This article reviews treatments and targets of interest in endometrial cancer by molecular subtype. The Cancer Genome Atlas (TCGA) classifies four molecular subtypes—mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H); copy number high (CNH)/p53abn; copy number low (CNL)/no specific molecular profile (NSMP); and POLEmut—which are validated and highly prognostic. Treatment consideration by subtype is now recommended. In March and April 2022, respectively, the US Food and Drug Administration (FDA) fully approved and the European Medicines Agency adopted a positive opinion recommending the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab for advanced/recurrent dMMR/MSI-H endometrial cancer which has progressed on or following a platinum-containing therapy. A second anti-PD-1, dostarlimab, received accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency in this group. The combination of pembrolizumab/lenvatinib for mismatch repair proficient/microsatellite stable endometrial cancer, including p53abn/CNH and NSMP/CNL, received accelerated FDA approval in conjunction with Australia’s Therapeutic Goods Administration and Health Canada in September 2019. The FDA and European Medicines Agency made full recommendations in July 2021 and October 2021. Trastuzumab is National Comprehensive Cancer Network (NCCN) compendium listed for human epidermal growth factor receptor-2-positive serous endometrial cancer, which is primarily within the p53abn/CNH subtype. In addition to hormonal therapy, maintenance therapy with selinexor (exportin-1 inhibitor) showed potential benefit in p53-wildtype cases in a subset analysis and is being investigated prospectively. Other treatment regimens being evaluated in NSMP/CNL are hormonal combinations with cyclin-dependent kinase 4/6 inhibitors and letrozole. Ongoing trials are evaluating immunotherapy in combination with frontline chemotherapy and other targeted agents. Treatment de-escalation is being evaluated in POLEmut cases given its favorable prognosis with or without adjuvant therapy. Molecular subtyping has important prognostic and therapeutic implications, and should guide patient management and clinical trial design in endometrial cancer, which is a molecularly driven disease.
- Endometrial Neoplasms
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Endometrial cancer is the most common gynecologic cancer in the USA with a rising incidence and mortality rate.1 Poor outcomes disproportionately affect Black patients, who are more likely to present with high-risk endometrial cancer and more likely to die from the disease regardless of stage or histology at time of diagnosis.1 Treatment for endometrial cancer consists of hysterectomy with bilateral salpingo-oophorectomy and possible lymph node dissection; approximately 80% of patients are treated with surgery alone with an overall 5-year survival rate >90%.2 Advanced/recurrent endometrial cancer remains a significant therapeutic challenge. Standard of care first-line therapy for these patients consists of platinum-based chemotherapy, usually carboplatin/paclitaxel. Treatment options following progression after first-line therapy are limited with 5-year survival rates as low as 17%.2 Additionally, a subset of early-stage endometrial cancers with high-risk features may need adjuvant treatment, emphasizing the need for a reliable risk stratification system to guide management.
The characterization of four molecular subtypes by The Cancer Genome Atlas (TCGA) has refined risk stratification of endometrial cancer. Using somatic mutations, copy number alterations, and microsatellite instability, TCGA determined four molecular subtypes: POLE (ultra-mutated); microsatellite instability-high, MSI-H (hypermutated); copy number low, CNL (endometrioid); and copy number high, CNH (serous-like).3 Subsequently, the Leiden/Trans PORTEC and Vancouver/Proactive Molecular Risk Classifier for Endometrial Cancer studies developed and validated an approach to reproduce such classifications using immunohistochemistry for p53 and mismatch repair status, and tumor sequencing for POLE exonuclease domain mutation status.4 The four molecular subtypes, POLEmut, mismatch repair deficient (dMMR), p53-abnormal (p53abn), and no specific molecular profile (NSMP), under this surrogate classification system are highly reproducible and consistent with TCGA subtypes.4 Further, molecular classification has stronger prognostic significance than traditional histology, leading to the inclusion of molecular typing in the 2020 guidelines for endometrial cancer management provided by the European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology, and the European Society of Pathology.4
We discuss these emerging biomarkers and outline current treatment approaches and future directions in the management of endometrial cancer by molecular subtype.
