Efficacy and Tolerance of an Ovarian Stimulation Protocol Combining Follicle Stimulating Hormone (FSH) and Degarelix Acetate in Female Candidates for Fertility Preservation Before Chemotherapy for Breast Cancer
Condition: Invasive Ductal Breast Carcinoma
MeSH terms: Breast Neoplasms; Carcinoma, Ductal, Breast
Study type: Interventional
Phase: Phase 2

Summary: 
      The present investigation aims to evaluate the efficacy of an innovative protocol of
      controlled ovarian stimulation for breast cancer patients, who are candidates for fertility
      preservation.

      Currently, vitrification of oocytes and/or embryos after controlled ovarian stimulation is
      the most established method for female fertility preservation. However, this stimulation
      induces an increase in serum estrogen levels, which is theoretically problematic in case of
      hormone-sensitive tumors such as breast cancer. The majority of oncology teams accept, in
      very specific situations (particularly when the tumor has been surgically removed), this
      ovarian stimulation, because the expected benefits of fertility preservation far outweigh the
      risks. However, everyone agrees that it would be more comfortable to be able to offer
      vitrification of oocytes and/or embryos using ovarian stimulation without increasing estrogen
      levels.

      In this research, investigators will evaluate the efficacy of degarelix (Firmagon®),
      currently indicated for the treatment of prostate cancer, as an innovative ovarian
      stimulation procedure. Administered at the beginning of ovarian stimulation, they believe it
      should maintain serum estradiol levels at physiological values at the end of stimulation.
    

Detailed description: 
      Recent improvements in freezing techniques have led to the development of fertility
      preservation techniques for young women diagnosed with cancer. Currently, vitrification of
      oocytes or embryos after controlled ovarian stimulation (COS) represents the only established
      method. This COS is based on the daily administration of exogenous Follicle Stimulating
      Hormone (FSH) and an ovulation blockage using Gonadotropin Releasing Hormone (GnRH)
      antagonists (0.25 mg/d) initiated after approximately 6 days of stimulation and continued
      until ovulation is triggered.

      In addition to requiring 15 days, COS induces supraphysiological hyperestradiolaemia (5-10
      times normal) which can be problematic in case of hormone-sensitive tumors such as breast
      cancer. The majority of oncology teams accept, in very specific situations (particularly when
      the tumor has been surgically removed), this ovarian stimulation, because the expected
      benefits of fertility preservation far outweigh the risks. However, everyone agrees that it
      would be more comfortable to be able to offer vitrification of oocytes and/or embryos using
      ovarian stimulation without increasing estrogen levels.

      Therefore, the limitation of serum estradiol concentrations during stimulation represents an
      important issue. To this end, stimulation protocols combining aromatase inhibitors have been
      proposed. Inhibition of the P450 aromatase enzyme in the granulosa cells of stimulated
      follicles prevents the conversion of androgens to estrogens. However, the teratogenic risk of
      these molecules, although discussed, limits their use in the indication of COS. Recently, a
      new "natos" protocol was proposed to stimulate the ovaries while maintaining physiological
      estradiolaemia, without using aromatase inhibitors. Thus, the administration of high doses of
      Gonadotropin Releasing Hormone (GnRH) antagonists (3 to 6 injections of 0.25 mg/day) from the
      beginning of COS, would allow a strong Luteinizing Hormone (LH) deprivation, thus limiting
      the production of androgens according to the 2 cells - 2 gonadotropins theory. In the absence
      of a precursor, estradiolemia remains at physiological ranges during the total duration of
      COS. However, the relative heaviness of a protocol combining up to 8 daily injections limits
      its use in young women who are candidates for fertility preservation.

      Investigators therefore propose to evaluate the efficacy and tolerance of a new natos-like
      COS protocol based on the administration of a long-acting GnRH antagonist, degarelix. This
      drug is currently off-label for women.

      The expected duration of the research is 14 months and participation will be 2 months.

      After signature of the consent, during the first visit (oncofertility counseling), the the
      research (consultations and examinations) will be carried out within the Antoine Béclère
      hospital. All visits and examinations performed are part of routine care, except for the
      injection(s) of degarelix which belongs to the research.

      Inclusion visit During the oncofertility consultation, the physician will make sure that the
      patient can be included in the research. Once the consent has been signed, the doctor will
      schedule the following visits based on the biological results obtained as part of the usual
      care.

      Research follow-up visits

      Stimulation: between the day of oncofertility counseling and the following 7 days, the doctor
      will check that patients are in the early follicular phase of the cycle, Degarelix injection:
      1 injection, under the skin (possibly renewable after 5-7 days if the serum LH is ≥2 IU / L
      and / or the estradiol is ≥400 pg / mL), Concomitant initiation of ovarian stimulation by
      administration of recombinant FSH - Follitropin alfa (usual care). The injections will be
      given by the patient or a nurse at home, between 7pm and 10pm.

      Stimulation follow-up visit #1 :

      After 5 days of ovarian stimulation, transvaginal pelvic ultrasound (counting of ovarian
      follicles and measurement of their diameters) and blood sampling for serum hormone assays
      (estradiol, LH, progesterone) will be performed as part of the usual care.

      Stimulation follow-up visits #2 and #3 Visits #2 and #3: transvaginal pelvic ultrasound
      (counting of ovarian follicles and measurement of their diameters) and a blood test for serum
      hormone assays (estradiol, LH, progesterone) will be required to monitor the response to
      stimulation, as part of routine care.

      Visits are repeated until 4 follicles 16 to 20 mm in diameter are obtained, which is the
      criterion for ovulation trigger using 1 injection of Human Chorionic Gonadotropin (hCG)
      (Ovitrelle 250 mcg, SC) (usual care). Thus visits #2 and #3 are systematic. One or two
      additional visits with the same examinations may sometimes be necessary if the trigger
      criteria are not met.

      Thirty-six hours after Human Chorionic Gonadotropin (hCG) , oocyte retrieval will be
      performed.

      Visit on the day of the oocyte retrieval:

      Patients will have a venous blood sample for serum hormone assays (estradiol, LH,
      progesterone) as part of the usual care.

      Oocyte collection will be scheduled, and those which are mature will then be frozen (by
      vitrification) or fertilized in vitro in case of embryo freezing.

      Visit following egg retrieval:

      A blood test for serum hormone assays (estradiol, LH, progesterone) will be performed 3-4
      days after oocyte retrieval.

      End of research visit Participants will be contacted by phone 2 months after the injection of
      degarelix (Firmagon®) to make sure they are fine.
    

Intervention name(s): Degarelix injection(s)
Intervention type(s): Drug
Intervention description(s): 1 or 2 degarelix injection(s)
Other intervention name(s): Firmagon®
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: Fertility preservation; Controlled ovarian stimulation; Oocyte vitrification; GnRH antagonist protocol