Oncological and reproductive outcomes following fertility-preserving treatment in mismatch repair-deficient endometrial cancer or atypical endometrial hyperplasia.

During the study period, 207 patients receiving FPT underwent immunohistochemical staining to detect MMR protein status. Among them, 17 patients exhibited MMR protein loss. After excluding one patient who received less than three months of FPT, one patient with suspected deep myometrial invasion prior to treatment, and one patient who had proficient MMR status prior to treatment but lost MMR protein after treatment, 14 patients were included in the final analysis after confirming the absence of POLE mutations. Table  1 shows the general clinical characteristics of the patients. The initial diagnosis included 6 cases of grade 1 EEC and 8 cases of AEH. The mean age at diagnosis was 33.6 ± 4.2 years, and the mean body mass index (BMI) was 25.4 ± 4.0 kg/m². Among the patients, 12 (85.7%) had not yet given birth at the time of diagnosis. Two cases had polycystic ovary syndrome, and two cases had a history of ovarian tumors (one with ovarian well-differentiated endometrioid carcinoma and the other with an ovarian endometrioid borderline tumor). Table 1 Clinicopathological and follow-up information of 14 patients with MMRd EEC or AEH Patient no. Age (year) BMI (kg/m 2 ) Comorbid disease Initial diagnosis Initial treatment Efficacy evaluation CR time (month) Time to recurrence (month) * Time to progression (month) † Treatment after recurrence /progression Final diagnosis Pregnancy after FPT Follow-up time (month) status 1 28 26 PCOS AEH GnRH-a [6 months] → PR → MPA [6 months] → Assisted reproduction resulting in one pregnancy CR 12 28 - LNG-IUS [6 months] → PD → Staged surgery ⅠA G2 EEC 1 117 NED 2 29 24.1 None AEH MA [6 months] → LNG-IUS maintenance therapy CR 6 12 - GnRH-a + Letrozole [6 months] → CR→COC [5 months] → RD → CRS + radiotherapy + chemotherapy + immunotherapy ⅢC1 G3 EEC 0 45 DOD 3 37 31.2 None G1 EEC MA + LNG-IUS [4 months] → persistence → GnRH-a + Letrozole [6 months] → LNG-IUS maintenance CR 10 8 - Staged surgery + radiotherapy + chemotherapy ⅠB G3 ECCC 0 68 NED 4 36 22 Pulmonary nodule→Stage ⅠB pulmonary adenocarcinoma (diagnosed after FPT) AEH MA [1 month] → GnRH-a [6 months] PD - - 7 CRS + chemotherapy + immunotherapy ⅢC2 G2 EEC 0 60 NED 5 31 31.9 Hypertension G1 EEC GnRH-a + Letrozole [6 months] → PR → GnRH-a + LNG-IUS [6 months] Persistence - - - Staged surgery ⅠA G1 EEC 0 58 NED 6 38 20.9 EBOT (during FPT); Stage ⅠA well-differentiated ovarian endometrioid carcinoma stage (after FPT) G1 EEC MPA [9 months] → ART CR 9 10 - LNG-IUS [10 months] → PD → GnRH-a + MA [6 months] → CR → ART - 0 31 NED 7 35 23.5 Stage ⅠC moderately-differentiated ovarian endometrioid adenocarcinoma. G1 EEC MA [3 months] PD - - 3 Staged surgery ⅠA G2 EEC 0 35 NED 8 34 27.3 None AEH GnRH-a + Letrozole [4 months] → Attempt natural conception CR 4 - - - - 0 35 NED 9 33 20.5 None AEH LNG-IUS [6 months] PD - - 6 CRS + chemotherapy + immunotherapy → Immunotherapy maintenance [24 months] ⅢC2 G3 EEC 0 34 NED 10 35 28.1 PCOS, Hyperthyroidism AEH GnRH-a + Letrozole [6 months] PD - - 6 CRS + chemotherapy + immunotherapy → Immunotherapy maintenance [24 months] ⅠA G1 EEC+ⅡB Ovarian dedifferentiated carcinoma 0 33 NED 11 40 22.2 None G1 EEC GnRH-a + Letrozole [8 months] → Attempt natural conception CR 8 - - - - 0 33 NED 12 38 31.7 Insulin resistance AEH MPA [3 months] PD - - 3 Staged surgery ⅠA G1 EEC 0 29 NED 13 25 20.6 None AEH GnRH-a + Letrozole [3 months] → Assisted reproduction resulting in one pregnancy CR 3 - - - - 1 27 NED 14 31 25.4 EBOT, Ovarian endometriosis G1 EEC GnRH-a + Immunotherapy [9 months] → PR → MA + Immunotherapy [10 months] → PR → LNG-IUS + Immunotherapy [6 months, still under treatment] PR - - - - - 0 26 AWD AEH Atypical endometrial hyperplasia, AWD Alive with disease, ART Assisted reproduction technique, CRS Cytoreductive surgery, DOD Dead of disease, EEC Endometrioid endometrial carcinoma, ECCC