dMMR/MSI-H endometrial cancer is characterized by loss of DNA mismatch repair and high mutation rates. This subtype accounts for 25–30% of endometrial cancers and over 90% have endometrioid histology.3 dMMR/MSI-H endometrial cancer can be identified through microsatellite or immunohistochemistry testing for loss of expression of DNA mismatch repair proteins (MLH1, MSH2, MSH6, PMS2). The majority of dMMR/MSI-H endometrial cancers are sporadic; 75% of cases result from MLH1-promoter hypermethylation. In contrast, Lynch syndrome is caused by germline mutations in mismatch repair genes and accounts for approximately 10–20% of dMMR and 3% of all endometrial cancers.5 Current guidelines recommend screening for mismatch repair at initial diagnosis, but data presented at the Society of Gynecologic Oncology annual meeting 2022 suggest it may be appropriate to retest mismatch repair status on relapse.2 6 In a retrospective cohort study, 3/32 (9.4%) patients with initially MMR proficient (pMMR) endometrial cancer were found to have dMMR at recurrence.6 These findings need confirmation in a larger prospective cohort.
Recent data suggest adjuvant radiation is effective in dMMR/MSI-H endometrial cancer. Molecular analysis of PORTEC-3, a randomized phase III trial of combined adjuvant chemotherapy and external beam radiotherapy versus radiotherapy alone, found no benefit with the addition of chemotherapy to adjuvant radiation in dMMR endometrial cancer. Five-year overall survival was 84% with radiotherapy alone and 79% with chemoradiation (p=0.445).7 A retrospective study of patients with advanced stage, MSI-H endometrial cancer found improved progression-free survival with the addition of radiation to chemotherapy versus chemotherapy alone in this group.8 Prospective studies are needed to confirm the role of adjuvant radiation and/or chemotherapy in dMMR/MSI-H endometrial cancer.
Hypermutated dMMR/MSI-H and ultra-mutated POLEmut endometrial cancers have immunogenic microenvironments.3 High mutational burden increases production of tumor-mutated antigens, leading to increased tumor infiltration by cytotoxic T-cells and upregulated T-cell mediated antitumor responses.9 Programmed cell death protein 1 (PD-1) on T-cells helps facilitate this immune response and is inhibited when bound to its ligands within the tumor microenvironment, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2).9 High expression of immune checkpoint-associated proteins, including PD-L1, in dMMR/MSI-H tumors make them susceptible to immune checkpoint inhibitors.3 9
Pembrolizumab (anti-PD-1) was the first immune checkpoint inhibitor approved in endometrial cancer. Blocking the interaction between PD-1 and its ligands, pembrolizumab prevents tumor cells from escaping immune surveillance.9 Pembrolizumab received accelerated US Food and Drug Administration (FDA) approval for unresectable/metastatic MSI-H solid tumors, including endometrial cancer, in 2017 and for unresectable/metastatic tumor mutational burden-high solid tumors, including endometrial cancer, in 2020.10 In March and April 2022, respectively, the FDA fully approved and the European Medicines Agency adopted a positive opinion recommending pembrolizumab for previously treated dMMR/MSI-H endometrial cancer following the non-randomized, open-label, phase II KEYNOTE-158 study (objective response rate (ORR) 48% (95% CI 36.7% to 59.6%); progression-free survival 13.1 (95% CI 4.3 to 34.4) months; overall survival, not reached).10–12
Dostarlimab (anti-PD-1) received both accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency for advanced/recurrent dMMR endometrial cancer that has progressed on or after platinum-based therapy.13 In the single-arm, open-label, phase I GARNET trial, dostarlimab conferred an ORR of 43.5% (95% CI 34.0% to 53.4%) with a 12-month duration of response in 90.6% of patients with dMMR/MSI-H disease.14 Long-term GARNET data presented at the 2022 annual meeting of the American Society of Clinical Oncology showed that 83.7% of patients treated with dostarlimab remained in response at 24 months.15 Other drugs within this class include nivolumab (anti-PD-1) and atezolizumab, avelumab, and durvalumab (anti-PD-L1), with ORRs in phase II trials of 23%, 13%, 26.7%, and 47%, respectively (Table 1).5 Interestingly, in a small cohort, Bellone et al found improved ORR, progression-free survival, and overall survival in Lynch-associated (n=6) versus sporadic (n=18) dMMR endometrial cancer when treated with pembrolizumab.16 Moreover, results at the Society of Gynecologic Oncology annual meeting 2022 suggest a correlation between MLH1-hypermethylation and poor response to single-agent immunotherapy with pembrolizumab in recurrent endometrial cancer.17 However, data from the GARNET trial in the largest cohort evaluating this noted that MSI-H tumors regardless of mutation or presumed methylation had similar efficacy with single-agent immunotherapy with dostarlimab.14
