Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies)

Abstract

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

SWI/SNF‐deficiency defines highly aggressive undifferentiated endometrial carcinoma

“…Given the expanded indication for immunotherapy of MMR protein‐deficient tumors, immune check point inhibitors may be considered as first line or second line systemic treatment option for SWI/SNF‐deficient DDEC/UEC that are also MMR protein‐deficient. Moreover, three recent studies have examined the expression of PD‐L1 in DDEC/UEC and all reported PD‐L1 expression in tumor and/or stromal immune cells in about half of the cases examined, which correlated with MMR deficiency status [34–36]. Early evidence also suggests that alterations within the SWI/SNF complex could be a predictive marker of response to checkpoint inhibitors [37,38].…”

Additional Value of PET/CT-Based Radiomics to Metabolic Parameters in Diagnosing Lynch Syndrome and Predicting PD1 Expression in Endometrial Carcinoma

“…In Cohort 1 and Cohort 2, we explore the relation between radiomic features and PD1 expression at the protein-expression level and the gene level. The 2 types of endometrial carcinoma included in Cohort 1 could represent PD1-enriched cancer tissue and PD1-deficient cancer tissue ( 8 , 37 ). The radiomic feature of GLCMEntropy reveals a significant difference in PD1-enriched cancer tissue and PD1-deficient cancer tissue, regardless of the angle used.…”

Magnetic resonance imaging findings in 11 cases of dedifferentiated endometrial carcinoma of the uterus

“…DEC has recently garnered a lot of clinical and pathological attention with respect to cancer gene therapy. Recent studies have shown that the UC component in DEC is associated with the loss of MMR protein [ 7 ], suggesting an association between DEC and Lynch syndrome [ 1 ]. Some studies have evaluated MRI findings in patients with endometrial carcinoma with MMR deficiency [ 8 ], and genetic mutations causing MMR deficiency are also attracting attention in the field of radiology.…”