Clinical And Basic Research On Fertility-preserving Therapy For Patients With Endometrial Carcinoma Or Severe Atypical Hyperplasia

Background & Objectives:About 3%-14% of the endometrial carcinoma occurs in young women aged 40 years or younger and 70%-85% of them are nulligravid. They usually have excellent prognosis because of early stage, good differentiations and hormone dependent. No guideline for progesterone fertility-preserving therapy can be found from the previous reports based on clinical observations of few cases.The purpose of this study is to summarize our experiences and try to provide evidences of progesterone fertility-preserving therapy for 44 cases of endometrial carcinoma and severe atypical hyperplasia. We also try to find some clues to predict the responses of progesterone fertility-preserving therapy by some molecular markers like ER, PR, P53, P16, EGFR or hTERC.Subjects & Methods:The inclusion criteria are:(1) age 20-40years; (2) histologically proved grade 1 endometrial carcinoma or severe atypical hyperplasia; (3) desire to preserve fertility; (4) no evidence of myometrial invasion or extrauterine extension (FIGO StageIA) after evaluation by pelvic ultrasonography and/or MRI and/or laparoscopic exploration.Methods:(1) Therapy regimen: continuous oral administrated MPA 250-500mg/d or MA 160-320mg/d, or intramuscular injection of Hydroxyprogesteron for 2 or 3 times a week; (2) All patients were followed up by endometrial curettage at intervals of 3 months; (3) Clomiphene citrate or IVF-ET was used to increase the chance of pregnancy after complete remission was achieved; (4) Imunohistochemistry was performed to determine the expression of ER, PR, p53, p16, and EGFR. FISH was performed to determine the amplification of hTERC in the curettage materials. Results:Mean age of all the patients was 29 years. Thirty-one of them were grade 1 endometrial carcinoma and 13 were severe atypical hyperplasia. Complete remission was achieved in 38 cases (86.4%) and 2 (4.5%) got PR, while 3 (6.8%) got SD and 1(2.3%) got PD. The mean duration to achieve CR was 4.9+2.5 months. One (1.4%) interrupted the therapy because of the severe adverse effects. Eight experienced recurrence (23.5%) and all were free of disease at follow-up of 47.1±34.8 months.Of the 26 patients who achieved CR and attempted pregnancy,11 (42.3%) achieved 16 pregnancies and 6 successfully delivered a healthy baby. The interval between the completion of progestin therapy and conception was 11.7±7.1 months。The pregnancy rate of patients with AH and EC was 66.7% and 29.4% respectively. The pregnancy rate after IVF-ET was 100%, which is significantly higher than those without IVF-ET.The expression of both ER and PR were over 90%. Strong PR expression was observed in 94.1% of the patients achieved CR and 33.3% in those not achieved CR (P<0.01). p53 mutation was positive in about 15%of all patients. Positive p53 expression was 66.7% and 8.1%, and low p16 expression was 100% and41.7% in the patients who achieved CR/PR and those achieved SD/PD, respectively (P<0.05)。Over-expression of EGFR in normal endometrium, AH and EC was 23.0%,50% and 70.6% respectively. Amplication of hTERC was 22.2%,50% and 90% in normal endometrum, hyperplasic endomerum and cancer after therapy.Conclusions:This study is the biggest single-center observation on progestin fertility preserving therapy for patients with EC or severe AH. Thirty-eight (86.4%) achieved CR and 42.3% of those achieved CR got pregnant. Assisted reproductive technology can significantly increase the chance of conception.23.5% experienced recurrence but all were free of disease. Mutation of p53 and loss of p16 expression may be correlated with response to hormone therapy. Amplication of hTERC had the potency to be the marker for predicting the response of hormone therapy in endometrial carcinoma..