient undifferentiated tumor with respiratory failure

et al. 2022

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Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is an extremely rare and poor-prognosis malignancy, which has recently been noted as a subtype of lung tumors. We presented a case of SMARCA4-UT in a 50-year-old man with progressively worsening respiratory failure. The tumor was the first reported to involve pulmonary artery, and 90% of tumor cells expressed programmed cell death ligand 1 (PD-L1). High tumor mutational burden (TMB, 23.93/Mb) and mutations in SMARCA4 were detected. It is the first reported case to receive Tislelizumab monotherapy with considerable improvement in clinical condition and no adverse events. As a result of our case, we highlight the importance of recognizing SMARCA4-UT as an individual entity, as well as the efficacy of immune checkpoint inhibitor therapy, particularly in patients with high levels of TMB and PD-L1 expression.

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Recent updates in thoracic SMARCA4-deficient undifferentiated tumor

Cited by 51 publications

References 46 publications

Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

Gene Expression-Based Signature Can Predict Sorafenib Response in Kidney Cancer

Case report: A rapid response to immunotherapy in a thoracic SMARCA4-deficient undifferentiated tumor with respiratory failure

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