The benefit of immune checkpoint inhibitors is evident in patients with advanced/recurrent dMMR/MSI-H endometrial cancer following first-line therapy. However, it has yet to be determined if patients with dMMR/MSI-H endometrial cancer could benefit from immunotherapy in other settings, such as adjuvant use in high-risk patients or combined use with first-line chemotherapy or other targeted therapies. Currently, NRG-GY020, the first molecularly selected adjuvant therapy trial in endometrial cancer, is evaluating the addition of pembrolizumab to radiation in newly diagnosed early-stage dMMR endometrioid endometrial cancer and has completed accrual (NCT0421406). Following GY020, ENGOT-en11/GOG-3053/KEYNOTE-B21 is a phase III study of pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy, which has also completed accrual (NCT04634877). Results of several clinical trials assessing the efficacy of immune checkpoint inhibitors in combination with first-line chemotherapy in advanced/recurrent endometrial cancer are pending: ENGOT-EN6/NSGO-RUBY using dostarlimab, AtTEnd/ENGOT-en7 using atezolizumab, and NRG-GY018 using pembrolizumab (NCT03981796, NCT03603184, NCT03914612). Chemotherapy may increase immune stimulation and induce PD-L1 expression on cancer cells, making the combination of immune checkpoint inhibitors and chemotherapy promising.9 Further, there is evidence for first-line treatment with immune checkpoint inhibitors in dMMR solid tumors outside of endometrial cancer. In locally advanced dMMR rectal cancer, first-line dostarlimab induced complete response in 100% of patients at 6 months of follow-up.18 Two studies are evaluating first-line immune checkpoint inhibitor versus carboplatin-paclitaxel in advanced/recurrent dMMR endometrial cancer: KEYNOTE-C93/GOG-3064/ENGOT-en15 using pembrolizumab, and GINECO-EN105b/ENGOT-en13 using dostarlimab (NCT05173987, NCT05201547).
Within the dMMR/MSI-H subtype, combination therapies for patients who failed or progressed through single-agent immunotherapy include inhibiting cytotoxic T-lymphocyte antigen-4, which decreases T-cell function when bound to co-stimulatory molecules on antigen presenting cells.9 NRG-GY025 is assessing nivolumab (anti-PD1) plus ipilimumab (anti-cytotoxic T-lymphocyte antigen-4) versus single-agent nivolumab in recurrent dMMR endometrial cancer (NCT05112601). Poly (ADP-ribose) polymerase (PARP) inhibitors are also being investigated in combination with immunotherapy. PARP inhibition causes accumulation of DNA damage, which may alter immune checkpoint receptor expression and increase immune checkpoint inhibitor activity. However, in the single-arm phase II DOMEC trial, the combination of durvalumab (anti-PD-L1) and olaparib (PARP inhibitor) did not meet the pre-specified 50% 6-month progression-free survival in the overall population (median progression-free survival 3.4 months, 95% CI 2.8 to 6.2 months) nor in the dMMR cohort (median progression-free survival 5.7 months, 95% CI 2.8 to NR).19 Two trials, RUBY part 2 and DUO-E, are investigating the combination of platinum-based chemotherapy, immune checkpoint inhibitors, and PARP inhibitors in first-line treatment of advanced endometrial cancer (NCT03981796, NCT04269200). Additionally, avelumab, in combination with either talazoparib (PARP inhibitor) or axitinib (tyrosine kinase inhibitor), is being studied in patients with endometrial cancer based on mismatch repair status (NCT02912572). Finally, one arm of an ongoing multicohort biomarker directed study of targeted agents with atezolizumab (AFT-50/ENDOMAP) is evaluating the combination of atezolizumab with tiragolumab (anti-TIGIT) in MSI-H endometrial cancer which has progressed following single-agent immunotherapy (NCT04486352).
