Controlled Ovarian Stimulation in Newly Diagnosed Breast Cancer PatiEnts (fAMHOPE)

Study Overview
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Brief Summary
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This is a multicenter hospital-based prospective cohort study conducted in institutions with known expertise in performing oocytes/embryo freezing for fertility preservation. The study aims at refining the understanding of the efficacy and safety of controlled ovarian stimulation with or without letrozole in young women with newly diagnosed breast cancer who are candidates to receive (neo)adjuvant chemotherapy.

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 Gonadotropin Releasing Hormone-GnRH agonist. After retrieval, oocytes are denuded and matured oocytes are subjected to fertilization before embryo freezing or direct vitrification. Primary objective is to evaluate the efficacy of performing a controlled ovarian stimulation with or without letrozole in young women with newly diagnosed breast cancer who are candidates to receive (neo)adjuvant chemotherapy in terms of mature oocytes collected.

Official Title
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A Multicenter Prospective coHort Study of Controlled Ovarian Stimulation in Newly Diagnosed Breast Cancer PatiEnts (fAMHOPE)

Conditions
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Breast Neoplasm Malignant Female

Intervention / Treatment
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* Drug: Letrozole
* Other: standard-stimulated cohort


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of invasive non-metastatic breast cancer (i.e. stage I to III); Breast cancer diagnosis ≥18 and ≤ 40 years; No prior history of gonadotoxic treatments; Fertility preservation counseling for fertility preservation; Written inform consent; FSH < 20 UI/L and/or antra-follicular count ≥ 6 (follicles of 2-9 mm) and/or AMH ≥ 6 pmol (only applicable for patients who undergo controlled ovarian stimulation for embryo/oocyte cryopreservation). Exclusion Criteria: Newly diagnosed stage IV breast cancer (i.e. de novo metastatic breast cancer); Prior diagnosis of other malignancies before breast cancer.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 3 groups: 113 patients in the standard-stimulated cohort, 113 patients in the letrozole-stimulated cohort, 339 patients in the non-stimulated cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: standard-stimulated cohort<br>this cohort includes all newly diagnosed breast cancer patients who are candidates to receive (neo)adjuvant chemotherapy and wish to preserve their fertility by undergoing oocyte/embryo cryopreservation at the French participating centres. | Other: standard-stimulated cohort<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: Gonadotrophins started from cycle day 2-3 throughout the ovarian stimulation until ovulation triggering. Random start protocol: Gonadotrophins started at any time of the cycle and throughout the stimulation. GnRH antagonist is administered at cycle day 7 or as soon as at least one follicle reaches 12-14 mm. Oocytes are collected 36h after ovulation triggering with GnRH agonist.<br>* Other names: COS;|
| Experimental: letrozole-stimulated cohort<br>this cohort includes all newly diagnosed breast cancer patients who are candidates to receive (neo)adjuvant chemotherapy and wish to preserve their fertility by undergoing oocyte/embryo cryopreservation at the Belgian participating centres. | 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 (5mg/d) from cycle day 2-3 throughout the ovarian stimulation with gonadotropins protocol until ovulation triggering. Random start protocol: letrozole is administered throughout the stimulation together with gonadotropins. GnRH antagonist is administered at cycle day 7 or as soon as at least one follicle reaches 12-14 mm. Oocytes are collected 36h after ovulation triggering with GnRH agonist.<br>* Other names: Controlled Ovarian Stimulation (COS);|
| No Intervention: non-stimulated cohort<br>this cohort includes all newly diagnosed breast cancer patients who are candidates to receive (neo)adjuvant chemotherapy and who have access to the Fertility Clinics in all the participating centres but are not willing to preserve their fertility by undergoing oocyte/embryo cryopreservation. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of the ovarian stimulation and oocyte collection procedure: Number of mature oocytes collected | Number of mature oocytes collected | an average of 2 weeks after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patient with adverse events due to COS: OHSS | Adverse events reporting during COS (Ovarian Hyperstimulation syndrome-OHSS) | Through treatment procedure, an average of 2 weeks after inclusion | 
| Characteristics of Ovarian stimulation: total gonadotropin doses | Total gonadotropin doses (International Unit- IU) | An average of 2 weeks after inclusion | 
| Characteristics of Ovarian stimulation: duration of the COS | duration of the COS (days) | An average of 2 weeks after inclusion | 
| Characteristics of Ovarian stimulation: type of stimulation | type of stimulation (standard or random-start). | An average of 2 weeks after inclusion | 
| Efficacy of the ovarian stimulation and oocyte collection: Maturation rate | Maturation rate (number of total oocyte collected/number of mature oocytes) | An average of 2 weeks after inclusion | 
| Outcomes of assisted reproductive technology procedures | Number of pregnancies and outcomes (premature delivery, miscarriage, abortion, delivery healthy babies, congenital malformation). | Through study completion, 5 years | 
| Anticancer therapies effect on ovarian function: progesterone | Hormonal measurements Progesterone ng/ml | Inclusion, an average of 2 weeks, 6 months, 18 months, 30 months, 60 months | 
| Anticancer therapies effect on ovarian function: AMH | Anti-Mullerian Hormone (AMH) measurements AMH ng/ml | Inclusion, an average of 2 weeks, 6 months, 18 months, 30 months, 60 months | 
| Anticancer therapies effect on ovarian function: FSH | Follicle-Stimulating Hormone (FSH) measurements FSH IU/L | Inclusion, an average of 2 weeks, 6 months, 18 months, 30 months, 60 months | 
| Anticancer therapies effect on ovarian function: E2 | Hormonal measurements E2 pg/ml | Inclusion, an average of 2 weeks, 6 months, 18 months, 30 months, 60 months | 
| Anticancer therapies effect on ovarian function | Amenorrhea rate (6months without spontaneous menstruation) | An average 18 months, 30 months, 60 months after inclusion | 
| Oncological outcomes 1 | Invasive disease-free survival (iDFS) | 5 years | 
| Oncological outcomes 2 | breast cancer-free interval (BCFI) | 5 years | 
| Oncological outcomes 3 | overall survival (OS) | 5 years | 
| Circulating breast cancer cells level before stimulation | circulating tumor DNA (ctDNA) | Inclusion | 
| Circulating breast cancer cells level after stimulation | circulating tumor DNA (ctDNA) | average of 2weeks after inclusion | 
| Number of patient with adverse events due to egg collection | bleeding | An average of 2 weeks after inclusion | 
| Number of patient with adverse events due to egg collection | pelvic infection | An average of 2 weeks after inclusion | 
| Efficacy of the in vitro fertilization procedure: Fertilization rate | Fertilization rate (number of oocyte fertilized/number of embryo obtained) | Through study completion, 5 years | 

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