Molecular Profiling to Guide Fertility Sparing Therapy in Early-Stage Endometrial Cancer: A EORTC Gynaecological Cancer Group Study.

Objective: Fertility-preserving therapies are a potential option for selected patients with early-stage endometrial cancer and atypical endometrial hyperplasia/endometrial intraepithelial neoplasia. This systematic review aims to evaluate the impact of fertility-preserving strategies according to molecular subtype. Methods: A comprehensive search was conducted in PubMed, Cochrane Library, EMBASE, and Web of Science for English-language studies published until June 2024, investigating fertility-sparing treatments using endocrine therapy in early-stage endometrial cancer, considering molecular classification. The PRISMA checklist was followed, and the protocol was registered in PROSPERO (CRD42025649342). Data on body mass index (BMI), age, and molecular classification (POLE-mutant, non-specific molecular profile [NSMP], p53-abnormal, and mismatch repair deficient [dMMR]) were extracted. The study assessed objective response rates (ORR), pregnancy outcomes, and survival outcomes. Statistical analyses were performed using R software. Results: The search identified 941 articles, and 10 studies with 457 patients were selected for final analysis. Pregnancy outcomes were reported in three studies, whilst all reported ORR data. Baseline median age (dMMR 35 years, POLE-mutant 38.2 years, p53-abnormal 33.9 years, and NSMP 31.6 years) and BMI (dMMR 24.3, POLE-mutant 27.9, p53-abnormal 26.2, and NSMP 29.8) differed by molecular subtype. Aggregated full-term delivery rates from the three studies reporting pregnancy outcomes were 36.4% (4/11) for POLE-mutant, 22.1% (27/122) for NSMP, 14.3% (1/7) for p53-abnormal, and 4.0% (1/25) for dMMR tumours, but statistical comparison was not feasible due to small sample size. Overall response rate was highest in NSMP (87.4%) and POLE-mutant tumours (84.6%), while dMMR (59.3%) and p53-abnormal (58.8%) had significantly lower ORR (compared to NSMP, p < 0.001 and p = 0.03, respectively). Conclusions: These findings support the potential role of molecular classification in refining patient selection for fertility-sparing treatment in early-stage endometrial cancer. Pregnancy-related outcomes should be interpreted with caution given the limited available evidence.