Agents on the Horizon
Lymphocyte activation gene-3 participates in the immune escape of tumor cells and is thus a target for immunotherapy. In March 2022, based on longer progression-free survival from RELATIVITY-047, the first lymphocyte activation gene-3 inhibitor, relatlimab, received FDA approval in combination with nivolumab for melanoma.20 In endometrial cancer, lymphocyte activation gene-3 expression is found in over 30% of patients, with greater prevalence in the dMMR/MSI-H (66.3%) and POLEmut (34.4%) subtypes.21
Another possible target for future therapy is T-cell immunoglobulin-3, an immune checkpoint molecule similar to PD-1. T-cell immunoglobulin-3 is found in multiple solid tumors, including endometrial cancer.22 Stronger expression was observed in dMMR endometrial cancer than pMMR, especially for MLH1-hypermethylated and MSH6-loss cases.23 Research targeting T-cell immunoglobulin-3 is ongoing. PODIUM 204 is a phase II study of retifanlimab (anti-PD-1) in advanced or metastatic endometrial cancer as monotherapy or in combination with other targeted agents, including one targeting lymphocyte activation gene-3 and one targeting T-cell immunoglobulin-3 (NCT04463771).
Bispecific antibodies, which target two different epitopes, are a novel approach in endometrial cancer. A phase II trial in advanced gynecologic cancers is evaluating an immunoglobulin G1 bispecific antibody against PD-1 and vascular endothelial growth factor (VEGF) and plans to assess differences by dMMR status in endometrial cancer (NCT04870177). A second phase II trial in advanced gynecologic cancers, including endometrial, is evaluating a bispecific monoclonal antibody that targets PD-1 and cytotoxic T-lymphocyte antigen-4 (NCT05032040). Additionally, next generation cytotoxic T-lymphocyte antigen-4 inhibitors have shown promise in multiple solid tumors, including endometrial cancer. AGEN1181, a fragment crystallizable-enhanced anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody, demonstrated clinical activity as a monotherapy and in combination with balstilimab (anti-PD-1) in heavily pretreated advanced solid tumors. In three patients with microsatellite stable endometrial cancer who received monotherapy or combination dosing, the disease control rate was 100% with one complete response and two partial responses.22
POLEmut endometrial cancer, characterized by extremely high mutation rates and microsatellite stability, has excellent prognosis. POLE mutations are found in 5–8% of all endometrial cancers and in 10–20% of grade 3 endometrioid endometrial cancer.24 However, further clarification of the pathogenicity of POLE mutations is needed as there are currently only 11 well-characterized missense mutations.25 A recent meta-analysis assessed outcomes between patients with pathogenic mutations as outlined by the criteria set forth by Leon-Castillo et al versus other non-pathogenic mutations, and found statistically significant differences in outcomes.26–28
In PORTEC-3, favorable survival for POLEmut persisted regardless of adjuvant therapy.4 A recent meta-analysis suggested de-escalation of treatment in POLEmut tumors is possible given low recurrence/progression (3.7%) and high salvage rates (72.7%).28 TAPER, PORTEC-4a, and Blue-POLE are prospective trials evaluating de-escalation of care in this subtype (NCT04705649, NCT03469674, NCT05255653).
POLEmut endometrial cancers have immunogenic tumor microenvironments and are expected to have favorable responses to immune checkpoint inhibitors as they express high levels of immune checkpoint-associated proteins including PD-L1.4 5 However, there are limited data on response to immune checkpoint inhibitors in POLEmut endometrial cancer. In a study of multiple cancer types with POLE mutations, nivolumab had a 50% ORR, with 4/16 patients diagnosed with endometrial cancer.29
The p53abn/CNH subtype is characterized by a very high number of somatic copy number alterations, low mutation frequencies, and recurrent TP53, PPP2R1A, and FBXW7 somatic mutations.3 The majority of serous carcinomas have abnormal P53 expression, but p53abn/CNH tumors occur in all histology types. Although p53abn/CNH cases account for only 15% of all endometrial cancer, they are associated with 50–70% of mortality.5 Importantly, a study of racial disparities in TCGA found a higher prevalence of the p53abn/CNH subtype in Black patients.1 Given the poor prognosis, and the racial inequities in outcomes for Black patients, it is imperative to identify and treat p53abn/CNH cases. Of note, grade 1/2 endometrioid endometrial cancers without lymphovascular invasion are typically considered low-risk and treated with surgery alone. However, 5% of grade 1/2 endometrioid endometrial cancers are p53abn/CNH and are thus at risk of undertreatment.5
Platinum-based chemotherapy appears to have greater benefit in p53abn/CNH endometrial cancer than in other molecular subtypes. Retrospective molecular analysis of PORTEC-3 found significantly improved outcomes for chemotherapy added to pelvic radiation in p53abn/CNH endometrial cancer (5-year recurrence-free survival of 59% with chemotherapy and radiation vs 36% with radiation).7 Nevertheless, additional treatments are needed given the poor survival outcomes in p53abn/CNH endometrial cancer.
