A comprehensive analysis of immunotherapy in advanced endometrial cancer (Review)

  • Authors:
    • Liping Wang
    • Lin Liu
    • Da Huo
    • Yixiang Zhang
  • View Affiliations

  • Published online on: December 28, 2023     https://doi.org/10.3892/ol.2023.14210
  • Article Number: 77
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


The morbidity and mortality rates of endometrial cancer (EC) are increasing yearly. Early‑stage EC can be effectively treated through surgery or surgery combined with radiotherapy and chemotherapy. Advanced and recurrent EC is treated with chemotherapy and comprehensive treatment; however, the prognosis for patients at this disease stage is poor. Consequently, novel and effective treatment strategies are urgently required for these patients. Breakthrough progress has been made with the use of immunosuppressants in the treatment of EC, which have been included in treatment guidelines. In the present review, the etiology and classification of EC was outlined and the relevant scientific basis for the application of immunosuppressants in advanced and recurrent EC was discussed. The relevant published and ongoing clinical trials are also summarized. As such, the present review aimed to provide a scientific summary of immunotherapy of EC.


Endometrial cancer (EC) is one of the three most common malignant tumors of the female reproductive system and it ranks sixth in incidence among female malignant tumors globally (1). The morbidity and mortality rates of EC in developed countries are higher compared with those in developing countries (2). Furthermore, 66,570 new cases of EC and 12,940 EC-related deaths in the US were estimated for 2021 (3). In China, the incidence and mortality rates of EC are also exhibiting gradual increases. Data from the China Cancer Statistics Report indicated that in 2022, there were 84,520 new cases and 17,543 deaths from cancer in corpus uteri in China (4). In total, ~80% of EC cases are limited to the uterus at the initial diagnosis and these patients have a relatively good prognosis with a 5-year survival rate of >95% (5,6). However, in cases with regional or distant metastasis, the prognosis is significantly worse (68 and 17%, respectively) (6,7). Paclitaxel plus carboplatin is the standard first-line treatment for patients with advanced, recurrent or metastatic EC (8). However, the effective rate of this treatment is limited and ranges from 7–14%, with a median overall survival (mOS) time of <1 year (912). Therefore, it is necessary to explore new treatment methods in order to prolong the survival time of patients with EC.

High-risk factors for EC

At present, the cause of EC remains unknown, but the related high-risk factors may be divided into several categories, including reproductive factors, hormonal use, metabolic syndromes and genetic factors (13). Reproductive risk factors include nulliparity, early menarche, late menopause, infertility and anovulatory menstrual cycles (13). There is evidence that, compared with non-parturient women, the incidence of EC in postpartum women is reduced by 40% (14). Furthermore, a large-scale meta-analysis reported that parity (the number of births after ≥24 weeks of pregnancy) may be associated with a reduced risk of EC, since the relative risk (RR) of EC decreased when the parity number increased (15). This outcome may be related to the protection of progesterone on the endometrium during pregnancy. EC is a hormone-driven type of cancer and ~80% of EC cases may be caused by excessive estrogen or lack of progesterone (16). Long-term continuous estrogen stimulation, including endogenous and exogenous, increases the risk of hormone-responsive EC. These sources of stimulation include using only estrogen in women with an intact uterus, selective estrogen receptor modulators (such as tamoxifen and raloxifene) and polycystic ovary syndrome (13).

The International Agency for Research on Cancer suggests that obesity is also a risk factor of EC (17). Furthermore, a Mendelian randomization study reported that an increase in BMI had a direct impact on EC risk and the overall impact of SNP alleles associated with an increase in BMI on EC risk exceeded their predicted impact on the BMI (18,19). The association of obesity with EC may be related to elevated estrogen levels, hyperinsulinemia and chronic inflammation (16,20,21). There is also evidence that diabetes increases the risk of EC (14). In a meta-analysis by Tsilidis et al (22), it was reported that the overall random impact on the incidence rate of EC in patients with diabetes was 1.97. EC is also associated with certain genetic factors. For instance, white women were reported to have a higher incidence of EC than women of other ethnicities in the US (23); however, this may also be due to the socio-economic differences and requires further study. An Italian study showed that ~5% of patients with EC have a family history of the disease in a first-degree relative (24). In addition, there are two genetic syndromes associated with EC, Lynch syndrome and Cowden syndrome (2527), with Lynch syndrome (also known as hereditary non-polyposis colorectal cancer) being the most common (25,26). It is estimated that up to 70% of women with Lynch syndrome will develop EC, which is typically hormone-responsive (25,26).

Certain studies have demonstrated that smoking reduces the risk of EC (28) and, compared with non-smokers, current or former smokers have a lower risk of EC (29,30). This reduced risk may be due to the mechanistic link between the anti-estrogen effects of smoking and the risk of EC (14,31). Of note, a study by Aune et al (32) reported that body height is significantly associated with the risk of EC [RR, 1.15; 95% confidence interval (CI), 1.09–1.22]. In summary, obesity is the main risk factor for EC and therefore, the importance of weight control to reduce the incidence of EC should be highlighted. However, additional risk factors such as diabetes, smoking and body height require further study.

Classification of EC

The classification of cancer is important, since different classifications may result in different treatment methods and prognoses. Based on clinical pathology and molecular characteristics, EC has historically been classified into two categories of Bokhman histopathology: Type I and type II (33). Type I (endometrioid carcinoma) is the most common type and accounts for 60–70% of EC cases, is graded 1 or 2 and exhibits high hormone receptor expression (33). These tumors are more likely to be detected at an early stage due to symptoms such as bleeding and patients with this type have a good prognosis. Type II accounts for 30–40% of all EC cases, typically includes high-grade endometrioid carcinoma and other histological types, such as serous or clear cell carcinoma, and is estrogen-independent (33). Type II is more invasive than type I and, even with an early diagnosis, the prognosis of type II is poor (34). However, the traditional pathological classification has certain limitations. For instance, certain high-level (grade 3) endometrial carcinoma and serous carcinoma are not easily distinguishable in terms of morphology. Furthermore, this classification cannot provide clear targets to assist in selecting new treatment methods or drugs.

In 2013, The Cancer Genome Atlas (TCGA) research network introduced a molecular classification system based on new advances in the understanding of the EC genome landscape (35). TCGA described the four molecular subgroups of EC as follows (35): i) Polymerase-ε (POLE) ultra-mutated, which is characterized by somatic mutations in the exonuclease domain of the DNA replication enzyme POLE and patients with this subtype have an excellent prognosis; ii) microsatellite instability hypermutated (MSI-H), which is characterized by high mutation rates in both sporadic and hereditary EC that are associated with changes in the mismatch repair (MMR) system genes, MLH1, MSH2, MSH6 and post-meiotic segregation 1 homolog 2 (PMS2) and the prognosis of patients with this subtype is intermediate; iii) copy-number low, which is characterized by a low mutational load and an intermediate prognosis, this subtype includes most EC cases and is often associated with gene mutations in phosphate and tension homology deleted on chromsome 10, catenin-β1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α subunit, AT-rich interactive domain-containing protein 1A and KRAS; and iv) copy-number high, which includes serous tumors and 25% of high-grade EC cases, patients with this subtype have a poor prognosis and the mutation rate of this subtype is the lowest, but TP53 mutations are frequent. A study of 50 patients with high-grade endometrial adenocarcinoma demonstrated that the clinical prognosis of each subgroup was different (36). At 48 months, the cancer-specific/disease-specific survival rate in the POLE mutation group was 100%, that in the MSI group was 82%, that in the copy-number low group was 77.8% and that in the copy-number high group was 42.9%. Therefore, this classification method reflects that these subgroups not only have different molecular and pathological characteristics, but also exhibit significant differences in clinical outcomes (35,37). This classification is also an example of tumor precision treatment. However, molecular subtyping is based on high-throughput deep sequencing, which is both costly and time-consuming and may limit the wider clinical application.

