Endometrial Cancer (EC) is one of the common malignant tumors of the female reproductive tract. In 2022, there were 420,242 new cases worldwide [1]. The incidence of EC has increased by 132% over the past three decades, indicating a trend toward younger patient populations, with the proportion of patients under 45 years old significantly rising [2,3]. Although endometrial cancer is predominantly diagnosed in postmenopausal women, approximately 5% of cases occur in women under the age of 40, with the majority being nulliparous at the time of diagnosis [3]. The National Comprehensive Cancer Network (NCCN) guidelines recommend that the standard treatment for early EC is total hysterectomy and bilateral adnexectomy, which has a significant impact on the quality of life of patients [4]. With the considerable delay in the age of first childbirth for women, the willingness of young patients to undergo fertility sparing treatment (FST) is growing stronger. Although a certain consensus has been reached on the FST regimen based on progesterone, there are still some patients who are not sensitive to hormones and are at risk of recurrence or even disease progression [5]. The International Federation of Gynecology and Obstetrics (FIGO) included molecular classification in the new staging of endometrial cancer in 2023 [6], but the clinical value of molecular classification in the conservation treatment of EC remains unclear. This article reviews the research progress of FST in patients with endometrial cancer of different molecular subtypes, as well as the potential value of molecular subtyping guiding targeted combined with traditional conservation therapy, to provide more individualized treatment options for patients who wish to preserve their fertility.

In 2013, The Cancer Genome Atlas (TCGA) proposed a new EC typing strategy based on multi-omics features, which was combined with prognosis and divided into four subtypes: polymerase epsilon-ultramutated (POLE), microsatellite instability-high (MSI-H), copy number high (CNH), and copy number low (CNL) [7]. Due to issues such as high detection costs, long time consumption, and complex analysis, the TCGA is not easily promoted and popularized in clinical practice. Subsequently, researchers proposed the simplified Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) [8] and Trans-PORTEC [9]. ProMisE uses immunohistochemistry instead of TCGA copy number variation detection, which is economical and practical, and the preoperative and postoperative specimen detections have high consistency. Therefore, it is widely used in clinical practice. Studies found that regardless of the subtype, the prognosis of patients will further deteriorate due to unfavorable clinical and pathological risk factors [10]. Therefore, molecular classification cannot replace traditional histopathology but should be combined with it to guide the treatment and prognosis of EC patients, especially bringing more hope to young patients with fertility requirements.

FST is not a standard treatment option for EC patients but rather a therapeutic choice for selected subgroups after comprehensive evaluation. To ensure its safety and efficacy, a series of indications have been proposed both domestically and internationally [4,11–12]. These assessment criteria vary among different guidelines and studies, but they mostly focus on clinical features and histopathology. With the application of molecular classification in clinical practice, more and more studies have begun to explore its guiding value in FST for EC. Molecular characteristics are closely related to tumor biological behavior. In the future, the molecular subtype of patients should be fully considered in the FST assessment criteria.

POLEmut

POLEmut is an uncommon molecular subtype of EC, accounting for a relatively small proportion in younger patients. POLEmut patients have experienced favorable survival outcomes, even in high-grade and advanced-stage cancers [13]. The study by Britton et al. found that 85% of FIGO stage I EC patients were of POLEmut, among whom 18% had lymphovascular space invasion (LVSI) and 25% had deep myometrial invasion [14]. In fertility-sparing treatment, only three patients were POLEmut EC. One patient experienced progression, while the others opted for hysterectomy. Similarly, Dagher et al. reported a single POLEmut patient who progressed during progestin treatment and later chose a hysterectomy [15]. Therefore, whether POLEmut is an indication for FST remains unclear, and further research is needed to evaluate its prognosis and pregnancy outcomes.