Immunotherapy and Targeted Therapy
For pMMR tumors including those in the p53abn/CNH subtype, single-agent immunotherapy had modest response rates. However, pembrolizumab plus lenvatinib (multi-kinase inhibitor) for advanced endometrial cancer that is not MSI-H/dMMR and has progressed following prior therapy was granted accelerated approval by the FDA in conjunction with Australia’s Therapeutic Goods Administration and Health Canada through Project Orbis in September 2019.10 Lenvatinib decreases tumor-associated macrophages, increases T-cells, and decreases VEGF-mediated immunosuppression.9 In the open-label, phase Ib/II KEYNOTE-146 trial, pembrolizumab/lenvatinib had an overall ORR at 24 weeks of 38.0% (95% CI 28.8% to 47.8%) in patients with previously treated advanced endometrial cancer, with ORRs for microsatellite stable tumors (94 patients) of 36.2% (95% CI 26.5% to 46.7%) and MSI-H tumors (11 patients) of 63.6% (95% CI 30.8% to 89.1%).30 In KEYNOTE-775/Study 309, the confirmatory phase III trial of pembrolizumab/lenvatinib in 697 patients with pMMR tumors, pembrolizumab/lenvatinib conferred a significant improvement versus chemotherapy in both progression-free survival (6.6 vs 3.8 months; hazard ratio (HR) 0.60, 95% CI 0.50 to 0.72) and overall survival (17.4 vs 12.0 months; HR 0.68, 95% CI 0.56 to 0.84).31 The FDA granted full approval in July 2021 and the European Medicines Agency adopted a positive opinion recommending approval in October 2021 for this combination in patients with endometrial cancer that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any settings, and who are not candidates for curative surgery or radiation.10 32 KEYNOTE-775/Study 309 also found significant improvements in all comers (pMMR and dMMR) using pembrolizumab/lenvatinib versus chemotherapy for progression-free survival (7.2 vs 3.8 months; HR 0.56, 95% CI 0.47 to 0.66) and overall survival (18.3 vs 11.4 months; HR 0.62, 95% CI 0.51 to 0.75).31 However, it is unknown if pembrolizumab/lenvatinib in dMMR tumors has additional benefit given the significant toxicities associated with the regimen, including hypertension, diarrhea, decreased appetite, fatigue, and hypothyroidism. In KEYNOTE-146, grade 3/4 toxicities occurred in 69% of patients.30 Results are pending from the recently completed phase III LEEP-001/ENGOT-en9 trial, which assessed pembrolizumab/lenvatinib as first-line treatment versus carboplatin/paclitaxel in advanced/recurrent endometrial cancer stratified by mismatch repair status (NCT03884101).
