Investigating L1CAM and β-catenin as prognostic indicators in fertility-sparing endometrial cancer treatment.

Jeong-Yeol Park Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea info_outline Jeong-Yeol Park, Ok-Ju Kang, Uiree Jo

Authors Jeong-Yeol Park Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea info_outline Jeong-Yeol Park, Ok-Ju Kang, Uiree Jo Organizations Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea, Asan Medical Center, Seoul, South Korea Abstract Disclosures Research Funding No funding sources reported Background: Fertility-sparing progestin therapy is well-known treatment option for young women with endometrium-confined, low-grade, endometrioid type endometrial cancer (EC). The introduction of a molecular diagnostic framework by the TCGA Research Network in 2013, categorizing tumors into four prognostic groups, has significantly influenced the prognosis prediction in EC. The ProMisE system further stratifies EC based on molecular profiles, highlighting the need for refined prognostic tools, especially for those undergoing conservative treatments. Our study aims to explore the effectiveness of ProMisE and various immunohistochemical (IHC) markers in predicting outcomes for more fertility-sparing progestin therapy in endometrial cancer. Methods: We included young EC patients treated with fertility-sparing progestin therapy at a single center between January 2011 and December 2020. Patients were categorized according to the results of IHC staining to detect mismatch repair (MMR) proteins and p53 and the results of DNA polymerase epsilon (POLE) mutations which were identified through hotspot sequencing with droplet digital polymerase chain reaction like ProMisE classification. We also measured L1CAM, β-catenin, ER, and PR expression levels through IHC staining. The Complete Response (CR) rate to progestin therapy and PFS after progestin therapy were analyzed between each biomarker-driven subgroup. Results: Out of 104 patients, 60 patients (57.7%) were treated with MPA alone, while 44 patients (42.3%) received a combination of MPA and LNG-IUS. The CR was observed in 64 patients (61.5%). Among those achieving CR, 31 patients (48.4%) experienced recurrence over a median follow-up period of 54.7 months (range:10-128 months). The 5-year PFS was recorded at 67.2%, and the 5-year OS was maintained at 100%. Each one patient showed a POLE mutation, MMRd, and P53 abnormality, leaving 101 (97.1%) with NSMP. IHC revealed L1CAM expression in 12 patients (11.5%) and dual membranous and nuclear β-catenin expression in 8 patients (7.7%). This β-catenin expression significantly correlated with higher CR rates (71.4% vs. 45.6%, p=0.022), while L1CAM presence significantly reduced PFS (3yr-PFS 28.6% vs. 53.9%, p=0.033). Conclusions: Almost all endometrium-confined, low-grade, endometrioid type EC were categorized to NSMP, so that molecular classification had little role in young women who received fertility-sparing progestin therapy. Rather, β-catenin emerges as a positive predictive biomarker for CR, and L1CAM as a negative prognostic biomarker for PFS in this treatment setting. This supports incorporating these IHC markers into molecular classifiers like ProMisE for enhanced risk stratification and personalized treatment in this disease setting.