Endometrial clear cell carcinoma, EBOT Endometrioid borderline ovarian tumor, MA Megestrol acetate, MPA Medroxyprogesterone acetate, NED No evidence of disease, PCOS Polycystic ovary syndrome * Time to recurrence was defined as the reappearance of pretreatment lesions (AEH or EEC) in specimens after achieving CR † Time to progression was defined as the duration from the initiation of FPT to tumor progression Clinicopathological and follow-up information of 14 patients with MMRd EEC or AEH AEH Atypical endometrial hyperplasia, AWD Alive with disease, ART Assisted reproduction technique, CRS Cytoreductive surgery, DOD Dead of disease, EEC Endometrioid endometrial carcinoma, ECCC Endometrial clear cell carcinoma, EBOT Endometrioid borderline ovarian tumor, MA Megestrol acetate, MPA Medroxyprogesterone acetate, NED No evidence of disease, PCOS Polycystic ovary syndrome * Time to recurrence was defined as the reappearance of pretreatment lesions (AEH or EEC) in specimens after achieving CR † Time to progression was defined as the duration from the initiation of FPT to tumor progression In one case (Patient 6), an ovarian mass was discovered during FPT. The mass was surgically removed and pathologically diagnosed as an endometrioid borderlineovarian tumor. The patient subsequently continued FPT and achieved CR. During follow-up, an ovarian mass was again detected, and a unilateral salpingo-oophorectomy was performed. Pathology revealed a well-differentiated ovarian endometrioid carcinoma. In another case (Patient 4), the patient had a history of pulmonary nodules for 2 years. After seven months of FPT and disease progression, the patient underwent treatment for EC, followed by segmentectomy. The pathology revealed pulmonary adenocarcinoma. Among the 14 cases, 9 (64.3%) exhibited combined loss of MLH1/PMS2, 1 (7.1%) showed combined loss of MSH2/MSH6, 3 (21.4%) had MSH6 loss, and 1 (7.1%) had PMS2 loss. In one case (Patient 10), the lesion displayed focal p53 abnormal expression pattern, while the other cases showed wild-type p53. Thirteen patients (92.9%) were estrogen receptor (ER) positive, and 8 patients (57.1%) were progesterone receptor (PR) positive. Of the 12 patients who underwent germline genetic testing, 3 (25%) had pathogenic/likely pathogenic mutations, with 2 cases of MLH1 mutations and 1 case of PMS2 mutation (Table  2 ). Table 2 Immunohistochemical and molecular characteristics of 14 patients with MMRd EEC or AEH Patients Family history * MMR deficiency p53 status ER status PR status MMR germline mutation 1 Deny MLH1/PMS2 Wild type + - Not detected 2 Lymphoma MLH1/PMS2 Wild type - - Unknown 3 Rectal cancer MLH1/PMS2 Wild type + - Pathogenic: MLH1 c.C1630T 4 Deny MSH2/MSH6 Wild type + + Not detected 5 Esophageal cancer MLH1/PMS2 Wild type + + Not detected 6 Deny MSH6 Wild type + + Not detected 7 Deny MLH1/PMS2 Wild type + + VUS: MLH1 c.1896 + 5G > A 8 Endometrial cancer MLH1/PMS2 Wild type + + Likely pathogenic: MLH1 c.161-164dup 9 Deny MLH1/PMS2 Wild type + - Not detected 10 Lung cancer MLH1/PMS2 Focal abnormal expression pattern + - VUS: MSH6 c.3260 C > A 11 Colon cancer MLH1/PMS2 Wild type + - Not detected 12 Deny MSH6 Wild type + + Unknown 13 Deny MSH6 Wild type + + Not detected 14 Lymphoma PMS2 Wild type + + Pathogenic: PMS2 c.741del ER Estrogen receptor, IHC Immunohistochemistry, MMR Mismatch repair, PR Progesterone receptor, VUS Variant of uncertain significance * Family history of cancer was defined as malignant neoplasms in first‑ and second‑degree relatives Immunohistochemical and molecular characteristics of 14 patients with MMRd EEC or AEH ER Estrogen receptor, IHC Immunohistochemistry, MMR Mismatch repair, PR Progesterone receptor, VUS Variant of uncertain significance * Family history of cancer was defined as malignant neoplasms in first‑ and second‑degree relatives During the follow-up period (median 34.5 months, range 26–117 months), 7 patients (50%) achieved CR after initial treatment, with a median time to CR of 8 months (range 