For p53abn/CNH tumors, human epidermal growth factor-2, a receptor tyrosine-protein kinase encoded by ERBB2, is a potential therapeutic target. Although anti-human epidermal growth factor-2 therapy with the monoclonal antibody trastuzumab has not been successful in unselected endometrial cancer, amplification of ERBB2 is found in approximately 30% of serous endometrial cancers and may be necessary for best response. Fader et al showed chemotherapy plus trastuzumab for advanced/recurrent human epidermal growth factor-2-positive serous endometrial cancer significantly improved progression-free survival (12.9 vs 8.0 months; HR 0.46, 90% CI 0.28 to 0.76) and overall survival (29.6 vs 24.4 months; HR 0.58, 90% CI 0.34 to 0.99) versus chemotherapy alone.33 The National Comprehensive Cancer Network (NCCN) guidelines now include trastuzumab in addition to chemotherapy for this patient group (Table 2).2 To evaluate dual human epidermal growth factor-2 inhibition, GYO-026 is assessing chemotherapy plus trastuzumab or trastuzumab/pertuzumab in human epidermal growth factor-2-positive serous endometrial cancer (NCT05256225). Although the above-cited studies did not use molecular stratification, serous endometrial cancers primarily fall into the p53abn/CNH molecular subtype. Further, a recent retrospective analysis of PORTEC-3 found the correlation between abnormal p53 status and human epidermal growth factor-2 was significantly stronger than between serous histology and human epidermal growth factor-2, highlighting the need for molecular classification in trials to identify patients who may benefit from anti-human epidermal growth factor-2 agents.34
PARP inhibitors also hold potential for p53abn/CNH endometrial cancer. There are molecular similarities between p53abn/CNH endometrial cancer and high-grade serous ovarian and basal-like breast cancers, which both benefit from PARP inhibitors due to deficiencies in homologous recombination.3 CAN-STAMP will assess niraparib plus first-line chemotherapy versus chemotherapy in advanced serous or p53abn endometrial cancer (NCT04159155). The Red-p53abn trial under TransPORTEC RAINBO will assess adjuvant chemoradiation±PARP inhibition in p53abn endometrial cancer (NCT05255653). Finally, anti-angiogenic agents show promise. The benefits of bevacizumab (anti-angiogenic) may be greater in p53abn/CNH endometrial cancers than in unstratified cohorts. A post hoc analysis of GOG-86P found improved progression-free survival and overall survival with bevacizumab and chemotherapy in p53abn, but not TP53-wildtype endometrial cancer.35 A recently published randomized phase II trial of nivolumab and cabozantinib, a tyrosine kinase inhibitor with multiple targets including VEGF, in primarily microsatellite stable recurrent endometrial cancer found improved progression-free survival with combination therapy versus nivolumab alone (5.3 months, 90% CI 3.5 to 9.2 vs 1.9 months, 90% CI 1.6 to 3.4). Further, in the cohort of patients who had previously been treated with single-agent immunotherapy, the combination resulted in objective responses in 25% and stable disease in 35% of patients.36
Agents on the Horizon
Antibody-drug-conjugates are a promising treatment modality, especially considering recent results of DESTINY-Breast04. Approximately 60% of breast cancers are classified as human epidermal growth factor-2-low based on immunohistochemistry and/or in situ hybridization, and respond poorly to anti-human epidermal growth factor-2 therapies.37 However, the antibody-drug conjugate trastuzumab-deruxtecan targets tumor cells expressing low human epidermal growth factor-2 levels. In DESTINY-Breast04, trastuzumab-deruxtecan conferred a 50% risk reduction in disease progression or death (progression-free survival 9.9 vs 5.1 months; HR 0.50, 95% CI 0.40 to 0.63).37 Considering there is no standardized scoring system for human epidermal growth factor-2 expression in endometrial cancer, and human epidermal growth factor-2 is found across histology types, the use of antibody-drug conjugates like trastuzumab-deruxtecan could be beneficial for a wide range of endometrial cancer patients. Preliminary results from the STATICE trial evaluating efficacy of trastuzumab-deruxtecan in human epidermal growth factor-2-positive uterine carcinosarcoma showed a response rate of 55% and a progression-free survival of 6.2 (95% CI 4.0 to 8.8) months in human epidermal growth factor-2 2+/3+ patients.38 Endometrial cancer is also being evaluated in the DESTINY-PanTumor02 trial using trastuzumab-deruxtecan in human epidermal growth factor-2-positive tumors (NCT04482309). In human epidermal growth factor-2-positive serous endometrial cancers, combined trastuzumab-deruxtecan and olaparib (PARP inhibitor) is being evaluated (NCT04585958). Human epidermal growth factor-2 small molecular inhibitors, such as tucatinib, may also be beneficial in this group. Tucatinib plus trastuzumab is currently approved in human epidermal growth factor-2-positive metastatic breast cancer and is being studied in combination with olaparib in the same population.39 A study of tucatinib and trastuzumab in solid tumors with human epidermal growth factor-2 alterations, including endometrial cancer, is currently recruiting (NCT03835819).
