Whether it is ESGO (uropean Society of Gynaecological Oncology)/ESTRO (European Society for Radiotherapy and Oncology)/ESP (European Society of Pathology) and other international societies or the endometrial cancer diagnosis and treatment guidelines of the Gynecologic Oncology Branch of the Chinese Medical Association, For patients with stage I-II, postoperative adjuvant therapy is recommended based on risk stratification (low-risk, intermediate-risk, intermediate-high-risk, and high-risk), and in the past, risk stratification was mostly determined based on histopathological factors such as tissue differentiation, depth of muscle invasion, and vascular tumor thrombus involvement.

Although there has been a lot of debate since the announcement of the new stage of endometrial cancer in FIGO2023, it is an industry consensus that different molecular characteristics determine the different prognosis of tumors, thus affecting the choice of adjuvant treatment for early endometrial cancer. In the past 2025, the first step has been taken to write molecular characteristics into guidelines to guide postoperative adjuvant therapy. For example, in patients with POLE supermutations, adjuvant treatment is not recommended after surgery, even if there is deep muscle invasion, LVSI and other factors. Adjuvant therapy is recommended even for superficial muscle infiltration in TP53 mutants, and more evidence favors chemotherapy or chemoradiotherapy to alter prognosis rather than radiotherapy alone. On the contrary, dMMR type has high-risk factors such as deep muscle infiltration and extensive LVSI and is more inclined to adjuvant radiotherapy. In addition, ER negativity should not be considered a poor prognosis factor, but also one of the molecular factors that determine the upgrade of adjuvant therapy.

On the basis of the results of clinical trials such as NRG-GY018, RUBY, and DUO-E, survival data were also released in 2025 at AtTEnd, and the results were consistent with previous trials: for patients with primary advanced endometrial cancer (stage III or stage IVA, IVB, or first recurrence without advanced systemic therapy with measurable lesions), immune checkpoint inhibitors (ICIs) combined with chemotherapy have become mismatch repair defects/ The first-line standard treatment regimen for people with microsatellite high instability (dMMR/MSI-H) significantly improved the survival prognosis of these patients, with the risk ratio HR value of PFS in different clinical trials being between 0.3-0.4 and the HR value of OS being 0.4-0.5.

The benefit in the pMMR/MSS population was not as obvious as in dMMR, but there was also a benefit compared with the control group with chemotherapy alone, with a risk ratio of 0.7-0.9 for PFS and an HR value of 0.8-1.0 for OS, but there was no head-to-head comparison with chemotherapy in combination with targeting.

Since the KEYNOTE-775 study established the basis of the "immune + anti-angiogenic" model, the "cola combination" of lenvatinib plus pembrolizumab for the second-line treatment of patients with recurrent advanced endometrial cancer who have received prior platinum-based chemotherapy has improved PFS, OS and ORR across the board compared with monotherapy chemotherapy. The LEAP-001 study further brought this target-free combination to the first-line treatment of patients with dMMR advanced relapsed EC: it was more effective than TC (paclitaxel + carboplatin) chemotherapy in the dMMR population, with a median PFS of 31.8 months and chemotherapy of 9.0 months in the LENVAP group (HR, 0.61).

In the second-line treatment, the announcement of the results of clinical trials of domestic anti-angiogenic and immune checkpoint inhibitors such as sintilimab + fruquintinib (based on the FRUSICA-1 study) and anlotinib + bemosubai and the approval of indications for the treatment of second-line endometrial cancer further confirm the synergistic effect of this target-free combination mechanism and provide more accessible options for Chinese patients.

Backline treatment for high-risk, refractory, advanced, and recurrent endometrial cancer, especially for pMMR patients, has always been a great challenge. Happily, a wide range of clinical trials will emerge in 2025 to try to improve outcomes for these refractory populations. For example, the concept of introducing maintenance therapy similar to ovarian high-grade serous carcinoma (RUBY PART2, DUO-E) for pMMR and P53 mutant endometrial carcinoma has initially shown benefits in PFS.

ADC drugs have also shown certain efficacy in the post-line treatment of recurrent metastatic endometrial cancer. In addition to the already well-known HER-2-targeting detrastuzumab, the results of the phase II clinical trial of trucansatuzumab targeting TROP-2 have also preliminarily shown efficacy: the ORR of monotherapy in patients with 2L+ endometrial cancer is 35.4%, the median DOR is 9.3 months, and the phase III clinical trial is being recruited. More ADC drugs, such as targeting folate receptor α and targeting B7-H4, are also being studied. Many different combination regimens of targeted-immune-chemotherapy are also being tried. We hope that for these refractory back-line cases, precise stratification with different molecular characteristics and new drug trials can bring more hope.