3–12 months). The cumulative CR rates at 6 months and 12 months were 21.3% (3/14) and 50.0% (7/14), respectively. Patient 14 with G1 EEC achieved PR over 26 months of therapy: GnRH-a plus immunotherapy for 9 months, MA plus immunotherapy for 10 months, and LNG-IUS plus immunotherapy for 6 months (ongoing treatment). Patient 5 with G1 EEC experienced persistent disease after 12 months of treatment: GnRH-a combined with letrozole for 6 months, followed by GnRH-a plus LNG-IUS for 6 months. Ultimately, the patient underwent staged surgery with a final diagnosis of stage ⅠA G1 EEC. Five patients experienced disease progression during treatment, with a median time to progression of 6 months (range 3–7 months), all of whom subsequently received standard surgery. The recurrence rate after FPT was 57.1% (4/7), with a median time to recurrence of 11 months (range 8–28 months). After recurrence, one patient underwent staged surgery, and three patients received repeated FPT: Patient 3 experienced recurrence 8 months after CR, followed by staged surgery, and the pathology revealed G3 endometrial clear cell carcinoma (ECCC). Patient 1 placed LNG-IUS after recurrence, but due to personal reasons, was not reassessed until 4 years later when the disease progressed to G2 EEC, followed by staged surgery. Patient 2 achieved CR again after 6 months of GnRH-a and letrozole treatment following recurrence. After 5 months of maintenance therapy with combined oral contraceptives (COC), disease progression was observed. The patient underwent tumor cytoreduction, with upgraded staging and pathological grade, and ultimately died from disease progression. Patient 6 underwent LNG-IUS treatment for 10 months after recurrence, and after PD was assessed, the treatment was switched to GnRH-a and MA for 6 months, resulting in CR. A total of 9 patients underwent standard staging surgery or tumor cytoreduction, with pathology confirming malignancy in all patients. Compared to the pre-treatment endometrial biopsy pathology, 8 patients showed upstaging in postoperative pathology: 6 patients had an increase in grade, 3 patients developed pelvic or para-aortic lymph node metastasis, one patient had a change in histologic type to ECCC, and one patient was combined with ovarian dedifferentiated carcinoma. In the subgroups, CR was achieved in 50.0% (4/8) of patients with initial AEH and in 50.0% (3/6) of patients with G1 EEC. Five patients switched therapeutic regimens during FPT. In terms of treatment exposure, CR was observed in 40.0% (4/10) of progestin-containing treatment courses and 44.4% (4/9) of GnRH-a-containing treatment courses. Of the 12 patients who underwent germline genetic testing, CR was achieved in 2 of 3 patients with pathogenic/likely‑pathogenic MMR germline variants, none of 2 patients with variants of uncertain significance (VUS), and 4 of 7 patients with no germline mutations. Among the 7 patients who achieved CR, 2 patients with no immediate plans for pregnancy were treated with LNG-IUS for maintenance. Two patients, unwilling to undergo assisted reproduction technology (ART), attempted natural conception with follow-up for 35 and 33 months respectively, but neither achieved pregnancy. Three patients underwent ART. Among them, Patients 1 and 13 successfully conceived and gave birth after in vitro fertilization and embryo transfer (IVF-ET). The infant of Patient 1 was born at term via vaginal delivery, while the infant of Patient 13 was delivered preterm by cesarean section at 31 weeks and 5 days of gestation. Neither infant presented with congenital malformations, and short-term follow-up revealed normal physical development and growth. Patient 6 had an AMH of 0.3 ng/ml before FPT and experienced recurrence, while she had an extremely strong desire for pregnancy. After ovarian stimulation and egg retrieval, embryos were cryopreserved. Following FPT and achieving CR, one embryo transfer cycle was attempted, but pregnancy was not attained, and the patient continues to try ART.