MMRd

MMRd is associated with a notable risk of cancer recurrence. Following the achievement of complete remission, it is advisable for patients to undergo careful monitoring and active interventions to prevent recurrence. Chung et al. found that patients with MMRd tend to have a less favorable response to progesterone treatment compared to those with NSMP, and were more prone to drug resistance and recurrence [16], however, other studies have not identified significant differences between these two subtypes [17,18]. Lynch syndrome (LS), resulting from germline mutations in one or more MMR genes, is associated with an increased risk of developing various cancers, especially colorectal cancer and endometrial cancer [19]. There is no consensus regarding the suitability of patients with Lynch syndrome-associated endometrial cancer (LS-EC) for FST, but LS-EC is not categorically contraindicated for FST. Some studies have reported successful pregnancies after FST in LS-EC patients [20]. Given that Lynch syndrome carries a genetic risk for disease, a comprehensive assessment must be conducted before fertility preservation. Ensuring that patients and their families are well-informed about the associated risks and options is vital for making an informed decision.

NSMP

NSMP is a common clinical subtype characterized by a low copy number and a high expression level of hormone receptors. Research showed that patients with NSMP are notably sensitive to progesterone therapy, which had a higher complete remission rate and a lower recurrence rate compared to other subtypes [21]. However, not all patients with NSMP are suitable for FST. L1-cell adhesion molecule (L1CAM) is a transmembrane glycoprotein involved in cell adhesion and migration, and is closely related to tumor invasion and metastasis. Studies found that L1CAM is an independent risk factor for poor prognosis in NSMP patients [22]. It is recommended to further stratify patients based on molecular heterogeneity. A retrospective study indicated that patients with L1CAM-positive NSMP had the worst prognosis compared to other groups, suggesting that L1CAM is a significant prognostic indicator for NSMP [23]. Additionally, β-catenin, which is involved in cell growth and repair, has been shown to correlate with poorer PFS for patients with positive β-catenin in the NSMP group [24]. Therefore, it is important to reclassify NSMP based on molecular markers to more effectively identify patients with high risk for FST in the future.

p53abn

Patients with p53abn has a high degree of malignancy, significant invasiveness, and a poor prognosis. It is associated with unfavorable characteristics such as non-endometrioid carcinoma, high grade, LVSI [25]. These patients are insensitive to hormone therapy and preserving fertility can increase the risk of recurrence and distant metastasis, making FST generally inadvisable. The number of p53abn patients in the current studies was extremely limited, and most studies reported only one or two cases, leaving the efficacy of treatment uncertain. Some research suggested that early-stage p53abn EC without myometrial invasion has a lower risk of adverse outcomes, suggesting that patients identified through molecular characteristics could potentially benefit from FST [26]. Therefore, careful and individualized assessment by a multidisciplinary team is crucial before performing FST. Comprehensive evaluations of treatment efficacy, prognosis, and safety are vital and should be validated through larger clinical studies.

POLEmut

POLEmut has a favorable prognosis, however, it is resistant to chemotherapy drugs such as platinum, which means it cannot benefit from traditional EC chemotherapy. Consequently, routine adjuvant therapy is not recommended. POLEmut exhibit an extremely high mutation load and are characterized by a large amount of lymphocyte infiltration, which can trigger an active tumor immune response. POLEmut tumor cells overexpress programmed cell death protein 1 (PD-1), indicating that they could be suitable candidates for immunotherapy [27].

MMRd

MMRd respond poorly to traditional progestin therapy and have a high risk of recurrence after complete remission. The overall prognosis for these patients is moderate [26]. Due to the presence of MMR deficiency, these cells accumulate a significant number of mutations and produce a large amount of antigens, making MMRd patients particularly sensitive to immune checkpoint inhibitors (ICIs), which presents new treatment opportunities, especially for LS. ICIs enhance the systemic immune response, thereby restoring the anti-tumor activity of T cells. They have shown promise in the treatment of MMRd patients [28], but more research is needed to evaluate pregnancy outcomes and long-term safety.

NSMP

A Chinese phase II trial involving NSMP demonstrated that patients with recurrent and advanced EC who were treated with a combination of sintilimab and anlotinib achieved an impressive objective response rate of 73.9% and a disease control rate of 91.3%. This suggests that the combination of ICIs and tyrosine kinase inhibitors (TKIs) is effective in the Chinese population [29]. NSMP patients have high heterogeneity. Some traditional immunohistochemical markers such as hormone expression receptor levels are protective factors for their prognosis, while gene mutations such as KRAS, PTEN, CTNNB1, and overexpression of L1CAM are associated with poor prognosis [22]. For these patients, comprehensive consideration of indicators such as ER, PR and specific molecular characteristics, and further refinement through molecular markers should be made to explore individualized treatment strategies.

p53abn

Patients with p53abn are considered high-risk for EC, with the poorest prognosis, a high risk of recurrence and low survival rates. While FST are not generally recommended for these patients, it should not be concluded that p53abn is a conservation prohibition. Research has demonstrated that patients with p53abn can achieve complete remission following conservative treatment [30]. Additionally, it has been found that HER2 positivity is more prevalent among p53abn EC patients, and trastuzumab combined treatment can significantly improve PFS and the objective response rate in HER2-positive patients [31].