Talhouk et al (38) proposed a simple and economical molecular classification method to replace high-throughput sequencing (Fig. 1). This method used immunohistochemistry to detect the expression of the MMR proteins MSH6 and PMS2 to determine the type of MMR deficiency (dMMR). Sequencing of the exonuclease domain of the catalytic subunit of POLE was then conducted to determine the type of POLE mutant. Finally, cases were divided into p53 mutant-type according to the p53 immunohistochemistry staining results (staining 2+ or 0) or p53 wild-type (staining 1+). By this method, EC was then finally divided into dMMR, POLE ultra-mutated, p53 wild-type or p53 abnormal type, respectively replacing MSI-H, POLE ultra-mutated, copy-number low or copy-number high type. Although this new grouping is not completely equivalent to the TCGA classification, the four survival curves of the groupings were similar to those of the TCGA classification (38). The authors of the aforementioned study suggested that this simple method may be used on a large scale in the clinic, which is of great significance for guiding the molecular classification, risk grading and treatment of EC.

Mechanism and application of immunotherapy

Programmed cell death protein 1 (PD-1) was first reported by Ishida et al (39) in apoptotic T cells in mice. PD-1 belongs to the CD28 family of proteins and is mainly expressed on the surface of immune cells, such as activated T cells, B cells and natural killer cells (40,41). The most notable ligand of PD-1, PD-1 ligand 1 (PD-L1), is frequently expressed in various types of tumor cell (42). Tumor cells activate the inhibitory signaling pathway of PD-1/PD-L1, inhibit the activation of T cells and finally form an immune microenvironment suitable for tumor cell growth (43,44). Therefore, immunosuppressive agents against PD-1 or PD-L1 restore the immune activity of T cells, enhance the immune response and improve the ability of the immune system to kill tumor cells. This has been a major breakthrough in the field of tumor treatment in recent years (45). At present, PD-1 inhibitors that are effective in cancer treatment include nivolumab, pembrolizumab and cemiplimab, while PD-L1 inhibitors include atezolizumab, avelumab and durvalumab (45). Markers related to the efficacy of immune checkpoint inhibitors include PD-L1, MSI-H or dMMR tumor mutation burden (TMB). A study by Mo et al (46) demonstrated that 61.3% of patients with EC expressed PD-L1 in their tumor tissues. Furthermore, the degree of tissue differentiation was negatively associated with PD-L1 expression levels (46). Another previous study has also shown that 25–30% of EC cases have MSI-H or dMMR (47). A study by Kautto et al (48) demonstrated that, compared with proficient MMR (pMMR) tumors, dMMR tumors had more somatic mutations and produced more neoantigens. Furthermore, the efficacy of pembrolizumab against dMMR tumors was significantly higher compared to pMMR tumors (48). The therapeutic effect of PD-1/PD-L1 inhibitors is related to the TMB, as PD-1/PD-L1 inhibitors are more effective against tumors with a high TMB (35). Among the four molecular subtypes of EC, the TMB of MSI-H and POLE ultra-mutated subtypes was determined to be higher compared with that of the other groups (35). In addition, a previous study reported that the expression rates of PD-1 in POLE-mutant and MSI-H EC tissues were 73 and 69%, respectively, and that the expression rates of PD-L1 were 100 and 71%, respectively (49). Another feature of the MSI-H and POLE ultra-mutated subtypes is that they are rich in tumor-infiltrating lymphocytes and CD3+ and CD8+ T lymphocytes (50). Therefore, this suggests that there are active immune responses in the local microenvironment of MSI-H and POLE ultra-mutated tumors and that blocking PD-1/PD-L1 may induce an effective antitumor immune response (51). As such, the MSI-H and POLE ultra-mutated subtypes are most likely to benefit from PD-1/PD-L1 inhibitory therapy.

Application of immunosuppressive agents in EC

Until now, the first-line treatment for advanced EC was carboplatin and paclitaxel combined chemotherapy, with an overall response rate (ORR) of 50–60% and a median progression-free survival (mPFS) time of 1 year (52,53). After platinum treatment failed, conventional single drug chemotherapy was administered, but the outcome was poor. For instance, doxorubicin and paclitaxel are the most commonly used second-line treatments for EC and can only provide an mPFS time of 4 months and an mOS time of 1 year (54). Therefore, the exploration of new therapies to improve the prognosis of patients with advanced EC is urgently needed. In previous years, there have been a number of clinical research studies regarding immune checkpoint inhibitors in EC, which have provided a comprehensive scientific basis for drug research and development for the treatment of advanced EC (Table I).

Table I.

Published clinical studies with results available.

Table I.

Published clinical studies with results available.

First author, yearDrugTargetTrial identifierPhasePatient population, number of patients (n)TreatmentFindingsAdverse reactions(Refs.)
Le et al, 2015PembrolizumabPD-1NCT01876511IIPts with metastatic cancer with or without dMMR (n=41), including pts with EC (n=2)Pembrolizumab 10 mg/kg IV every 14 daysIn pts with dMMR, CRC; ORR, 40.0% (4/10); 20-week PFS, 77.8% (7/9). In pts with pMMR, CRC; ORR, 0% (0/18); 20-week PFS, 11.1% (2/18). In pts with dMMR, non-CRC; ORR, 71.4% (5/7); 20-week PFS, 66.7% (4/6)Rash, itching, thyroiditis, hypothyroidism, hypophysitis and asymptomatic pancreatitis(55)
Le et al, 2017PembrolizumabPD-1NCT01876511IIPts with 12 dMMR tumor types (n=86), including pts with EC (n=15)Pembrolizumab 10 mg/kg IV every 14 daysIn pts with dMMR ORR, 53.5% (46/86); DCR, 76.7% (66/86) In pts with dMMR of EC ORR, 53.3% (8/15); DCR, 73.3% (11/15)Hypothyroidism(57)
Ott et al, 2017PembrolizumabPD-1NCT02054806 (KEYNOTE-028)IbPts with locally advanced or metastatic PD-L1-positive EC (n=24)Pembrolizumab 10 mg/kg IV every 2 weeksORR, 13.0% (3/23); PFS, 1.8 months; 6-month PFS, 19%; 12-month PFS, 14.3%; 6-month OS, 67%; 12-month OS, 51%Fatigue, itching, fever and anorexia(58)
Marabelle et al, 2020PembrolizumabPD-1NCT02628067 (KEYNOTE-158)IIPts with advanced MSI-H or dMMR solid tumors (n=233), including pts with EC (n=49)Pembrolizumab 200 mg IV once every 3 weeksORR, 57.1% (28/49); PFS, 25.7 monthsFatigue, itching, diarrhea and weakness(59)
Tamura et al, 2019NivolumabPD-1 JapicCTI-163212IIPts with advanced/recurrent uterine cervical cancer (n=20), uterine corpus cancer (n=23) and soft tissue sarcoma (n=21)Nivolumab 240 mg IV every 2 weeksIn pts with EC (n=22): ORR, 22.7% (5/22); DCR, 68.2% (15/22); mPFS, 3.4 months; mOS, 8.7 monthsPruritus(61)
Oaknin et al, 2020DostarlimabPD-1NCT02715284 (GARNET trial)IPts with defective mismatch mutation repair EC (n=104)Dostarlimab 500 mg IV once every 3 weeks for 4 doses, then 1,000 mg once every 6 weeksORR, 42.3% (30/71); DCR, 57.7% (41/71)Anemia, colitis and diarrhea(63)
Liu et al, 2019AtezolizumabPD-L1NCT01375842IPts with advanced/recurrent epithelial ovarian (n=12) and uterine cancers (n=15)In the dose-expansion phase, atezolizumab 15 mg/kg or 1,200 mg IV every 3 weeks for 16 cycles or 1 year of treatment, whichever occurred firstORR, 13.3% (2/15); mPFS, 1.4 monthsDiarrhea and fatigue(64)
Konstantinopoulos et al, 2019AvelumabPD-L1NCT02912572IIPts with dMMR (n=15) and pMMR (n=16) recurrent/persistent ECAvelumab 10 mg/kg IV every 2 weeksIn pts with dMMR (n=15): ORR, 26.7% (4/15); PFS6 rate, 40%. In pts with pMMR/non-POLE (n=16): ORR, 6.25% (1/16); PFS6 rate, 6.25%Fatigue and nausea(65)
Antill et al, 2021DurvalumabPD-L1NCT03015129IIPts with advanced mismatch repair-deficient (n=36) and repair-proficient (n=31) ECDurvalumab 1,500 mg IV every 4 weeksIn pts with dMMR (n=36): ORR, 47% (17/36); mPFS, 8.3 months. In pts with pMMR (n=31): ORR, 3% (1/16); mPFS, 1.8 monthsHyperthyroidism and hypothyroidism(66)
Makker et al, 2020Pembrolizumab + lenvatinibPD-L1NCT02501096 (KEYNOTE-146)IIPts with previously treated EC (n=108)Lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg IV once every 3 weeks, in 3-week cyclesORRWk24, 38% (41/108); ORR, 38.9% (42/108); mDOR, 21.2 months; mPFS, 7.4 months; mOS, 16.7 months. In pts with MSI-H/dMMR at 24 weeks (n=11): ORR, 63.6% (7/11); in pts with MSS/pMMR at 24 weeks (n=94): ORR, 36.2% (34/94)Hypertension, diarrhea, fatigue, decreased appetite, hypothyroidism and nausea(71)

