Endometrial cancer is the most common gynecologic malignancy in the United States, with over 66,000 new cases estimated in 2023 [1,2]. While only 6% of patients are diagnosed before age 45 years [3], the diagnosis and treatment can be devastating for patients who have yet to fulfill their family-building goals. Recognizing the importance of fertility-sparing treatment, national guidelines describe appropriate candidates as those with well-differentiated tumors, no evidence of myometrial invasion, absence of metastatic disease, no contraindications for medical management (or pregnancy), and an explicit understanding that fertility preservation is not standard oncologic treatment [4,5]. This understanding is crucial as while most patients experience a response to progestins [6], the mainstay of fertility-sparing management, there is no consensus regarding the optimal duration of treatment or the regimen. Unfortunately, over a third of patients will experience a recurrence after an initial response [6,7], and the long-term survival data are conflicting [7,8].

It has become evident over the past decade that histologic classification of endometrial carcinomas is subpar to molecular classification, per The Cancer Genome Atlas (TCGA), a joint effort of the National Cancer Institute and the National Human Genome Research Institute that utilizes genomic sequencing to uncover and catalogue genomic alterations in human cancer and create an “atlas” of cancer genome profiles [9,10] This may also be extrapolated to fertility-sparing management, where hormonal therapy may be universally offered without consideration of the molecular landscape of the tumor. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) is a validated and clinically feasible approximation of TCGA categories that may be applied to and aid in individualizing care [11]. Understanding how this novel molecular classification system may be used to describe the response to fertility-sparing treatments will aid in selecting young patients who are eligible for fertility-sparing management while ensuring their oncological safety.

In this review, we summarize the available literature on and establish the framework for future investigations focused on molecular profiling–based risk assessment, with the goal of utilizing precision medicine to optimally counsel patients with endometrial cancer who are seeking fertility preservation.