The data of young patients with EEC or AEH who had received fertility-sparing treatment at Peking Union Medical College Hospital (PUMCH) from January 2020 to December 2023 were retrospectively reviewed, including both treatment-naive and treatment-experienced patients. The study was approved by the ethics committee of PUMCH (IRB number: I-25PJ3197), and all the patients signed the informed consent form. Inclusion criteria: (1) Meeting the criteria for fertility-sparing treatment [ 14 ]: the pathological diagnosis was well-differentiated EEC (G1) or AEH; the lesions confined to the endometrium; patients had a strong desire to preserve fertility; (2) Immunohistochemical staining indicated loss of expression of at least one MMR protein (MLH1, PMS2, MSH2, and MSH6); (3) No POLE mutation was detected. Exclusion criteria: (1) Receiving fertility-sparing treatment for less than 3 months; (2) Patients who showed normal MMR proteins on immunohistochemistry prior to FPT but developed MMR protein loss during subsequent treatment. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue by the MagPure FFPE DNA LQ kit (Magen, Guangzhou, China). The extracted DNA concentration was measured by QuantiFluor dsDNA System (Promega, Madison, Wisconsin, USA). POLE mutation screening was performed using targeted next-generation sequencing (NGS) focusing on POLE ( NM_006231.4 ) exons 3–14 (exonuclease domain) and exon 19 (part of the region with complete coding sequence) according to the BPTM-plus Panel (Amoy Diagnostics, Xiamen, China). Library construction was performed following a single‑tube workflow including hybridization, extension‑ligation, exonuclease digestion, PCR amplification, and library purification. Qualified libraries were sequenced on the Illumina NextSeq 500 platform with 2 × 150 bp paired-end reads. Variant calling for POLE single-nucleotide variants (SNVs) and insertions/deletions (InDels) was analyzed using the AmoyDx NGS Data Analysis System (ANDAS), with a detection threshold of variant allele frequency (VAF) ≥ 5%. All patients underwent hysteroscopic resection of the pathology followed by drug therapy. The progestin-based regimens included daily oral medroxyprogesterone acetate (MPA) 250–500 mg, medroxyprogesterone (MA) 160–320 mg, or the LNG-IUS. Non-progestin regimens involved gonadotropin-releasing hormone agonist (GnRH-a) 3.6 mg/3.75 mg every 4 weeks, combined with daily oral letrozole 2.5 mg. During treatment, hysteroscopy and endometrial biopsy were performed every 3–4 months to evaluate the treatment response. After achieving complete remission, patients with fertility plans were referred to reproductive center for evaluation. For patients without short-term fertility plans, maintenance therapy was recommended using LNG-IUS or combined oral contraceptives with reassessment every 3–6 months. For patients with disease progression or no longer requiring fertility preservation, standard staging surgery was performed. The pathological diagnosis was reviewed by two independent pathologists. The therapeutic effects were evaluated based on endometrial pathological examinations obtained during FPT, using defined assessment criteria [ 15 ]. Complete remission (CR): Pathological examination shows complete disappearance of EEC or AEH. Partial remission (PR): The lesion is reduced, but atypical glands remain. Persistence: There is no change in tumor tissue compared to the pretreatment pathological results. Progressive disease (PD): Pathological progression to a higher-grade lesion or imaging indicating disease progression, including myometrial invasion, extrauterine disease, or lymph node metastasis. Recurrence: The reappearance of pretreatment lesions (AEH or EEC) in specimens after achieving CR. Time to CR was defined as the duration from the initiation of FPT to pathological CR. Time to recurrence was defined as the duration from CR to biopsy-confirmed endometrial atypical hyperplasia or cancer. Time to progression was defined as the duration from the initiation of FPT to tumor progression. The follow-up was conducted through outpatient and inpatient medical records or telephone calls, with the follow-up period ending on December 31, 2025. Follow-up time was defined as the duration from the initiation of FPT to death or last follow-up. Statistical Package for the Social Sciences software version 26.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. Measurement data were tested for normality. Normally distributed data were described as mean ± standard deviation, while non-normally distributed data were described as median (range). Categorical data were described as frequencies and percentages.