[i] Pts, patients; n, number; EC, endometrial cancer; DCR, disease control rate; dMMR, mismatch repair deficient; pMMR, mismatch repair proficient; mPFS, median progression-free survival; PFS6, PFS rate at 6 months; IV, intravenous; ORR, overall response rate; mOS, median overall survival; MSI-H, microsatellite instability-high; ORRWk24, overall response rate at 24 weeks; OS, overall survival; PD-1, programmed cell death protein 1; PD-L1, PD-1 ligand 1; POLE, polymerase ε; MSS, microsatellite stability; CRC, colorectal cancer; mDOR, median duration of response.

Immune checkpoint inhibitors in monotherapy
Anti-PD-1. Pembrolizumab

In 2015, Le et al (55) demonstrated the efficacy of the anti-PD-1 monoclonal antibody pembrolizumab against EC, which provided the first evidence for the administration of immunotherapy in advanced EC. The aforementioned study conducted a phase II clinical trial of 41 patients with metastatic cancer with or without dMMR, including 2 patients with EC. The 2 patients with EC achieved partial response (PR) and the ORR and PFS rates were 71 and 67%, respectively. In addition, >5% of patients experienced adverse events (AEs), including rash or itching (24%), thyroiditis, hypothyroidism or hypophysitis (10%) and asymptomatic pancreatitis (15%). To our knowledge, this study was the first to report the relationship between the tumor microenvironment, genotype and response to checkpoint inhibitors, which are critical for identifying predictors of response to immune checkpoint inhibitor therapy.

In 2016, Mehnert et al (56) reported on a 53-year-old patient with high-grade metastatic endometrial adenocarcinoma who received 10 mg/kg pembrolizumab treatment every 2 weeks and ultimately achieved a rapid and sustained (>14 months) clinical response.

In 2017, Le et al (57) published the results of a phase II clinical trial (NCT01876511) of pembrolizumab as a single-agent treatment for patients with the dMMR tumor subtype. An ORR of 53% (46 patients) was observed in the 86 patients enrolled and 21% of patients reached complete response (CR; 18 patients). The 15-patient EC cohort also exhibited an ORR of 53% (8 patients) and the disease control rate was 73.3% (11 patients). Throughout the study, 74% of patients experienced adverse reactions, but the majority had low-grade reactions. Endocrine disorders, mainly hypothyroidism, occur in 21% of patients and may be easily treated by thyroid hormone replacement therapy (57). This study further supported the hypothesis that dMMR tumors are sensitive to immunosuppressive agents, regardless of the location of the primary tumor. In the same year, the results of a phase IB trial, KEYNOTE-028 (NCT02054806), were also published (58). The 24 subjects of this study had advanced or metastatic PD-L1+ EC. Patients who progressed after standard treatment received 10 mg/kg intravenous (IV) pembrolizumab every 2 weeks for up to 24 months or until the disease progressed or the toxicity was intolerable. Among them, 3 patients achieved PR and 2 patients maintained stable disease (SD). The ORR was 13% and the 6-month PFS and OS rates were 19.0 and 68.8%, respectively. As for toxicity, minor adverse reactions were observed in 54.2% of patients, including fatigue, itching, fever and anorexia. Based on the aforementioned results, the US Food and Drug Administration (FDA) approved pembrolizumab for the treatment of solid tumors with MSI-H/dMMR in May 2017. This was the first antitumor drug approved following a diagnosis by biomarker rather than tissue type. In 2019, pembrolizumab was added to The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for EC, stating that pembrolizumab can be used for the treatment of EC when accompanied by MSI-H/dMMR recurrence or metastasis that has not responded to previous treatment (8).

In January 2020, phase II clinical trial (KEYNOTE-158) results were published involving 27 cases of advanced MSI-H or dMMR solid tumors, which were consistent with the results of NCT01876511 (59). Among the 233 patients enrolled, 49 had EC. The ORR of the patients with EC was 57.1%, of which 16% (8 patients) had a CR and 41% (20 patients) had a PR. The mPFS time was 25.7 months. Of the 233 enrolled patients, 151 (64.8%) had treatment-related AEs, of which 34 (14.6%) had grade 3–5 AEs. The most common toxicities were fatigue (14.6%), itching (12.9%), diarrhea (12.0%) and weakness (10.7%). Due to these AEs, 22 patients (9.4%) had to stop treatment.


Nivolumab is also an anti-PD-1 immunosuppressant. In 2016, Santin et al (60) reported on 2 patients with recurrent POLE ultra-mutated and MSH6 hypermutated EC tumors who were unresponsive to conventional surgery and chemotherapy. During the treatment of these 2 patients, nivolumab was administered as a single IV drug at a dose of 3 mg/kg once every 2 weeks. Following computed tomography scanning over several months, it was confirmed that the patients demonstrated a sustained clinical reaction to nivolumab and reported no severe toxicity. In addition, results from a multicenter, open-label nivolumab phase II clinical trial were released in 2019 (61). The 22 patients in this study with advanced/recurrent uterine cancer received 240 mg nivolumab every 2 weeks. The primary endpoint was the ORR and the secondary endpoints included OS, PFS and safety. The resulting ORR was 23%, the mPFS time was 3.4 months and the 6-month OS rate was 73%. In the uterine cancer cohort, the most common treatment-related adverse event was pruritus, which was mostly mild.


