Potential of Molecular Classification to Guide Fertility-sparing Management Among Young Patients with Endometrial Cancer

The traditional histological classification system for endometrial carcinoma falls short in addressing the disease's molecular heterogeneity, prompting the need for alternative stratification methods. Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has emerged as a clinically efficient tool to categorize endometrial cancers according to mismatch repair deficiency, POLE exonuclease domain mutations, and p53 expression. However, the application of this classification to fertility-sparing treatments remains unexplored, and current guidelines lack specificity in how it should be used. In this review, we summarize the available literature and establish the framework for future investigations focused on molecular profiling-based risk assessment of endometrial cancer, with the goal of utilizing precision medicine to optimally counsel patients seeking fertility-sparing treatment. While the available evidence is limited and of low quality, it does provide insights and frames future perspectives for managing fertility-sparing approaches on the basis of molecular subtypes. Evidence suggests that mismatch repair-deficient tumors are likely to recur despite progestin therapy, emphasizing the need for alternative treatments, with targeted therapies being a new landscape that still needs to be explored. Tumors with POLE mutations exhibit a favorable prognosis, but the safety of hysteroscopic resection alone requires further investigation. p53 abnormal tumors have an unfavorable prognosis, raising questions about their suitability for fertility-sparing treatment. Lastly, the no specific molecular profile (or p53 wild-type) tumors, while having a relatively good prognosis, are heterogeneous and require more precise biomarkers to effectively guide therapy for those with poorer prognoses. Addressing these research gaps will lead to more precise guidelines to ensure optimal selection for fertility-sparing treatment.