Molecular classification plays a significant role in the diagnosis, treatment, and prognosis of endometrial cancer, and guidelines recommend molecular classification for patients with endometrial lesions who wish to preserve fertility [ 6 ]. In this study, the CR rate for MMRd patients undergoing FPT was lower than that of the overall population, and the reproductive outcomes were also unsatisfactory. The ProMisE molecular classification is a cost-effective and rapid classification algorithm. It first classifies patients with MMR protein expression loss as MMRd-type based on immunohistochemical staining, while the remaining patients are categorized by sequencing for POLE mutation and immunohistochemistry to determine p53 protein expression [ 16 ]. Clinical validation showed similar results to the TCGA classification [ 17 ]. In our study, the proportion of MMRd patients identified by the ProMisE algorithm was less than one-tenth of the overall fertility-preserving population. In several other small-scale retrospective studies, this proportion ranged from 6.7% to 15.8% [ 8 , 10 , 11 , 18 ], which is lower than the 30% proportion of MMRd patients in the overall EC population [ 17 ]. This may be due to MMRd subtype patients being more likely to have factors that do not meet the criteria for FPT, such as deep myometrial invasion and higher histological grade. In previous single-center retrospective studies, Xue et al. [ 8 ] and Ran et al. [ 19 ] did not find significant difference in FPT remission rates between MMRd and NSMP subtypes. Chung et al. [ 10 ] reported that the remission rate for MMRd was lower than for p53 wild-type (44.4% vs. 82.2%, p < 0.018). Additionally, in the study by Zakhour et al. [ 11 ], no MMRd EC patients achieved CR. In our study, the CR rate for MMRd patients was 50.0%, which is lower than the 71%-88.6% CR rate reported in several meta-analysis for EC and AEH [ 20 – 23 ]. Currently, the molecular mechanisms of progesterone resistance have not been fully elucidated. It may antagonize estrogen-induced endometrial proliferation by reducing ER synthesis and promoting the conversion of estradiol to estrone [ 24 ], or act through non-estrogen-dependent pathways, modulating the progesterone B receptor to regulate adhesion molecules and inhibit tumor invasion [ 25 ]. MMR is one of the DNA damage repair mechanisms, and its dysfunction leads to the loss of MMR protein expression, MSI-H, and a higher gene mutation frequency in tumors. This high mutation load may affect cellular response to progesterone by activating non-progesterone receptor-dependent pathways [ 26 , 27 ]. Given the high tumor mutation burden (TMB) of MMRd EC or AEH, studies have reported successful cases of FPT using ICIs [ 13 , 28 ]. In our study, patient 14 also received a combination of PD-1 inhibitors in FPT, but had not yet achieved CR and required further follow-up. Currently, several clinical trials of ICIs monotherapy or combined with progesterone ( NCT06278857 , NCT06549855 , and NCT06914297 ) are ongoing in the population for FPT of MMRd subtype, with further outcome data anticipated. The overall recurrence rate of EEC or AEH after FPT is 21.0%–42.4% [ 23 , 29 ], and it gradually increases over time [ 30 ]. Wang et al. [ 31 ] showed that the 2-year recurrence rate in MMRd patients was higher than in p53 wild-type patients (83.33% vs. 17.39%, p < 0.05). The recurrence rate for our patients was 57.1%, with a median recurrence time of 11 months, which is similar to the 48.9% recurrence rate and 11.5-month median recurrence time reported in meta-analysis [ 32 ]. Among the 9 patients who underwent surgery, 8 experienced pathological upstaging postoperatively, three developed extrauterine metastases, and one died due to the disease. This outcome highlights the need for clinicians to remain cautious when considering FPT for this subtype, carefully balancing fertility and survival. Considering the risk of recurrence and disease progression, patients who have completed childbearing, are unresponsive to FPT, or develop disease progression are generally recommended to undergo definitive staging surgery, including total hysterectomy, bilateral salpingo-oophorectomy (or ovarian preservation in selected cases), and lymph node assessment [ 33 , 34 ]. Even among patients who achieve CR, the higher recurrence rate and shorter recurrence time still pose a significant challenge to fertility. Therefore, the assessment of fertility preservation should be integrated into multidisciplinary management from the initial decision-making stage [ 6 , 35 , 36 ]. Multiple meta-analyses reported overall pregnancy rates of 26.7%–34.0% and live birth rates of 20.0%–30.6% in FPT patients [ 20 – 22 ]. In our study, two patients achieved live births following ART, while one experienced initial embryo transfer failure and is currently undergoing subsequent embryo transfer cycles. In other FPT studies of MMRd patients, Peng et al. [ 37 ] documented one successful birth (1/11), whereas the remaining four studies reported no pregnancies [ 19 , 38 – 40 ]. Xue et al. [ 8 ] reported that patients who underwent ART after CR achieved a cumulative pregnancy rate of over 66.7% and a live birth rate of over 50%. Therefore, for patients who desire fertility, an active assisted reproduction strategy is recommended