Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity

Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Massimo Aglietta, Sofia Genta and Giorgio Valabrega _

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Oncotarget. 2017; 8:90532-90544. https://doi.org/10.18632/oncotarget.20042

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Gloria Mittica1,2,*, Eleonora Ghisoni1,2,*, Gaia Giannone1,2, Massimo Aglietta1,2, Sofia Genta1,2 and Giorgio Valabrega1,2

1Department of Oncology, University of Turin, Turin, Italy

2Division of Medical Oncology-1, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy

*These authors contributed equally to this work

Correspondence to:

Giorgio Valabrega, email: [email protected]

Keywords: endometrial cancer, immunotherapy, tumor infiltrating lymphocytes (TILs), polymerase epsilon (POLE)-ultra-mutated, microsatellite instability (MSI)

Received: June 08, 2017     Accepted: July 26, 2017     Published: August 08, 2017


Context: Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors.

Materials and Methods: We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords ‘endometrial cancer’ and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types.

Results: POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients.

Conclusions: Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

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