Objective: Endometrial cancer is the most common gynecological malignancy in high-income countries. While early-stage endometrial cancer generally has a favorable prognosis, a small proportion of low-risk patients experience unexpected recurrence. This study aimed to identify molecular factors contributing to recurrence in stage 1 A grade 1-2 low-risk endometrioid endometrial cancer.

Methods: We performed next-generation sequencing (NGS) on tumor samples from 19 patients who experienced recurrence despite favorable clinicopathological features and compared them with six control patients without recurrence. Results were also compared to a matched cohort of low-risk endometrial cancers from The Cancer Genome Atlas (TCGA) database.

Results: Mutations in PTEN, PIK3CA, ARID1A, and FGFR2 were the most frequent in the recurrence group. FGFR2 mutations were exclusive to the recurrence group (9/19, 47.4 %) and absent in the non-recurrent group (0/6), a difference approaching statistical significance (p = 0.0571). FGFR2 mutations were also significantly more prevalent in the recurrence cohort compared to the TCGA low-risk cohort (p = 0.0039). Prominent FGFR2 missense mutations included S252W, K659E, and N549K, which may drive oncogenesis and tumor progression. Among the recurrence group, a rare POLE-mutated tumor recurred unexpectedly and proved fatal, highlighting the potential for poor outcomes even in typically favorable molecular subtypes.

Conclusion: FGFR2 mutations may play a role in tumor recurrence in a subset of low-risk endometrial cancers, underscoring the importance of molecular profiling in identifying patients at risk. FGFR2 represents a potential therapeutic target, warranting further validation in larger cohorts to establish its clinical utility.