Dostarlimab (TSR-042) is an effective, selective and humanized anti-PD-1 immunoglobulin G4 monoclonal antibody, which has a high affinity for the PD-1 receptor and can effectively block the binding of PD-1 and PD-L1 (62). To date, the GARNET trial (NCT02715284) is the only published study to evaluate the curative effect of dostarlimab in EC and is the largest single study of an anti-PD-1 monotherapy for advanced or relapsed EC (63). As of the data cut-off point, 104 patients with dMMR EC were enrolled and received dostarlimab treatment. Among these patients, 71 with measurable lesions at baseline and a follow-up of ≥6 months were ultimately included in the analysis. The results indicated an ORR of 42.3% (30 patients), a CR rate of 12.7% (9 patients) and a PR rate of 29.6% (21 patients). The treatment response to dostarlimab was long-lasting and the adverse reactions were reported to be tolerable. The most common treatment-related AEs at level 3 or above were anemia (2.9%), colitis (1.9%) and diarrhea (1.9%).


The NCT01375842 study by Liu et al (64) was the first to detail the use of atezolizumab as a single drug treatment for gynecological cancer. In the aforementioned study, all 15 patients with EC were treated with atezolizumab in the dose-expansion phase of the study (15 mg/kg atezolizumab, n=1; 1,200 mg atezolizumab, n=14). As of December 31, 2016, 2 patients showed a PR, 2 patients maintained SD, 9 patients had progressive disease and 2 patients were not evaluable. The ORR was 13.3% [95% CI, 1.7–40.5%]. However, all patients experienced ≥1 AE and 7 patients (46.7%) in the uterine cancer cohort developed treatment-related AEs. In the uterine cancer cohort, the most common treatment-related AEs of any grade were diarrhea (20.0%) and fatigue (13.3%), with no occurrence of treatment-related grade 4 or 5 AEs. It can therefore be suggested that atezolizumab is safe for patients with advanced EC and it may have certain clinical benefits in some patients.


Avelumab, another anti-PD-L1 immunosuppressant, has also shown promising activity in patients with dMMR EC. Konstantinopoulos et al (65) published the results of a phase II clinical trial (NCT02912572) with 33 patients that were divided into two cohorts, dMMR and pMMR. The co-primary endpoints were the ORR and PFS rate at 6 months (PFS6). The ORR in the dMMR and pMMR/non-POLE cohorts was 26.7 and 6.25%, respectively. In the dMMR cohort, there were 4 patients with objective responses (1 withCR and 3 with PR). The PFS6 was 40.0% in the dMMR cohort and 6.25% in the pMMR/non-POLE cohort. Of the 31 patients who started the regimen, 22 (71%) had treatment-related AEs of any grade, but there were no grade 4 and 5 treatment-related AEs in any cohort. The most common adverse reactions were fatigue (35.5%) and nausea (16.1%).


Durvalumab is an IgG1 κ monoclonal antibody that binds to PD-L1 on tumor cells, blocking the interaction with PD-1 on T cells and antigen-presenting cells, thereby alleviating PD-1/PD-L1-mediated immunosuppression and allowing T cells to attack tumor cells (66). Results from the PHAEDRA study demonstrating the activity of durvalumab as a single agent in a dMMR and pMMR EC cohort were published in 2021 (66). The study included 71 patients with advanced EC, of which 36 were dMMR and 35 were pMMR. All patients received IV durvalumab at a dose of 1,500 mg every 4 weeks. The ORR of patients with dMMR was 47% (6 cases of CR and 11 cases of PR), while the ORR of patients with pMMR was 3% (1 case of PR). Furthermore, the mPFS time was 8.3 months in the dMMR cohort, while it was only 1.8 months in the pMMR cohort. A total of 14 patients reported immune-related AEs, most of which were grade 1 or 2, including hyperthyroidism, hypothyroidism, pneumonia and hepatitis.

In summary, the reported efficacy of immune checkpoint inhibitors as monotherapies in treating EC is considerable. However, the results of the aforementioned PD-1 and PD-L1 immunosuppressive drug clinical trials are different, which may be related to various factors, including the size of the samples, the genotype of the subjects and the choice of observation indicators. Therefore, if a large-scale clinical study on PD-1 and PD-L1 immunosuppressive drugs was conducted through a multi-center collaboration that followed a unified research scheme, jointly collecting study subjects and conducting an overall analysis, the clinical trial results would be more robust and reliable.

Immune checkpoint inhibitor-based drug combinations

As mentioned above, the use of immune checkpoint inhibitor monotherapy in EC is mainly limited to patients with dMMR or MSI-H mutations. However, patients with MSI-H/dMMR only account for 25–30% of cases and 70–75% of patients have microsatellite stability (MSS)/pMMR (47). The efficacy of single immune checkpoint inhibitor treatment in patients with MSS/pMMR is not optimal. Furthermore, with the increasingly widespread application of immunosuppressants and the complexity of immune response activation, immunosuppressive drug resistance is gradually increasing. Therefore, finding an improved treatment plan for patients with MSS/pMMR is required and researchers have adopted a joint strategy in the hope of achieving synergistic benefits and reducing the occurrence of primary or secondary drug resistance.

Immune checkpoint inhibitors and angiogenesis inhibitors

Lenvatinib is a kinase inhibitor against VEGFR1-3 and a small molecule targeted drug against angiogenesis (67). In a preclinical model, lenvatinib reduced the number of tumor-associated macrophages and increased the proportion of CD8+ T cells, thereby inducing immune activation (67). In multiple mouse xenograft models, the combination of anti-PD-1 monoclonal antibody and levatinib had a more optimal antitumor activity compared with monotherapy using either drug (68). Therefore, pembrolizumab combined with lenvatinib was hypothesized to be an effective antitumor strategy and as such, KEYNOTE-146 (NCT02501096) aimed to study the safety and initial efficacy of the combined drugs in the treatment of a variety of advanced solid tumors (69). The phase IB component of the study established that the maximum tolerated dose and the recommended phase II dose was 20 mg levatinib orally once a day combined with 200 mg pembrolizumab intravenously every 3 weeks (69). A multi-center, open-label, single-arm, phase II trial further investigated the efficacy of lenvatinib plus pembrolizumab in patients with primary advanced or recurrent EC (70). Between September 10, 2015 and July 24, 2017, 53 patients were included in the analysis. Of these patients, 39.6% (21/53) reported an objective response at week 24 and 30% (16/53) experienced serious treatment-related AEs. In the final efficacy analysis, the median follow-up time for 108 patients was 18.7 months at the time of data cut-off (71). The resulting ORR at week 24 (ORRWK24) of the 108 patients was 38% (41/108). Among these patients, 3 achieved CR and 38 achieved PR at week 24. In the subgroup analysis, the ORRWK24 of patients with MSS/pMMR (n=94) and MSI-H/dMMR (n=11) was 36.2% (95% CI, 26.5–46.7%) and 63.6% (95% CI, 30.8–89.1%), respectively. Regardless of the MSI status of the tumor, the median responseduration was 21.2 months, the mPFS time was 7.4 months and the mOS time was 16.7 months. Furthermore, 83/124 (66.9%) patients experienced grade 3 or 4 treatment-related AEs. The most common adverse reactions were hypertension, diarrhea, fatigue, decreased appetite, hypothyroidism and nausea. Based on the aforementioned studies, lenvatinib combined with pambrolizumab was approved by the FDA for the treatment of advanced EC that was not MSI-H/dMMR and had progressed following prior therapy.

