Molecular Predictors for Fertility-Sparing Treatment in Endometrial Cancer and Atypical Hyperplasia

Abstract

Introduction: Endometrial cancer (EC) is the most common gynecologic malignancy in developed nations. Incidence and mortality are rising each year. Standard treatment is hysterectomy, but 4% - 14% of cases occur in women under 45 who may desire fertility preservation. Fertility-sparing treatment (FST) with progestins is an option for selected patients with atypical endometrial hyperplasia (AEH) or early-stage, low-grade endometrioid EC. With this approach, however, treatment failure and recurrence risks remain high. The Cancer Genome Atlas (TCGA) and Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) frameworks divide EC into four subtypes: POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), p53-abnormal (p53abn), and no specific molecular profile (NSMP). Each subtype has distinct prognostic and therapeutic impacts. Integration of molecular classification improves precision oncology in FST. Objective: This narrative review summarizes the current evidence on the role of molecular classification and additional biomarkers in FST outcomes for AEH and early-stage EC. It aims to guide patient selection and optimize conservative management strategies. Methods: A comprehensive literature search was conducted in PubMed, Cochrane Library, and Google Scholar. The search used MeSH terms and keywords for EC, FST, and molecular markers. Eligible studies included clinical trials, retrospective and prospective cohort studies, systematic reviews and meta-analyses, narrative reviews, clinical guidelines, and experimental or observational research. Eligibility was limited to studies published in English and we prioritized studies published from 2013 onward. Results: NSMP tumors are the most common FST candidates and have the best outcomes. Complete response (CR) rates are 72% - 92% with low recurrence rates (14% - 20%). MMRd tumors show lower CR rates (33% - 71%) and higher recurrence rates (42% - 100%). The p53abn subtype has the poorest outcomes among all subgroups, with CR rates of 33% - 55% and recurrence rates of 33% - 100%. POLEmut outcomes are variable and despite their excellent post-surgical prognosis, the role of FST in this subtype remains unclear. Among additional biomarkers, progesterone receptor (PR) expression, particularly the PR-B isoform, is one of the strongest predictors of treatment response. PTEN, PIK3CA, and KRAS mutations may predict poor response. High Ki-67 expression links to higher recurrence rates and may be a useful marker during follow-up. CTNNB1, ARID1A, and L1CAM are emerging markers that may help refine NSMP risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly recognized as novel adjuncts to FST, supported by preclinical evidence of synergistic antitumor effects and early clinical data suggesting improved FST outcomes when combined with progestins. Conclusions: FST decision-making should integrate molecular classification to improve patient selection and treatment outcomes. NSMP tumors are the most suitable candidates for conservative management, while p53abn tumors should be excluded from FST approach. MMRd tumors require cautious selection and close surveillance. The role of FST for treatment of POLEmut tumors remains unclear. Additional biomarkers and emerging therapies such as GLP-1 RAs may refine FST strategies. Prospective trials are needed to validate these findings and establish and inform personalized treatment strategies.