Fertility Preservation in Breast Cancer Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficiency and safety of controlled ovarian stimulation (COS) associated with an aromatase inhibitor (letrozole) for fertility preservation in breast cancer patients.

Detailed Description
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Patients enrolled in this study undergo standard or random start ovarian stimulation with Gonadotropins using antagonist protocol before the beginning of chemotherapy. Ovulation is triggered in all patients with a GnRH agonist since amendment P2015/091 (Decapeptyl 0,2mg). At oocyte retrieval, aspirated follicular fluid is separated from the flush medium for hormonal assays, and oocytes are denuded for ICSI(Intra Cytoplasmic Sperm Injection) or vitrification. Cumulus cells are collected for subsequent analysis of oocyte quality gene expression. A. Primary objective of the study is to evaluate efficiency of letrozole associated ovarian stimulation for fertility preservation in breast cancer patients in terms of oocyte maturation rate. Patients' results for primary endpoint are prospectively compared to infertile patients undergoing COS without letrozole. B. Secondary objectives of the study aim to evaluate safety of the protocol: Estradiol and progesterone levels at ovulation triggering, ovulation and during luteal phase after oocyte retrieval (days 3 and 8) The risk of disease relapse will be assessed by long-term follow-up of these patients (up to 5 years) as well as an evaluation of circulating tumoral DNA before and after ovarian stimulation. Finally obstetrical outcomes will also be recorded.

Official Title
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Efficiency and Safety Study of Ovarian Stimulation With Letrozole for Fertility Preservation in Breast Cancer Patients

Conditions
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Fertility, Breast Neoplasms

Intervention / Treatment
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* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Breast cancer female patients of less than 41 years old Addressed to fertility preservation Unit before starting chemotherapy Exclusion Criteria: Metastatic breast cancer Known premature ovarian failure Basal FSH > 20 IU(International Unit) Surgical contra-indications

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole associated COS<br>Breast cancer patients undergo fertility preservation with letrozole associated COS for oocyte collection. Letrozole is administered orally (5mg/day) during the entire stimulation protocol until ovulation triggering. | Drug: Letrozole<br>* Patients start ovarian stimulation protocol according to their menstrual cycle phase at enrollment (standard or random start). Ovarian stimulation includes gonadotropins administration in a GnRH antagonist protocol Standard Protocol: letrozole is orally administered 2 tablets per day (2,5mgx2/d) from cycle day 2 throughout the ovarian stimulation with gonadotropins protocol until ovulation triggering. GnRH antagonist is administered as soon as at least one follicle reaches 14 mm. Random start protocol: letrozole is administered throughout the stimulation together with gonadotropins and GnRH antagonist, until ovulation triggering. Oocytes are collected 36h after ovulation triggering. All patients receive GnRH antagonist after oocyte retrieval for 3-7 days or until chemotherapy starts, to induce luteolysis.<br>* Other names: Femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oocyte maturation rate | Following letrozole associated COS, oocytes are collected and evaluated for maturation rate (%). These results are prospectively compared to infertile patients undergoing similar COS (GnRH antagonist protocol) without letrozole. | At oocyte collection (48 hours after last administration of letrozole, following COS protocol). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hormonal levels | Estradiol and Progesterone levels are measured on serum samples to confirm the effect of COS associated with letrozole on hormonal levels | during stimulation at ovulation trigger and oocyte retrieval and during luteal phase (days 3 and 8) | 
| Circulating tumoral DNA | 3 EDTA (Ethylene Diamine Tetra-Acetic Acid) tubes are collected for plasma extraction. 1 EDTA tube is collected for whole blood. Circulating tumoral DNA will be assessed on plasma samples according to primary tumoral mutation screening. Whole blood will used as reference. | At enrollment (before letrozole associated COS) and at oocyte retrieval (48 hours after last administration of letrozole, following COS protocol) | 
| Comparison of breast cancer recurrence rate in patients who underwent letrozole associated COS with an oncological control group | Oncological follow-up for relapse risk assessment will be carried out at 2 and 5 years of follow-up by medical chart review. Local, contralateral and/or distant recurrence of the disease will be reported. These data will be compared to a control group matched for age and type of disease who were diagnosed with breast cancer during the same period but did not undergo letrozole associated COS for fertility preservation. | 2 and 5 years after letrozole associated COS | 
| Ovarian reserve | AMH (anti-mullerian hormone) and FSH (follicle stimulating hormone) are assessed on blood samples to evaluate the gonadotoxicity of chemotherapy. | At enrollment, 2 and 5 years after letrozole associated COS for fertility preservation | 
| Obstetrical outcome: malformation rate | Malformation will be evaluated in patients who conceive with a previously vitrified oocyte (following letrozole associated COS): malformation assessment during prenatal morphology ultrasound and/or at birth | Through study completion: data collection at 2 and 5 years after letrozole associated COS | 
| Neonatal outcomes: gestational age at birth | Neonatal outcomes will be evaluated in patients who conceive with a previously vitrified oocyte (following letrozole associated COS): gestational age at birth. Preterm delivery is defined by birth < 37 weeks gestation. | Through study completion: data collection at 2 and 5 years after letrozole associated COS | 
| Neonatal outcomes: delivery procedure | Neonatal outcomes will be evaluated in patients who conceive with a previously vitrified oocyte (following letrozole associated COS). Delivery procedure is defined as spontaneous, instrumental or cesarean section | Through study completion: data collection at 2 and 5 years after letrozole associated COS | 
| Neonatal outcomes: birth weight | Neonatal outcomes will be evaluated in patients who conceive with a previously vitrified oocyte (following letrozole associated COS). Birth weight will be reported in grams. | Through study completion: data collection at 2 and 5 years after letrozole associated COS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fertility preservation, letrozole, Ovarian stimulation