Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?

Highlights

• Survival of advanced EC is a challenge and new treatment modalities are needed.

• EC is an immunogenic tumor, and immunotherapy might be a promising option.

• Genotype studies showed different immune microenvironment in EC subtypes.

• Blocking PD-1/PD-L1 axis could reduce the cancer-induced immunosuppression.

• POLE-ultramutated, and MSI-hypermutated might most benefit from immunotherapy.

Abstract

Endometrial Cancer (EC) is still a challenge for gynecological oncologists because the treatment of the advanced disease remains an unmet need for patients. The Cancer Genome Atlas Research Network (TCGA) recently provided a comprehensive genomic and transcriptomic analysis of EC, offering a new classification of the disease, based on genetic features, which defines four subgroups of cancer rather than the two traditionally recognized. In the molecular classification two types of EC, the polymerase epsilon (POLE)-ultramutated and the microsatellite instability (MSI)-hypermutated, seem to present an enhanced immune microenvironment and a high mutation burden. The blockade of the immune checkpoints is an innovative approach that has largely demonstrated to be effective in solid malignancies, such as lung, renal and melanoma; it acts by reducing the cancer-induced immune-suppression through inhibition of the PD-1/PD-L1 (Programmed Death and PD-Ligand) axis. All available evidence supporting an over-expression of the PD-1/PD-L1 pathway in EC has been reviewed. In particular in the POLE and MSI ECs an up-regulation of this pathway was found, aiming to suggest a rationale for testing the PD-1/PD-L1 immunotherapy in these cancer subgroups.

Introduction

EC is the most common gynecological malignancy in the Western world, accounting approximately for 150,000 women per year in Europe and the United States combined [1], while the localized disease is largely curable with surgery, in some cases followed by radiotherapy [2], the treatment of the advanced EC remains an unmet need for patients. In metastatic and relapsed EC, chemotherapy and hormonal therapy are the only available options for treatment but survival remains poor [2].

With regards to chemotherapy the carboplatin–paclitaxel doublet has progressively replaced the combination of paclitaxel, adriamycine, and cisplatin in the first line setting, being equally effective but less toxic [2]. Among the hormonal agents currently used in clinical practice the most popular are progestins (megestrol acetate and medroxyprogesterone), followed by anti-estrogens (tamoxifen) and aromatase inhibitors with response rates up to 30% [2].

Nevertheless the options in second and third line are limited and the approach is absolutely not standardized, different treatments have failed to demonstrate a benefit in this setting [2]. Many new-targeted therapies have been tested in clinical trials but only few agents have shown an impact on survival and response and to date none has been approved [2]. Among them, the mTOR inhibitors had the highest response rate [3], particularly the combination of everolimus plus letrozole resulted in an objective response rate of 32% [4]. Also the combination with temsirolimus and bevacizumab was efficacious even if more toxic [5]. Bevacizumab and sunitinib as single agents have resulted in objective response rates of 12–15% [6], [7]. Use of multitargeted VEGF/FGFR inhibitors (brivatinib, lenvatinib) has produced encouraging findings (response rates 14–19%) [3], [8]. In a phase II trial, AEZS-108, an LHRH agonist conjugated to doxorubicin, was active and well-tolerated in LHRH receptor positive recurrent EC [9].

In such context new treatment modalities are urgently needed and the comprehension of the EC genotype is likely to represent a milestone in the development of new therapeutic strategies.

The mapping of the genomic landscape of ECs has recently identified 4 molecular subgroups: (1) POLE-ultramutated, (2) MSI-hypermutated (3) copy-number low and (4) copy-number high, serous like [10].

The POLE-ultramutated and the MSI groups are characterized by an active immune microenvironment demonstrated by the abundance of tumor specific neo-antigens and the high number of Tumor Infiltrating Lymphocytes (TILs) [11], leading to over-expression of PD-1 and PD-L1 [11]. Immune checkpoints other than PD-1 and PD-L1, such as CTLA-4 (Cytotoxic T Lymphocyte Antigen-4), LAG-3 (Lymphocyte Activation Gene-3), and IDO (indoleamine 2,3-dioxygenase), may also be up-regulated in the POLE and in the MSI EC, this phenomenon is known as ‘adaptive immune resistance’ [11], [12], [13].

On note, the response to the checkpoint inhibitors seems to correlate both with the number of the predicted antigenic tumor mutations and the T-cell infiltration [14], [15], [16], suggesting that patients with POLE-ultra mutated and MSI EC may have the maximum benefit from these drugs [2].

This review focuses on the available data supporting (i) the enhanced immune microenvironment and the significant mutation burden in the POLE-ultramutated and in the MSI-hypermutated EC (ii) the correlation between the efficacy of the PD-1/PD-L1 blockade and these cancer features. The aim of this review is to suggest a rational for testing the anti- PD-1/PD-L1 agents in these subgroups of EC.