A 2:1 randomized phase II clinical trial (NCT03367741) compared the efficacy of a cabozantinib and nivolumab combination (arm A) vs. nivolumab (arm B) in the treatment of recurrent EC (72). The primary endpoint of the study was PFS. The results demonstrated that the mPFS of arms A and B were 5.3 months (95% CI, 3.5–9.5) and 1.9 months (95% CI, 1.6–3.8), respectively. Furthermore, the ORR was 25% in arm A and 16.7% in arm B and the SD rate was 44.4 and 11.1%, respectively. Furthermore, the clinical benefit in arm A was significantly higher compared with that in arm B (P<0.001). The most common AEs in arm A were diarrhea (47.2%), elevated liver enzymes (44.4%), fatigue (38.9%), anorexia, hypertension and nausea (30.6%), which were mainly grade 1 or 2.

Further single arm phase II trials (NCT04042116 and NCT04157491) of anti-PD-1 drugs combined with other angiogenesis inhibitors (lucinib and anlotinib) for the treatment of EC are also under investigation at present (73).

Combination immunotherapy

Since any treatment may eventually result in drug resistance, there are ongoing efforts to study combined immunotherapy, which is a combination of immunosuppressive agents with different mechanisms.

A phase II study by Fumet et al (74) was the first trial to study a combination of olaparib and dual immunotherapy based on molecular screening. The study will aim to evaluate the effectiveness and safety of an olaparib/durvalumab/tremelimumab combination in patients with several types of solid cancer (n=213) that have at least one homologous repair gene mutation. Patients initially receive 300 mg olaparib twice per day. If there is no progress after receiving olaparib for 6 weeks, the patients receive olaparib and durvalumab (1,500 mg every 4 weeks) and tremelimumab (75 mg IV every 4 weeks) immunotherapy within 4 months. Patients are further administered durvalumab alone until the disease progresses, or patient death or intolerable toxicity occur or the patient/researcher decides to stop treatment.

There are currently additional early trials, such as the combination of nivolumab and ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4; NCT03508570 and NCT02982486), for the treatment of advanced EC (75) and the combination or non-combination of nivolumab and indoleamine 2,3-dioxygenase inhibitors (BMS-986205; NCT04106414) (75).

Immune checkpoint inhibitors and chemotherapy

Preclinical studies have indicated that chemotherapy may generate immune stimulation, enhance the presentation of tumor cell-specific antigens and lead to cancer cells triggering immune responses or increasing their susceptibility to immune system attack (76,77). These mechanisms lay the biological foundation for the later clinical research design of using a combination of chemotherapy and immunotherapy to treat cancer. At present, there are a number of phase III trials of immunosuppressive agents combined with carboplatin and paclitaxel for the treatment of patients with advanced or recurrent EC, such as dostarlimab (RUBY; NCT03981796), atezolizumab (AtTEnd; NCT03603184) and pembrolizumab (GY018; NCT02549209) (75). Although these studies do not consider the MMR status when recruiting patients, differences will be assessed in a subgroup analysis of patients with MSI-H and MSS tumors. In addition, a phase III trial of lenvatinib with pembrolizumab vs. doxorubicin or weekly paclitaxel (NCT03517449) in the treatment of advanced EC and a first-line lenvatinib with pembrolizumab vs. carboplatin and paclitaxel chemotherapy (NCT03884101) trial are currently ongoing (75). To the best of our knowledge, there are currently no preliminary data reported on the efficacy of immunotherapy combined with chemotherapy in advanced EC. However, it is esteemed that their combination provides promising results for patients with advanced EC.

Other combinations

Radiotherapy is also an important means to treat malignant tumors. A number of clinical studies have reported that radiotherapy combined with immunotherapy has an acceptable toxicity (78) and enhances the immune response at the irradiated site (79,80). The PRIMMO study (NCT04214067) is an ongoing randomized phase II trial evaluating the efficacy of pembrolizumab combined with low-fraction radiotherapy and immunomodulatory mixtures (vitamin D, curcumin, lansoprazole, aspirin and low-dose cyclophosphamide) in patients with pretreated advanced uterine tumors (cervical or endometrial carcinoma and uterine sarcoma) (81). The main endpoint of the study is the ORR at week 26.

Netrin-1, a protein upregulated in >80% of uterine tumors, serves an important role in cancer progression by regulating cell apoptosis (82). NP137 is a monoclonal antibody targeting netrin-1 that may reduce resistance to chemotherapy (83). A phase IB/II clinical trial (NCT04652076) evaluating the combination of NP137 with pembrolizumab and/or chemotherapy in the treatment of locally advanced/metastatic endometrial or cervical cancer has recently been initiated (73).

Conclusions and perspectives

In previous years, immunotherapy has received increasing attention in antitumor therapy. When the immune function of the body functions in a healthy manner, cancerous cells can be eliminated by the immune response in time and most individuals do not develop any tumors. When cancerous cells evade surveillance and elimination by immune cells due to certain changes, tumors may occur (84). Immunotherapy is aimed at all aspects of tumor immunity, using the immune response of the patient to treat tumors, which is safer and more efficient than other treatment methods and may potentially become a new method for the treatment of EC (85). However, following in-depth research on tumor immunotherapy, its drawbacks have also attracted attention. Indeed, an excessively enhanced immune response may damage normal tissues. For example, the gastrointestinal tract, endocrine glands, skin and liver are the organs most prone to immune-related AEs, while the central nervous system and cardiovascular, lung, musculoskeletal and blood systems are less involved (6). In addition, immune cells recognize tumor cells with a single target, low specificity and a weak killing effect. In previous studies, it was reported that immunosuppressive drug monotherapy has certain effects in the treatment of advanced EC, but the efficacy is not optimal (5566). Therefore, the ongoing combined strategies of targeted therapy, other immunotherapeutic agents, chemotherapy and radiotherapy may change the therapeutic prospects of advanced EC. In addition, antiangiogenic agents and poly(ADP-ribose) polymerase, PI3K/AKT/mTOR, EGFR, MEK, cyclin-dependent kinase and Wee1 inhibitors have all demonstrated certain activities, generating promising preliminary data (86) and are therefore research areas requiring closer attention.

The prognosis of patients with late-stage recurrent EC is poor. Currently, the NCCN guidelines still consider the chemotherapy regimen of carboplatin combined with paclitaxel as the first-line treatment for recurrent disease (87). Pembrolizumab is also listed as a class 1 treatment option for MSI-H/dMMR endometrial tumors and it is recommended that MSI-H or dMMR testing are performed for recurrent endometrial tumors, if not previously tested. As aforementioned, the effective rate of traditional chemotherapy, such as paclitaxel and carboplatin in the treatment of patients with advanced EC, ranges from 7–14% (912), while PD-1/PD-L1 inhibitors have a significant therapeutic effect on MSI-H/dMMR ECs, with an ORR of ~50% (57,59). Therefore, after the patients are fully informed of the efficacy, adverse reactions, medical expenses of immunotherapy and other related content and agree to the application, the markers related to the immunotherapy of the patient (including MSI, MMR, TMB and POLE mutations) can be determined and finally, the most suitable individualized treatment plan for the patient can be chosen. In addition, further research is required to elucidate the resistance mechanism of immunotherapy and for the implementation of immunotherapy early in the first-line treatment of tumors. In summary, it is esteemed that immunotherapy can play an increasingly important role in the treatment of EC and act in combination with various treatment methods to prolong the survival period and improve the quality of life of patients.


Not applicable.


Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

LW collected and analyzed data and drafted the original manuscript. LL analyzed the data and made modifications to the article. DH collected and analyzed data. YZ edited, reviewed and revised the manuscript. Data authentication is not applicable. All authors have read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.





endometrial cancer


The Cancer Genome Atlas


polymerase ε


microsatellite instability-high


mismatch repair deficient


programmed cell death protein 1


PD-1 ligand 1


tumor mutation burden


mismatch repair proficient


overall response rate


median progression-free survival


partial response


complete response


stable disease


The National Comprehensive Cancer Network


adverse events


PFS rate at 6 months




microsatellite stability


ORR at 24 weeks


median overall survival



Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI


Gu B, Shang X, Yan M, Li X, Wang W, Wang Q and Zhang C: Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990–2019. Gynecol Oncol. 161:573–580. 2021. View Article : Google Scholar : PubMed/NCBI


American Cancer Society, . Endometrial cancer survival rates, by stage. https://www.cancer.org/cancer/endometrial-cancer/detection-diagnosis-staging/survival-rates.html


Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N, et al: Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin Med J (Engl). 135:584–590. 2022. View Article : Google Scholar : PubMed/NCBI


Colombo N, Creutzberg C, Amant F, Bosse T, González-Martín A, Ledermann J, Marth C, Nout R, Querleu D, Mirza MR, et al: ESMO-ESGO-ESTRO Endometrial Consensus Conference Working Group. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: Diagnosis, treatment and follow-up. Ann Oncol. 27:16–41. 2016. View Article : Google Scholar : PubMed/NCBI


Musacchio L, Boccia SM, Caruso G, Santangelo G, Fischetti M, Tomao F, Perniola G, Palaia I, Muzii L, Pignata S, et al: Immune checkpoint inhibitors: A promising choice for endometrial cancer patients? J Clin Med. 9:17212020. View Article : Google Scholar : PubMed/NCBI


National Cancer Institute, . Endometrial cancer treatment Physician Data Query (PDQ). 2021.Available online. http://www.cancer.gov/cancertopics/pdq/treatment/endometrial/healthprofessional13–August. 2021


NCCN Clinical Practice Guidelines in Oncology, . Available online. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf13–August. 2020


Miller DS, Blessing JA, Lentz SS and Waggoner SE: A phase II trial of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma: A gynecologic oncology group study. Gynecol Oncol. 87:247–251. 2002. View Article : Google Scholar : PubMed/NCBI


Fracasso PM, Blessing JA, Molpus KL, Adler LM, Sorosky JI and Rose PG: Phase II study of oxaliplatin as second-line chemotherapy in endometrial carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol. 103:523–526. 2006. View Article : Google Scholar : PubMed/NCBI


Garcia AA, Blessing JA, Nolte S and Mannel RS; Gynecologic Oncology Group, : A phase II evaluation of weekly docetaxel in the treatment of recurrent or persistent endometrial carcinoma: A study by the Gynecologic Oncology Group. Gynecol Oncol. 111:22–26. 2008. View Article : Google Scholar : PubMed/NCBI


Dizon DS, Blessing JA, McMeekin DS, Sharma SK, Disilvestro P and Alvarez RD: Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: Gynecologic oncology group trial 129-P. J Clin Oncol. 27:3104–3108. 2009. View Article : Google Scholar : PubMed/NCBI


Smith RA, von Eschenbach AC, Wender R, Levin B, Byers T, Rothenberger D, Brooks D, Creasman W, Cohen C, Runowicz C, et al: American Cancer Society guidelines for the early detection of cancer: Update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: Update 2001-testing for early lung cancer detection. CA Cancer J Clin. 51:38–75; quiz 77–80. 2001. View Article : Google Scholar : PubMed/NCBI


Raglan O, Kalliala I, Markozannes G, Cividini S, Gunter MJ, Nautiyal J, Gabra H, Paraskevaidis E, Martin-Hirsch P, Tsilidis KK, et al: Risk factors for endometrial cancer: An umbrella review of the literature. Int J Cancer. 145:1719–1730. 2019. View Article : Google Scholar : PubMed/NCBI


Wu QJ, Li YY, Tu C, Zhu J, Qian KQ, Feng TB, Li C, Wu L and Ma XX: Parity and endometrial cancer risk: A meta-analysis of epidemiological studies. Sci Rep. 5:142432015. View Article : Google Scholar : PubMed/NCBI


Dunneram Y, Greenwood DC and Cade JE: Diet, menopause and the risk of ovarian, endometrial and breast cancer. Proc Nutr Soc. 78:438–448. 2019. View Article : Google Scholar : PubMed/NCBI


Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F and Straif K; International Agency for Research on Cancer Handbook Working Group, : Body fatness and cancer-viewpoint of the IARC working group. N Engl J Med. 375:794–798. 2016. View Article : Google Scholar : PubMed/NCBI


Painter JN, O'Mara TA, Marquart L, Webb PM, Attia J, Medland SE, Cheng T, Dennis J, Holliday EG, McEvoy M, et al: Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist: Hip ratio, is causal for endometrial cancer. Cancer Epidemiol Biomarkers Prev. 25:1503–1510. 2016. View Article : Google Scholar : PubMed/NCBI


Nead KT, Sharp SJ, Thompson DJ, Painter JN, Savage DB, Semple RK, Barker A; Australian National Endometrial Cancer Study Group (ANECS), ; Perry JR, Attia J, et al: Evidence of a causal association between insulinemia and endometrial cancer: A mendelian randomization analysis. J Natl Cancer Inst. 107:djv1782015. View Article : Google Scholar : PubMed/NCBI


Marlson MJ, Thiel KW, Yang S and Leslie KK: Catch it before it kills: Progesterone, obesity, and the prevention of endometrial cancer. Discov Med. 14:215–222. 2012.PubMed/NCBI


Khandekar MJ, Cohen P and Spiegelman BM: Molecular mechanisms of cancer development in obesity. Nat Rev Cancer. 11:886–895. 2011. View Article : Google Scholar : PubMed/NCBI


Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE and Ioannidis JP: Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ. 350:g76072015. View Article : Google Scholar : PubMed/NCBI


Buchanan EM, Weinstein LC and Hillson C: Endometrial cancer. Am Fam Physician. 80:1075–1080. 2009.PubMed/NCBI


Parazzini F, La Vecchia C, Moroni S, Chatenoud L and Ricci E: Family history and the risk of endometrial cancer. Int J Cancer. 59:460–462. 1994. View Article : Google Scholar : PubMed/NCBI


Aarnio M, Mecklin JP, Aaltonen LA, Nyström-Lahti M and Järvinen HJ: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 64:430–433. 1995. View Article : Google Scholar : PubMed/NCBI


Obermair A, Youlden DR, Young JP, Lindor NM, Baron JA, Newcomb P, Parry S, Hopper JL, Haile R and Jenkins MA: Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer. 127:2678–2684. 2010. View Article : Google Scholar : PubMed/NCBI


Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM and Swisher E: Cowden syndrome and the PTEN hamartoma tumor syndrome: Systematic review and revised diagnostic criteria. J Natl Cancer Inst. 105:1607–1616. 2013. View Article : Google Scholar : PubMed/NCBI


Zhou B, Yang L, Sun Q, Cong R, Gu H, Tang N, Zhu H and Wang B: Cigarette smoking and the risk of endometrial cancer: A meta-analysis. Am J Med. 121:501–508.e3. 2008. View Article : Google Scholar : PubMed/NCBI


Loerbroks A, Schouten LJ, Goldbohm RA and van den Brandt PA: Alcohol consumption, cigarette smoking, and endometrial cancer risk: Results from the Netherlands Cohort Study. Cancer Causes Control. 18:551–560. 2007. View Article : Google Scholar : PubMed/NCBI


