Molecular Classification Sharpens Risk Stratification in Endometrial Cancer

Efforts to enhance the predictive ability of risk stratification in patients with endometrial cancer got a boost when molecular classification (MC) was incorporated into clinical evaluation, according to a retrospective study published in BMC Cancer.¹ The findings offer community oncologists a data-driven argument for adopting molecular testing to guide surgical planning and patient counseling.

The research, conducted by Bretová and colleagues, compared the preoperative risk category, as defined by the ESGO/ESTRO/ESP 2020 guidelines, both with and without the inclusion of molecular classification. This preoperative assessment was then measured against the final, postoperative pathological diagnosis.

In particular, patients with high-risk disease had improved preoperative risk stratification accuracy, improving from 59.4% to 73.4%. Further, MC enhanced the accuracy in identifying the low-risk group preoperatively. The investigators noted, however, that distinguishing the intermediate and high-intermediate risk groups preoperatively remains challenging.

The retrospective, single-institution study identified 293 patients with endometrial cancer overall. Patients were included if they had early-stage endometrial cancer, histology from biopsy and definitive hysterectomy, immunohistochemistry results for p53 or mismatch-repair proteins, next-generation sequencing, and pelvic-abdominal chest CT. Patients were excluded if they had synchronous malignancies, apparent advanced-stage disease, or were missing essential data such as molecular classification or imaging results.

In the preoperative group without MC, 52.4% of patients were low risk, 21.0% were intermediate risk, 17.5% were high-intermediate risk, and 9.1% were high risk. With MC, the distribution was 49.75, 15.4%, 14.7%, and 20.3%, respectively. Postoperative assessment revealed 42.7%, 17.5%, 11.2%, and 28.7%, respectively.

The final analysis included 143 patients with a median age of 66 years (range, 29–85). Most (67.8%) patients had undergone sentinel lymph node biopsy followed by systematic lymphadenectomy (18.9%) and most had endometrioid tumors (89.5%) and low-grade (91.1%) disease.

Without MC, only 59.4% of patients were correctly classified into the correct risk group, but with MC, the accuracy of preoperative risk assessment was improved in 14.0% of cases. Using Kappa values between preoperative and postoperative risk classification improved from 0.551 (95% CI, 0.430–0.671) without molecular classification to 0.767 (95% CI, 0.675–0.849) with molecular classification, indicating an improvement from moderate to good agreement. The investigators reported that the 95% confidence intervals did not overlap, suggesting that the difference was statistically significant.

The investigators noted that in Betella et al,² p53 combined with imaging tests was found to be a reliable preoperative indicator of advanced disease. This study included patients with preoperatively advanced stages of endometrium cancer according to imaging results, which are already considered high risk. The current analysis focused on preoperative early stages of endometrium cancer in which specific histopathological and molecular features can play a key role in risk stratification.

Although molecular classification improved preoperative risk stratification prediction in the study, 26.6% of patients were misclassified due to factors such as lymphovascular space invasion (LVSI), cervical and myometrial invasion, and lymph node metastasis, particularly in the intermediate and high-intermediate risk groups. The authors noted that LVSI is a strong prognostic factor that can upstage a case, but it is typically identified only in the definitive surgery specimen.

“Although [these factors were] not the primary focus of the study, it represents a relevant secondary observation that further highlights the limitations of preoperative assessment,” lead investigator Petra Bretová and colleagues wrote.

The investigators also point out potential sources of bias including the study’s retrospective design and discrepancies in assessment of myometrial and cervical invasion between preoperative imaging and definitive histopathology.

Bretová et al concluded that although imaging and molecular classification provide complementary data to improve preoperative decision-making, further discussion and consensus within the gynecologic oncology community is warranted.

REFERENCES:

1. Bretová P, Ndukwe MI, Laco J, et al. Preoperative risk stratification in endometrial cancer using ESGO/ESTRO/ESP 2021 guidelines: accuracy with and without molecular classification. BMC Cancer. 2025;25(1):1302. Published 2025 Aug 11. doi:10.1186/s12885-025-14741-5

2. Betella I, De Vitis LA, Calidona C, Multinu F, Colombo N. Letter to the editor-The new FIGO staging system for endometrial cancer: Is the paradigm shift clinically feasible? Int J Gynaecol Obstet. 2024;164(1):364-365. doi:10.1002/ijgo.15265