after CR to achieve pregnancy as early as possible, given the risk and timing of recurrence. In our study, a 38-year-old patient with an AMH level of 0.3 ng/ml was unfortunately unable to achieve pregnancy despite undergoing ART. A study indicated that approximately 22% of patients had decreased ovarian reserve at the initiation of FPT, and long-term use of high-dose progestin may also cause the decreased of ovarian reserve [ 41 ]. In the future, it will be necessary to expand the sample size and conduct long-term follow-up to provide more robust evidence to support reproductive strategies. Lynch syndrome (LS) is a common hereditary cancer syndrome caused by pathogenic germline mutations in mismatch repair genes. Although the molecular pathogenic mechanisms of LS-EC differ from those of sporadic EC, it is not considered an absolute contraindication for FPT. Some LS patients may present with a hyperestrogenic state, and progestin therapy may alleviate endometrial lesions [ 42 ]. In our study, three patients were found to carry pathogenic or likely pathogenic germline mutations in MMR genes. Two patients achieved CR, and one achieved PR, but none have conceived. Yang et al. [ 13 ] and Cao et al. [ 28 ] reported two patients with LS-EC who achieved CR after treatment with PD-1 inhibitors and subsequently conceived successfully, suggesting that ICIs may be a viable treatment option. Given the autosomal dominant inheritance pattern of LS, preimplantation genetic testing (PGT) may be considered a reproductive option for patients desiring fertility [ 43 , 44 ]. For the relatively rare MMRd subtype among patients undergoing FPT, this study comprehensively evaluated oncological and reproductive outcomes in a single-center real-world setting, providing a valuable clinical reference for patient management. In addition, germline testing provided preliminary evidence for treatment decision-making in patients with LS-EC undergoing FPT. Several limitations should also be noted, including the relatively small sample size, absence of centralized pathological review of immunohistochemistry results, potential selection bias due to inclusion of treatment-experienced patients, lack of formal quality-of-life assessment, and short follow-up duration for reproductive outcomes. Therefore, the conclusions should be interpreted with caution. In the future, long-term, multicenter collaborative studies are required to assess the safety of FPT for MMRd endometrial lesions. In conclusion, patients with MMRd EEC or AEH undergoing FPT have a relatively low remission rate, a high recurrence rate, and poor reproductive outcomes. For patients with strong fertility desires, it is crucial to thoroughly inform the oncological risks and potential pregnancy outcomes. After achieving CR, ART should be actively pursued to shorten the time to pregnancy, while surveillance for recurrence should be strengthened to achieve an optimal balance between fertility goals and disease control.

Endometrial cancer (EC) is one of the most common malignant tumors in women, with an increasing incidence and a trend toward younger age at diagnosis [ 1 , 2 ]. Approximately 5% of patients are diagnosed before the age of 40 [ 3 ]. Atypical endometrial hyperplasia (AEH) is a precancerous lesion of endometrial endometrioid carcinoma (EEC), with 15–28% of patients progressing to cancer [ 4 ]. Fertility-preserving treatment (FPT) provides these young patients with an opportunity for reproduction. The therapeutic options primarily include high-dose progestins, the levonorgestrel-releasing intrauterine system (LNG-IUS), and gonadotropin-releasing hormone agonist (GnRHa)-based therapy [ 5 ]. The molecular classification provides crucial guidance for the diagnosis, treatment selection, and prognosis assessment of EEC, and also influences the management of fertility preservation. The guidelines issued by the European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) recommend the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE) molecular classification algorithm for patients wishing to preserve fertility [ 6 ]. The no specific molecular profile (NSMP) subtype generally shows a good response to progestin therapy, making it a suitable candidate for FPT. The p53-mutant subtype is associated with poorer prognosis and higher metastatic risk, and FPT is not recommended [ 6 ]. Patients with POLE-mutant tumors often present with contraindications to FPT, such as high-grade lesions or myometrial invasion, and whether they can benefit from such treatment remains to be explored [ 6 , 7 ]. The mismatch repair deficient (MMRd) subtype presents greater complexity. Multiple small-sample studies indicated inconsistent responses to progestin therapy, with resistance and recurrence being more common than NSMP subtype [ 8 – 12 ]. The safety and pregnancy outcomes of FPT remain uncertain. Some patients may also carry pathogenic germline mutations related to mismatch repair system, and whether fertility-preservation is appropriate for patients with Lynch syndrome-associated endometrial cancer (LS-EC) remains controversial [ 13 ]. This study retrospectively reviewed the tumor and fertility outcomes of 14 patients with MMRd subtype of EEC or AEH who underwent FPT, aiming to provide reference for the management of this subtype.