Prognostic Role of molEcular classiFication in Fertility-sparing treAtment of Endometrial canCEr (PREFACE)

Prognostic Role of molEcular classiFication in Fertility-sparing treAtment of Endometrial canCEr: PREFACE Study

Endometrial cancer, the most common gynecologic malignancy in high-income countries, is increasing among reproductive-age women. While hysterectomy prevents pregnancy, hormonal therapies offer fertility-sparing options for select early-stage cases, with ~80% achieving complete response (CR). Molecular classifications (POLEmut, p53abn, MMRd/MSI-H, NSMP) reveal subtype-specific prognostic differences, with NSMP showing higher CR rates and lower recurrence, while p53abn and MMRd/MSI-H fare worse. Recent studies emphasize molecular profiling's potential to guide personalized fertility-sparing treatments. This study explores the prognostic role of these classifications in treatment outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Uterine Cancer
• Intervention / Treatment: Other: Observation only

Detailed Description

Endometrial cancer is the most common gynecologic malignancy in high-income countries, with an increasing incidence among women of reproductive age. In 2024, over 65,000 new cases were diagnosed in the United States alone. The prevalence of endometrial cancer in younger women who desire to preserve their fertility presents a significant clinical challenge. Traditional treatment for endometrial cancer involves hysterectomy, which precludes future pregnancies. However, fertility-sparing treatments, primarily using hormonal therapies, have emerged as a viable option for select patients with low-grade, early-stage endometrial cancer. Despite reported complete response (CR) rates of approximately 80% with fertility-sparing therapy, the outcomes vary significantly among patients. Molecular classifications have revolutionized the understanding of endometrial cancer by identifying four distinct subtypes: POLEmut (ultramutated), p53abn (TP53-mutant), MMRd/MSI-H (mismatch repair deficiency/microsatellite instability-high), and NSMP (no specific molecular profile). These classifications have demonstrated prognostic value in predicting oncologic outcomes in endometrial cancer. For instance, the NSMP subtype is associated with higher CR rates (78.4%) and lower recurrence rates (18.4%), whereas MMRd/MSI-H and p53abn subtypes show significantly poorer outcomes, including lower CR rates (48.8% and 50%, respectively) and higher recurrence rates (42.8% and 33%). However, the role of these molecular subtypes in guiding fertility-sparing treatment remains underexplored.

A recent meta-analysis synthesized data from eight studies involving 363 patients who underwent fertility-sparing treatment for endometrial cancer. This analysis highlighted significant differences in complete response to treatment and in oncologic outcomes among the molecular subtypes, emphasizing the potential utility of molecular classification in personalizing treatment strategies. This study aims to build on these findings by prospectively evaluating the prognostic role of molecular classifications in a well-defined cohort of endometrial cancer patients undergoing fertility-sparing treatment.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Filippo Ferrari, MD; Phone Number: 3803933116; Email: filippo.ferrari@istitutotumori.mi.it

Study Locations

• Italy
  • Michigan
    • Milan, Michigan, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei tumori di Milano

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This is a prospective study enrolling patients with endometrial cancer eligible for fertility-sparing treatment.

Data of consecutive patients treated from the 21st of January 2025.

Description

Inclusion Criteria:

1. Patients aged 18-45 years with a hysteroscopic confirmed diagnosis of endometrial cancer (FIGO stage IA without myometrial invasion, grade 1 or grade 2, endometrioid histology).
2. Patients desiring fertility preservation
3. Molecular classification of the tumor using next-generation sequencing (NGS) or Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE).
4. Adequate pre-treatment imaging (MRI or transvaginal ultrasound) confirming no evidence of myometrial invasion or extrauterine spread.

Exclusion Criteria:

1. Patients with atypical endometrial hyperplasia or intraepithelial neoplasia
2. Individuals with tumor samples of insufficient quantity or inadequate quality were not included in the analysis
3. Non-endometrioid histology.
4. Patients with a history of prior uterine malignancy or current synchronous malignancies.
5. Medical contraindications to hormonal therapy

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with endometrial cancer eligible for fertility-sparing treatment; Patients diagnosed with endometrial cancer who meet the criteria for inclusion in a fertility-sparing treatment pathway and for whom molecular classification data is available.	Other: Observation only; Only observation following standard of care (histological diagnosis, molecular classification, progestine therapy)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to fertility sparing treatmetn	To assess the differences in Complete Response (CR), Partial response/stable disease (PR/SD) and progression disease (PD) rates among molecular subtypes (NSMP, POLEmut, p53abn, MMRd/MSI-H) of endometrial cancer in patients undergoing fertility-sparing treatment.	12 months
Recurrence	To evaluate the recurrence rates of endometrial cancer among these molecular subtypes following fertility-sparing treatment after a CR	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to CR response	The number of months elapsed from the start of therapy to achieving a complete response.	12 months
Obstetric outcomes	After fertility-sparing treatment, we assess outcomes such as pregnancy rate (percentage of individuals achieving pregnancy) and live birth rate (percentage of pregnancies resulting in a live baby) for the cohort.	12 mesi

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): January 31, 2028

Study Registration Dates

• First Submitted: January 23, 2025
• First Submitted That Met QC Criteria: January 23, 2025
• First Posted (Actual): January 29, 2025

Study Record Updates

• Last Update Posted (Actual): December 23, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: molecular classification; uterine cancer; fertility-sparing
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Uterine Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Uterine Neoplasms
• Other Study ID Numbers: int

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No