Lindemann K, Vatten LJ, Ellstrøm-Engh M and Eskild A: Body mass, diabetes and smoking, and endometrial cancer risk: A follow-up study. Br J Cancer. 98:1582–1585. 2008. View Article : Google Scholar : PubMed/NCBI


Michnovicz JJ, Hershcopf RJ, Naganuma H, Bradlow HL and Fishman J: Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med. 315:1305–1309. 1986. View Article : Google Scholar : PubMed/NCBI


Aune D, Navarro Rosenblatt DA, Chan DS, Vingeliene S, Abar L, Vieira AR, Greenwood DC, Bandera EV and Norat T: Anthropometric factors and endometrial cancer risk: A systematic review and dose-response meta-analysis of prospective studies. Ann Oncol. 26:1635–1648. 2015. View Article : Google Scholar : PubMed/NCBI


Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15:10–17. 1983. View Article : Google Scholar : PubMed/NCBI


Wilczyński M, Danielska J and Wilczyński J: An update of the classical Bokhman's dualistic model of endometrial cancer. Prz Menopauzalny. 15:63–68. 2016.PubMed/NCBI


Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, et al: Integrated genomic characterization of endometrial carcinoma. Nature. 497:67–73. 2013. View Article : Google Scholar : PubMed/NCBI


Piulats JM, Guerra E, Gil-Martín M, Roman-Canal B, Gatius S, Sanz-Pamplona R, Velasco A, Vidal A and Matias-Guiu X: Molecular approaches for classifying endometrial carcinoma. Gynecol Oncol. 145:200–207. 2017. View Article : Google Scholar : PubMed/NCBI


Oaknin A, León-Castillo A and Lorusso D: Progress in the management of endometrial cancer (subtypes, immunotherapy, alterations in PIK3CA pathway): Data and perspectives. Curr Opin Oncol. 32:471–480. 2020. View Article : Google Scholar : PubMed/NCBI


Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, Yang W, Senz J, Boyd N, Karnezis AN, et al: A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 113:299–310. 2015. View Article : Google Scholar : PubMed/NCBI


Ishida Y, Agata Y, Shibahara K and Honjo T: Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11:3887–3895. 1992. View Article : Google Scholar : PubMed/NCBI


Mamalis A, Garcha M and Jagdeo J: Targeting the PD-1 pathway: A promising future for the treatment of melanoma. Arch Dermatol Res. 306:511–519. 2014. View Article : Google Scholar : PubMed/NCBI


Keir ME, Butte MJ, Freeman GJ and Sharpe AH: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 26:677–704. 2008. View Article : Google Scholar : PubMed/NCBI


Wu Y, Chen W, Xu ZP and Gu W: PD-L1 Distribution and perspective for cancer immunotherapy-blockade, knockdown, or inhibition. Front Immunol. 10:20222019. View Article : Google Scholar : PubMed/NCBI


Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK and Iyer AK: PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol. 8:5612017. View Article : Google Scholar : PubMed/NCBI


Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI


Post CCB, Westermann AM, Bosse T, Creutzberg CL and Kroep JR: PARP and PD-1/PD-L1 checkpoint inhibition in recurrent or metastatic endometrial cancer. Crit Rev Oncol Hematol. 152:1029732020. View Article : Google Scholar : PubMed/NCBI


Mo Z, Liu J, Zhang Q, Chen Z, Mei J, Liu L, Yang S, Li H, Zhou L and You Z: Expression of PD-1, PD-L1 and PD-L2 is associated with differentiation status and histological type of endometrial cancer. Oncol Lett. 12:944–950. 2016. View Article : Google Scholar : PubMed/NCBI


McMeekin DS, Tritchler DL, Cohn DE, Mutch DG, Lankes HA, Geller MA, Powell MA, Backes FJ, Landrum LM, Zaino R, et al: Clinicopathologic significance of mismatch repair defects in endometrial cancer: An NRG Oncology/Gynecologic oncology group study. J Clin Oncol. 34:3062–3068. 2016. View Article : Google Scholar : PubMed/NCBI


Kautto EA, Bonneville R, Miya J, Yu L, Krook MA, Reeser JW and Roychowdhury S: Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. Oncotarget. 8:7452–7463. 2017. View Article : Google Scholar : PubMed/NCBI


Eggink FA, Van Gool IC, Leary A, Pollock PM, Crosbie EJ, Mileshkin L, Jordanova ES, Adam J, Freeman-Mills L, Church DN, et al: Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology. 6:e12645652016. View Article : Google Scholar : PubMed/NCBI


Yamashita H, Nakayama K, Ishikawa M, Nakamura K, Ishibashi T, Sanuki K, Ono R, Sasamori H, Minamoto T, Iida K, et al: Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer. Oncotarget. 9:5652–5664. 2017. View Article : Google Scholar : PubMed/NCBI


Piulats JM and Matias-Guiu X: Immunotherapy in endometrial cancer: In the nick of time. Clin Cancer Res. 22:5623–5625. 2016. View Article : Google Scholar : PubMed/NCBI


Miller DS, Filiaci VL, Mannel RS, Cohn DE, Matsumoto T, Tewari KS, DiSilvestro P, Pearl ML, Argenta PA, Powell MA, et al: Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol. 38:3841–3850. 2020. View Article : Google Scholar : PubMed/NCBI


Nomura H, Aoki D, Takahashi F, Katsumata N, Watanabe Y, Konishi I, Jobo T, Hatae M, Hiura M and Yaegashi N: Randomized phase II study comparing docetaxel plus cisplatin, docetaxel plus carboplatin, and paclitaxel plus carboplatin in patients with advanced or recurrent endometrial carcinoma: A Japanese Gynecologic Oncology Group study (JGOG2041). Ann Oncol. 22:636–642. 2011. View Article : Google Scholar : PubMed/NCBI


McMeekin S, Dizon D, Barter J, Scambia G, Manzyuk L, Lisyanskaya A, Oaknin A, Ringuette S, Mukhopadhyay P, Rosenberg J, et al: Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol. 138:18–23. 2015. View Article : Google Scholar : PubMed/NCBI


Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al: PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372:2509–2520. 2015. View Article : Google Scholar : PubMed/NCBI


Mehnert JM, Panda A, Zhong H, Hirshfield K, Damare S, Lane K, Sokol L, Stein MN, Rodriguez-Rodriquez L, Kaufman HL, et al: Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J Clin Invest. 126:2334–2340. 2016. View Article : Google Scholar : PubMed/NCBI


Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 357:409–413. 2017. View Article : Google Scholar : PubMed/NCBI


Ott PA, Bang YJ, Berton-Rigaud D, Elez E, Pishvaian MJ, Rugo HS, Puzanov I, Mehnert JM, Aung KL, Lopez J, et al: Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: Results From the KEYNOTE-028 study. J Clin Oncol. 35:2535–2541. 2017. View Article : Google Scholar : PubMed/NCBI


Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, et al: Efficacy of pembrolizumab in patients with noncolorectal high microsatellite Instability/Mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol. 38:1–10. 2020. View Article : Google Scholar : PubMed/NCBI


Santin AD, Bellone S, Buza N, Choi J, Schwartz PE, Schlessinger J and Lifton RP: Regression of chemotherapy-resistant polymerase ε (POLE) Ultra-mutated and MSH6 Hyper-mutated endometrial tumors with nivolumab. Clin Cancer Res. 22:5682–5687. 2016. View Article : Google Scholar : PubMed/NCBI


Tamura K, Hasegawa K, Katsumata N, Matsumoto K, Mukai H, Takahashi S, Nomura H and Minami H: Efficacy and safety of nivolumab in Japanese patients with uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma: Multicenter, open-label phase 2 trial. Cancer Sci. 110:2894–2904. 2019. View Article : Google Scholar : PubMed/NCBI