The prospects of targeted combination with FST

The preliminary results of the KEYNOTE-B21 study indicated that combining pembrolizumab with chemotherapy improved the prognosis for patients with MMRd [32]. Early data from the RUBY study suggested that MMRd patients experienced significant benefits from dostarlimab combined with chemotherapy [33]. Additionally, the results of the NIVEC study demonstrated high sensitivity among MMRd patients to immune monotherapy, with 80% of patients achieving both imaging and biopsy negative results after treatment, providing a potentially effective treatment option for preserving fertility in EC [34]. The results of the phase II trial showed that trastuzumab deruxtecan achieved an objective response rate of 57.5% in 40 HER2-positive EC patients treated with monotherapy, and 84.6% in patients with HER2 IHC 3+. This development brings new treatment options for HER2-positive EC patients undergoing preservation [35]. The PI3K/AKT/mTOR pathway is crucial for tumor growth and plays a key role in drug resistance. Long- term progesterone treatment may activate the PI3K/AKT/mTOR pathway, leading to the development of drug resistance. Blocking this pathway can significantly improve hormone resistance [36]. Therefore, inhibiting the PI3K/AKT/mTOR pathway is considered a potential target for improving progesterone resistance, providing new possibilities for EC preservation therapy. Currently, the reported PI3K/AKT/mTOR inhibitors mainly include mTOR inhibitors, PI3K inhibitors, and AKT inhibitors. In the phase II triall, the mTOR inhibitors temsirolimus and everolimus demonstrated good efficacy in patients with metastatic or recurrent EC [37]. Studies have confirmed that PI3K/AKT inhibitors can improve the ability of progesterone to inhibit tumor cell proliferation and reduce the volume of xenograft tumors, confirming that PI3K/AKT/mTOR inhibitors have a promising prospect in EC preservation [38–39].

In recent years, with the increase in the incidence of EC and the postponement of the first childbirth age, the demand for preserving fertility among young patients has become increasingly urgent. By integrating traditional preservation criteria with molecular classification, we can more effectively identify individuals who would benefit from such interventions and evaluate their treatment outcomes and prognosis. Although molecular classification has been widely applied in clinical practice, the existing classifications cannot fully cover the unique characteristics of the preservation population. Some patients exhibit multiple molecular features, and the classification standards and treatment strategies for these patients still have significant controversies. Future studies with larger sample sizes and longer follow-up are needed to focus on a deeper understanding of the molecular characteristics specific to young patients seeking fertility preservation. Furthermore, prospective registries should systematically collect data on reproductive outcomes, including ovulation resumption, pregnancy rates, and live birth rates, to fully assess the success of molecularly-guided FST beyond oncological safety.

Although the current FST regimen has a high remission rate, it does not mean that all patients can benefit from it. Patients with EC who fail conservative treatment often show hormone resistance, which presents a significant challenge for FST. The primary goal of FST should be to preserve fertility while effectively controlling the tumor. Treatment should be based on progestogens, combined with targeted therapies and immunotherapy, and ovarian function should be protected. With the expansion of treatment options for EC, multi-level combined screening of molecular characteristics in patient populations is essential to determine optimal combination therapy regimens. This approach enhances efficacy while minimizing toxic side effects, enabling personalized treatment plans for each patient. Future efforts should integrate molecular subtyping, multidisciplinary collaboration, and fertility preservation to establish the FST strategy for EC—combining molecular classification, drug combination therapy, and fertility preservation. This will advance precision diagnosis and treatment of EC to higher levels.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This study was not supported by any sponsor or funder.

YH conceived the project. XM drafted the article. YH revised the manuscript. All authors contributed to the article and approved the submitted version.