Investigator
Obstetrics And Gynecology Hospital Of Fudan University
Pregnancy complications and outcomes in patients with early endometrial cancer or atypical hyperplasia after fertility-sparing treatment
To explore the characteristics of pregnancy outcomes in patients with early-stage endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH) after successful fertility-sparing treatment. This was a retrospective, single-center analysis of 481 patients with EEC/EAH who desired to conceive after successful fertility-sparing treatment from January 2015 to June 2023. Pregnancy outcomes across reproductive methods were compared. The pregnancy rate was 58.24% and the live birth rate was 48.65% in patients with EAH/EEC after successful fertility-preserving treatment. An age ≥35 years, BMI ≥25 kg/m², and hypertension were independent risk factors for failure of pregnancy. Higher pregnancy (65.77% and 63.64%) and live birth (53.08% and 48.86%) rates were achieved in the in vitro fertilization and embryo transfer (IVF-ET) and ovulation induction group than in the natural conception group (47.68% and 35.10%, respectively). The incidence of threatened abortion (56.52%), cervical insufficiency (5.58%), and placenta accrete/increta (11.15%) appeared to be numerically higher in patients with EAH/EEC than in epidemiological data. More than 5 times of hysteroscopic evaluation was an independent risk factor for placenta accreta/increta. Assisted reproductive technology including IVF-ET and ovulation induction might be preferred for patients with EEC/EAH after successful fertility-sparing treatment to achieve a relatively better pregnancy outcome, though IVF-ET has a higher incidence risk of threatened abortion, preterm birth and placenta accreta/increta. Obstetricians should be prepared for the treatment of threatened abortion, cervical insufficiency, and placenta accreta/increta in patients with EEC/EAH once they become pregnant, especially in those receiving more than 5 times of hysteroscopic evaluation.
Comparison of the effect of oral megestrol acetate with or without levonorgestrel-intrauterine system on fertility-preserving treatment in patients with early-stage endometrial cancer: a prospective, open-label, randomized controlled phase II trial (ClinicalTrials.gov NCT03241914)
To evaluate the effect of levonorgestrel-releasing intrauterine system (LNG-IUS) plus oral megestrol acetate (MA) as fertility-preserving treatment in patients with early-stage endometrial cancer (EEC). In this single-center, phase II study with open-label, randomized and controlled design, young patients (18-45 years) diagnosed with primary EEC were screened, who strongly required fertility-preserving treatment. Patients were randomly assigned (1:1) into MA group (160 mg oral daily) or MA (160 mg oral daily) plus LNG-IUS group. Pathologic evaluation on endometrium retrieved by hysteroscopy was performed every 3 months. The primary endpoint was complete response (CR) rate within 16 weeks of treatment. The secondary endpoints were CR rate within 32 weeks of treatment, adverse events, recurrent and pregnancy rate. Between July 2017 and June 2020, 63 patients were enrolled and randomly assigned. Totally 56 patients (26 in MA group; 28 in MA + LNG-IUS group) were included into primary-endpoint analyses. The median follow-up was 31.6 months (range, 3.1-94.0). No significant difference in 16-week CR rate were found between MA and MA + LNG-IUS groups (19.2% vs. 25.0%, p=0.610; odds ratio=1.40; 95% confidence interval=0.38-5.12), while the 32-week CR rates were also similar (57.1% and 61.5%, p=0.743), accordingly. More women in MA + LNG-IUS group experienced vaginal hemorrhage (46.4% vs. 16.1%; p=0.012) compared with MA group. No intergroup difference was found regarding recurrence or pregnancy rate. Compared with MA alone, the addition of LNG-IUS may not improve the early CR rate for EEC, and may produce more adverse events instead. ClinicalTrials.gov Identifier: NCT03241914.
Characteristics of progestin-insensitive early stage endometrial cancer and atypical hyperplasia patients receiving second-line fertility-sparing treatment
This study investigated the characteristics of progestin-insensitive endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) patients receiving fertility-sparing treatments and assessed the therapeutic effects of second-line fertility-preserving treatments. Three hundred and thirty-eight patients with EEC (n=75) or AEH (n=263) receiving fertility-preserving treatment were retrospectively analyzed. 'Progestin-insensitive' was defined as meeting one of the following criteria: 1) presented with progressed disease at any time during conservative treatment, 2) remained with stable disease after 7 months of treatment, and/or 3) did not achieve complete response (CR) after 10 months of treatment. Clinical characteristics and treatment results of progestin-insensitive patients receiving second-line treatment and those of progestin-sensitive patients were compared. Eight-two patients (59 AEH and 23 EEC) were defined as progestin-insensitive and 256 as progestin-sensitive. In multivariate analysis, body mass index ≥28.0 kg/m² (odds ratio [OR]=1.898) and lesion size >2 cm (OR=2.077) were independent predictors of progestin-insensitive status. Compared to AEH patients, progestin-insensitive EEC patients had poorer second-line treatment responses (28-week cumulative CR rate after changing second-line treatment, 56.3% vs. 85.4%, p=0.011). No statistical difference was found in CR rate among different second-line treatments. Obesity and larger lesion size were independent risk factors associated with progestin-insensitive status. In progestin-insensitive patients receiving second-line treatment, EEC patients had lower CR rate comparing with AEH patients. Further study with larger sample size is needed to evaluate efficacy of different second-line treatments for progestin insensitive patients.
Cholesterol desensitizes the response of endometrial cancer to progestin by attenuating progestin signaling.
Progestin is the primary fertility-preserving treatment for patients with endometrial cancer (EC) and its precursor lesions, endometrial atypical hyperplasia (EAH); however, a subset of patients exhibits a poor response. In this study, through the analysis of serum lipid differences, we found that progestin-resistant patients with EC/EAH exhibited reduced serum apolipoprotein A-I concentrations and increased cholesterol accumulation in endometrial tissue. Mechanistically, molecular docking simulations and cellular models confirmed that cellular cholesterol interfered with progestin-driven signaling by competing with progestin for binding to progesterone receptor B (PRB), thereby impairing its phosphorylation, nuclear translocation, and downstream gene activation. Substitution of leucine 887 with alanine 887 in PRB disrupted cholesterol binding but preserved progestin responsiveness. Furthermore, cholesterol-lowering therapy with rosuvastatin calcium restored progestin sensitivity in animal models and in a single-arm, open-label phase 2 clinical trial. Our work shows that cholesterol accumulation contributes to progestin resistance and that combining progestin with statins may enhance therapeutic efficacy in EC.
GnRHa + Letrozole in Non-obese Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients
To investigate the efficacy of GnRHa plus letrozole vs Diane-35 plus metformin in non-obese progestin-insensitive early-stage endometrial cancer (EEC) and atypical hyperplasia(EAH) patients asking for conservative treatment.
GnRHa + Letrozole in Obese Progestin-insensitive Endometrial Cancer Patients
To investigate the efficacy of GnRHa plus letrozole in obese progestin-insensitive EEC patients.
Megestrol Acetate Plus LNG-IUS in Young Women With Early Endometrial Cancer
To see if megestrol acetate plus Levonorgestrel-releasing intrauterine system (LNG-IUS) will not be inferior to returning the endometrial tissue to a normal state than megestrol acetate alone in patients with early endometrial cancer.