Kasherman L, Ahrari S and Lheureux S: Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer. Future Oncol. 17:877–892. 2021. View Article : Google Scholar : PubMed/NCBI


Oaknin A, Tinker AV, Gilbert L, Samouëlian V, Mathews C, Brown J, Barretina-Ginesta MP, Moreno V, Gravina A, Abdeddaim C, et al: Clinical activity and safety of the anti-programmed Death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: A nonrandomized phase 1 clinical Trial. JAMA Oncol. 6:1766–1772. 2020. View Article : Google Scholar : PubMed/NCBI


Liu JF, Gordon M, Veneris J, Braiteh F, Balmanoukian A, Eder JP, Oaknin A, Hamilton E, Wang Y, Sarkar I, et al: Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. Gynecol Oncol. 154:314–322. 2019. View Article : Google Scholar : PubMed/NCBI


Konstantinopoulos PA, Luo W, Liu JF, Gulhan DC, Krasner C, Ishizuka JJ, Gockley AA, Buss M, Growdon WB, Crowe H, et al: Phase II Study of Avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer. J Clin Oncol. 37:2786–2794. 2019. View Article : Google Scholar : PubMed/NCBI


Antill Y, Kok PS, Robledo K, Yip S, Cummins M, Smith D, Spurdle A, Barnes E, Lee YC, Friedlander M, et al: Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial. J Immunother Cancer. 9:e0022552021. View Article : Google Scholar : PubMed/NCBI


Mittica G, Ghisoni E, Giannone G, Aglietta M, Genta S and Valabrega G: Checkpoint inhibitors in endometrial cancer: Preclinical rationale and clinical activity. Oncotarget. 8:90532–90544. 2017. View Article : Google Scholar : PubMed/NCBI


Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, Ito J, Tachino S, Hori Y, Matsuki M, et al: Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 14:e02125132019. View Article : Google Scholar : PubMed/NCBI


Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, Stepan DE, Shumaker RC and Motzer RJ: Phase IB/II trial of Lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 38:1154–1163. 2020. View Article : Google Scholar : PubMed/NCBI


Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, Di Simone C, Hyman DM, Stepan DE, Dutcus CE, et al: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: An interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 20:711–718. 2019. View Article : Google Scholar : PubMed/NCBI


Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, Romeo M, Bratos R, Brose MS, DiSimone C, et al: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 38:2981–2992. 2020. View Article : Google Scholar : PubMed/NCBI


Lheureux S, Matei D, Konstantinopoulos PA, Block MS, Jewell A, Gaillard S, McHale MS, McCourt CK, Temkin S, Girda E, et al: A randomized phase II study of cabozantinib and nivolumab versus nivolumab in recurrent endometrial cancer. J Clin Oncol. 38:60102020. View Article : Google Scholar


Rousset-Rouviere S, Rochigneux P, Chrétien AS, Fattori S, Gorvel L, Provansal M, Lambaudie E, Olive D and Sabatier R: Endometrial carcinoma: Immune microenvironment and emerging treatments in immuno-oncology. Biomedicines. 9:6322021. View Article : Google Scholar : PubMed/NCBI


Fumet JD, Limagne E, Thibaudin M, Truntzer C, Bertaut A, Rederstorff E and Ghiringhelli F: Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment. BMC Cancer. 20:7482020. View Article : Google Scholar : PubMed/NCBI


Green AK, Feinberg J and Makker V: A review of immune checkpoint blockade therapy in endometrial cancer. Am Soc Clin Oncol Educ Book. 40:1–7. 2020.PubMed/NCBI


Zitvogel L, Kepp O and Kroemer G: Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 8:151–160. 2011. View Article : Google Scholar : PubMed/NCBI


Liu WM, Fowler DW, Smith P and Dalgleish AG: Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 102:115–123. 2010. View Article : Google Scholar : PubMed/NCBI


Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, Al-Hallaq HA, Arina A, Khodarev NN, Janisch L, et al: Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 36:1611–1618. 2018. View Article : Google Scholar : PubMed/NCBI


Walle T, Martinez Monge R, Cerwenka A, Ajona D, Melero I and Lecanda F: Radiation effects on antitumor immune responses: Current perspectives and challenges. Ther Adv Med Oncol. 10:17588340177425752018. View Article : Google Scholar : PubMed/NCBI


Lee L and Matulonis U: Immunotherapy and radiation combinatorial trials in gynecologic cancer: A potential synergy? Gynecol Oncol. 154:236–245. 2019. View Article : Google Scholar : PubMed/NCBI


Tuyaerts S, Van Nuffel AMT, Naert E, Van Dam PA, Vuylsteke P, De Caluwé A, Aspeslagh S, Dirix P, Lippens L, De Jaeghere E, et al: PRIMMO study protocol: A phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer. BMC Cancer. 19:5062019. View Article : Google Scholar : PubMed/NCBI


Grandin M, Meier M, Delcros JG, Nikodemus D, Reuten R, Patel TR, Goldschneider D, Orriss G, Krahn N, Boussouar A, et al: Structural decoding of the Netrin-1/UNC5 interaction and its therapeutical implications in cancers. Cancer Cell. 29:173–185. 2016. View Article : Google Scholar : PubMed/NCBI


Paradisi A, Creveaux M, Gibert B, Devailly G, Redoulez E, Neves D, Cleyssac E, Treilleux I, Klein C, Niederfellner G, et al: Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death. EMBO Mol Med. 5:1821–1834. 2013. View Article : Google Scholar : PubMed/NCBI


Pakish JB and Jazaeri AA: Immunotherapy in gynecologic cancers: Are We there yet? Curr Treat Options Oncol. 18:592017. View Article : Google Scholar : PubMed/NCBI


Pakish JB, Zhang Q, Chen Z, Liang H, Chisholm GB, Yuan Y, Mok SC, Broaddus RR, Lu KH and Yates MS: Immune microenvironment in microsatellite-instable endometrial cancers: Hereditary or sporadic origin matters. Clin Cancer Res. 23:4473–4481. 2017. View Article : Google Scholar : PubMed/NCBI


Tronconi F, Nero C, Giudice E, Salutari V, Musacchio L, Ricci C, Carbone MV, Ghizzoni V, Perri MT, Camarda F, et al: Advanced and recurrent endometrial cancer: State of the art and future perspectives. Crit Rev Oncol Hematol. 180:1038512022. View Article : Google Scholar : PubMed/NCBI


Abu-Rustum N, Yashar C, Arend R, Barber E, Bradley K, Brooks R, Campos SM, Chino J, Chon HS, Chu C, et al: Uterine Neoplasms, Version 1.2023, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 21:181–209. 2023. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

Volume 27 Issue 2

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Wang L, Liu L, Huo D and Zhang Y: A comprehensive analysis of immunotherapy in advanced endometrial cancer (Review). Oncol Lett 27: 77, 2024
Wang, L., Liu, L., Huo, D., & Zhang, Y. (2024). A comprehensive analysis of immunotherapy in advanced endometrial cancer (Review). Oncology Letters, 27, 77. https://doi.org/10.3892/ol.2023.14210
Wang, L., Liu, L., Huo, D., Zhang, Y."A comprehensive analysis of immunotherapy in advanced endometrial cancer (Review)". Oncology Letters 27.2 (2024): 77.
Wang, L., Liu, L., Huo, D., Zhang, Y."A comprehensive analysis of immunotherapy in advanced endometrial cancer (Review)". Oncology Letters 27, no. 2 (2024): 77. https://doi.org/10.3892/ol.2023.14210