Stratifying Advanced Endometrial Cancer: Real-World Outcomes by Molecular Subtype

Molecular classification has transformed the landscape of endometrial cancer management in early-stage disease, but its relevance in advanced or recurrent settings remains less defined. In one of the largest real-world analyses to date, Lindemann and colleagues investigated long-term oncologic outcomes in patients with advanced or recurrent endometrial cancer treated with platinum-based chemotherapy, stratified by molecular subtype. Their findings, recently published in the International Journal of Gynecological Cancer, underscore the prognostic utility of molecular profiling, particularly in advanced disease, while also revealing its limitations in recurrent settings.

Study Design and Patient Cohort
This retrospective cohort study included 360 patients treated at Norwegian Radium Hospital between 2006 and 2017. Molecular classification followed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), categorizing tumors as:

• POLE-mutated (POLEmut)
• Mismatch repair-deficient (MMRd)
• TP53-abnormal (p53abn)
• No specific molecular profile (NSMP)

Patients were divided into two groups:

• Advanced disease cohort: 264 patients, primarily FIGO stage III/IV, treated post-hysterectomy
• Recurrent disease cohort: 96 patients with recurrence after prior surgery, stratified by primary FIGO stage

Molecular classification was successfully performed in 263 advanced and 94 recurrent cases. Median follow-up was five years.

Molecular Class Drives Prognosis in Advanced Disease
In patients with advanced disease, molecular subtype was a statistically significant predictorfor both time-to-recurrence and cancer-specific survival (P < .0001 for both):

• Best outcomes were seen in POLE-mutated tumors, with a median time-to-recurrence of 11.6 years (95 percent CI, 0.5–15.8) and no cancer-specific deaths in stage III patients.
• MMRd tumors demonstrated improved survival:
• Time-to-recurrence: HR 0.56 (95 percent CI, 0.33–0.94)
• Cancer-specific survival: HR 0.50 (95 percent CI, 0.29–0.87)
• p53abn tumors had the worst outcomes:
• Time-to-recurrence: HR 1.57 (95 percent CI, 1.07–2.30)
• Cancer-specific survival: HR 1.78 (95 percent CI, 1.19–2.65)
• NSMP was used as the reference group.

Stratification by stage showed improved outcomes for stage III versus stage IV patients across all molecular classes.

No Clear Prognostic Signal in Recurrent Disease
In contrast, molecular classification was not predictive of outcomes in patients with recurrent disease. Median time from first to second recurrence was only 0.73 years (95 percent CI, 0.66–0.79), and median time from first recurrence to cancer-specific death was 1.47 years (95 percent CI, 1.12–2.18).

• For p53abn tumors, the HR for cancer-specific death was 1.60 (95 percent CI, 0.99–2.68), indicating a trend toward worse outcomes but not reaching statistical significance.
• POLE-mutated recurrent tumors remained rare (n = 1), but showed no recurrence or cancer-specific death.

Clinical Implications and Future Directions
The real-world results provide important validation of molecular classification as a prognostic tool in advanced endometrial cancer. Notably:

• Patients with p53-abnormal tumors continue to fare poorly, reinforcing the need for novel strategies beyond platinum doublets.
• MMRd status remains predictive of better outcomes, aligning with recent trial data on immune checkpoint inhibition.
• The strong outcomes in POLE-mutated tumors suggest the possibility of treatment de-escalation, even in advanced cases.

This study reinforces the imperative to molecularly subtype all patients with newly diagnosed advanced endometrial cancer to identify which patients are least likely to benefit from chemotherapy alone and may need early access to combination or investigational regimens.

However, recurrent disease remains a major unmet clinical need, and the absence of a prognostic signal supports the rationale for biopsies at recurrence as well as the exploration of additional biomarkers.

Reference:

1. Lindemann K, Kildal W, Kleppe A, et al. Real-world outcomes in molecular subgroups for patients with advanced or recurrent endometrial cancer treated with platinum-based chemotherapy. Int J Gynecol Cancer. 2025;35(5):101618. doi:10.1016/j.ijgc.2024.101618