Folate receptor-alpha (α) is expressed on endometrial cancer cells and is associated with poor prognosis. Mirvetuximab soravtansine, an antibody-drug conjugate including a folate receptor-α-binding antibody, showed single agent activity in a phase I study in advanced/recurrent endometrial cancer and is currently being studied in combination with pembrolizumab in patients with microsatellite stable endometrial cancer in a phase II study (NCT03835819).40 It received accelerated FDA approval for folate receptor-α-positive, platinum resistant epithelial ovarian cancer in November 2022.41 Additionally, STRO-002, an anti-folate receptor-α antibody-drug conjugate, is currently being evaluated in a phase I multicenter study in advanced epithelial ovarian cancer and endometrial cancer and has received FDA fast track designation for ovarian cancer (NCT03748186).42 MORAb-202 is another anti-folate receptor-α antibody-drug conjugate that shows promise in ovarian cancer and is being evaluated in endometrial cancer (NCT04300556).
Another potential target is WEE1 kinase, which regulates the G2/M and S cell-cycle checkpoints. p53abn/CNH tumors may benefit from WEE1 inhibition because cells with aberrant p53 function lose regulation of the G1/S checkpoint and increasingly depend on G2/M checkpoint regulation by WEE1. As more than 90% of serous tumors have aberrant p53 expression, WEE1 inhibitor adavosertib was evaluated in serous endometrial cancer with an ORR of 29.4% (95% CI 15.1% to 47.5%) and a clinical benefit rate of 50% (95% CI 32.4% to 67.6%).43 Another phase II trial is currently assessing the Zentalis WEE-1 inhibitor in recurrent or persistent uterine serous carcinoma (NCT04814108).
NSMP endometrial cancers are characterized by low somatic copy number alterations, low mutational burden, and estrogen and progesterone receptor overexpression. This subtype accounts for approximately half of all endometrial cancers and confers an intermediate prognosis. The majority of endometrioid tumors fall into this subtype.3 4 Efforts to further differentiate NSMP/CNL are ongoing given its lack of predictive biomarkers. Beta-catenin (CTNNB1) is present in approximately half of NSMP endometrial cancers, and evidence suggests low-grade endometrioid endometrial cancers with CTNNB1 mutations have a higher risk of disease recurrence.3 4 Additionally, L1-cell adhesion molecular overexpression is also associated with poor prognosis in this subtype.4
Given estrogen and progesterone receptor expression, hormonal therapy is an option within this subgroup. Hormonal therapy has been used for several decades in estrogen and progesterone receptor-positive endometrial cancer, primarily in recurrent/metastatic disease, with varied response rates (OnlineSupplemental Table S1). Per the NCCN, the options for hormonal therapy are progestins (megestrol or medroxyprogesterone), aromatase inhibitors, fulvestrant, and tamoxifen.2
Combined Hormonal and Targeted Therapy
An area of active research is hormonal therapy plus targeted therapy disrupting estrogen receptor signaling to increase response rates and mitigate resistance. One option is mammalian target of rapamycin (mTOR) inhibitors, as mutations in the phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR pathway are frequently seen in endometrial cancer.9 Additionally, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss is observed in 77% and PIK3CA mutations in 53% of NSMP/CNL endometrial cancer.3 Given cross-regulation between the estrogen receptor and PI3K/Akt/mTOR pathways, a phase II trial studied everolimus (mTOR inhibitor) and letrozole in recurrent endometrial cancer and found an ORR of 32% (95% CI 17% to 49%) with patients with endometrioid histology and CTNNB1 mutations responding well to the combination.44 GOG-3007 then compared everolimus plus letrozole versus medroxyprogesterone and tamoxifen in 74 patients with metastatic endometrial cancer, most of who had endometrioid histology. Progression-free survival and overall survival were longer with the everolimus and letrozole combination (6 (95% CI 4 to 18) vs 4 (95% CI 3 to 6) months and 31 (95% CI 14 to 40) vs 17 (95% CI 9 to 289) months, respectively). A higher progression-free survival was observed in chemo-naïve patients for both combinations.45 The 2022 NCCN guidelines list this approach for patients with endometrioid histology (Table 3).2 Metformin is associated with downregulation of the PI3K/Akt/mTOR pathway, and its addition to everolimus and letrozole in a single arm phase II study resulted in an overall clinical benefit rate of 50% (95% CI 36.1% to 63.9%) in advanced/recurrent endometrial cancers.46
Cyclin-dependent kinase 4/6 inhibitors are another possibility to overcome resistance to hormonal therapy. Cyclin-dependent kinase 4/6 inhibitors induce cell cycle arrest at the G1/S checkpoint. The cyclin D/cyclin-dependent kinase complex is downstream of estrogen signaling, representing potential synergistic antitumor activity when combined with aromatase inhibitors. In the randomized, phase II NSGO-PALEO/ENGOT-EN3 trial, palbociclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole had a 64% disease control rate versus 38% with letrozole only, and a significantly improved progression-free survival (8.3 vs 3.0 months; HR 0.56, 95% CI 0.32 to 0.98).47 More recently, a phase II study of letrozole plus abemaciclib in estrogen receptor-positive recurrent/persistent endometrial cancer found a 30% ORR (95% CI 14.7% to 49.4%).48 Hormonal therapy plus cyclin-dependent kinase 4/6 inhibitors need further evaluation in phase III trials.
