SWI/SNF-deficiency defines highly aggressive undifferentiated endometrial carcinoma.

Abstract

Dedifferentiated/undifferentiated endometrial carcinoma (DDEC/UEC) is an endometrial cancer characterized by the presence of histologically undifferentiated carcinoma. Genomic inactivation of core switch/sucrose nonfermentable (SWI/SNF) complex proteins was recently identified in approximately two-thirds of DDEC/UEC. The aim of this study was to delineate the clinical behavior of SWI/SNF-deficient DDEC/UEC in comparison to SWI/SNF-intact DDEC/UEC. The study cohort consisted of 56 SWI/SNF-deficient DDEC/UEC (2 POLE-mutated), which showed either SMARCA4 (BRG1) loss, ARID1A/1B co-loss, or SMARCB1 (INI1) loss in the undifferentiated tumor, and 26 SWI/SNF-intact DDEC/UEC (4 POLE-mutated). The average age at diagnosis was 61 years for patients with SWI/SNF-deficient tumors and 64 years for SWI/SNF-intact tumors. Mismatch repair (MMR) protein deficiency was seen in 66% of SWI/SNF-deficient and 50% of SWI/SNF-intact tumors. At initial presentation, 55% of patients with SWI/SNF-deficient tumors had extrauterine disease spread in contrast to 38% of patients with SWI/SNF-intact tumors. The 2-year disease specific survival (DSS) for stages I and II disease was 65% for SWI/SNF deficient tumors relative to 100% for SWI/SNF-intact tumors (p = 0.042). For patients with stages III and IV disease, the median survival was 4 months for SWI/SNF-deficient tumors compared to 36 months for SWI/SNF-intact tumors (p = 0.0003). All six patients with POLE-mutated tumors, including one with stage IV SWI/SNF-deficient tumor were alive with no evidence of disease. Among the patients with advanced stage SWI/SNF-deficient tumors, 68% (21 of 31) received adjuvant or neoadjuvant chemotherapy (platinum/taxane-based) and all except the patient with a POLE-mutated tumor (20 of 21) experienced disease progression either during chemotherapy or within 4 months after its completion. These findings show that core SWI/SNF-deficiency defines a highly aggressive group of undifferentiated cancer characterized by rapid disease progression that is refractory to conventional platinum/taxane-based chemotherapy. This underscores the importance of accurate clinical recognition of this aggressive tumor and the need to consider alternative systemic therapy for these tumors.

• Authors: Basile Tessier-Cloutier, Mackenzie Coatham, Mark Carey, Gregg S Nelson, Sarah Hamilton, Amy Lum, Robert A Soslow, Colin Jr Stewart, Lynne M Postovit, Martin Köbel, Cheng-Han Lee
• Journal: The journal of pathology. Clinical research (J Pathol Clin Res) Vol. 7 Issue 2 Pg. 144-153 (03 2021) ISSN: 2056-4538 [Electronic] England
• PMID: 33125840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.

Chemical References

• ARID1A protein, human
• ARID1B protein, human
• DNA-Binding Proteins
• Nuclear Proteins
• SMARCB1 Protein
• SMARCB1 protein, human
• Transcription Factors
• SMARCA4 protein, human
• DNA Helicases

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma (genetics, metabolism, pathology)
• DNA Helicases (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Endometrial Neoplasms (genetics, metabolism, pathology)
• Female
• Humans
• Immunohistochemistry
• Middle Aged
• Nuclear Proteins (genetics, metabolism)
• Retrospective Studies
• SMARCB1 Protein (genetics, metabolism)
• Transcription Factors (genetics, metabolism)