Immunotherapy and Targeted Therapy
Selinexor, an oral selective inhibitor of exportin 1, is the major nuclear export protein for tumor-suppressor proteins including p53. By inhibiting exportin 1, nuclear levels and activation of tumor suppressor proteins increase and oncoproteins decrease. In the randomized, phase III ENGOT-EN5/GOG-3055/SIENDO trial, selinexor maintenance therapy in advanced/recurrent endometrial cancer after partial or complete remission with first-line chemotherapy had an overall 30% risk reduction (adjusted HR 0.705, 95% CI 0.499 to 0.996) for disease progression and/or death compared with placebo, and those with TP53 wild-type tumors had a 62% risk reduction (HR 0.375, 95% CI 0.210 to 0.670). The robust response in TP53 wild-type tumors is reasonable as selinexor reactivates p53 by preventing nuclear export.49 Further, EXPORT-EC is evaluating selinexor in TP53 wild-type endometrial cancer.
Finally, in post hoc analyses of KEYNOTE-775 by tumor histology within the pMMR subgroup, pembrolizumab/lenvatinib had improved progression-free survival versus chemotherapy in endometrioid tumors.50 As the majority of endometrioid tumors fall into the NSMP/CNL group, pembrolizumab/lenvatinib is a reasonable treatment option for this molecular subtype.
In the era of personalized medicine, management of endometrial cancer should be based on individualized risk assessment. Molecular classification has consistently provided stronger prognostic significance than traditional histology and, as evidenced above, treatments based on molecular classification have improved outcomes in endometrial cancer. As such, molecular subtyping should be performed in all endometrial cancer to help guide adjuvant treatment. Further stratification within each molecular subtype is ongoing and clinical trials using molecular classification must be a priority.
Patient consent for publication
Contributors HK: writing – original draft preparation. BS: writing – review and editing. RLC: writing – review and editing. BP: writing – review and editing, project administration.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests BS reports consulting fees and payment for educational events outside the submitted work including from AstraZeneca, Clovis, GSK, Genentech, Merck, Eisai, Lilly, Novartis, Genmab, Seagen, Immunogen, Karyopharm, and Seagen. RLC reports grants, consulting fees and payment for educational events outside the submitted work including from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Janssen, Roche/Genentech, Agenus, Alkermes, Deciphera, GSK, OncoQuest, Onxerna, Regeneron, Novocure, Abbvie. Compensated advisory boards include VBL Therapeutics. BP reports grants, personal fees and non-financial support outside the submitted work; institutional PI for industry sponsored trials from Tesaro/GSK, AstraZeneca, Merck, Genetech/Roche, Celsion, Karyopharm, Mersana, Takeda Pharmaceuticals, Eisai, and Clovis Oncology. Compensated advisory boards include Tesaro/GSK, AstraZeneca, Mersana, Merck, Clovis Oncology, Eisai, Lily, Toray, Sutro and GOG Foundation.
Provenance and peer review Commissioned; internally peer reviewed.
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