A Randomized Open Label Clinical Trial of Fixed Dose Letrozole vs. Titrated Letrozole for In Vitro Fertilization With Cryopreservation of Oocytes and Embryos in Breast Cancer Patients

IVF is a process which involves a schedule of injectable medication to recruit several follicles, each containing an egg, to be retrieved under ultrasound guidance where they can be fertilized. Embryos are then selected to be transferred back into the patient's uterus or are cryopreserved and transferred at a later date.

Letrozole is a potent and highly selective third generation aromatase inhibitor that was developed in the early 1990's. Aromatase is an enzyme of the cytochrome P-450 superfamily and the product of the CYP19 gene, which catalyzes the reaction that converts androgenic substances to estrogens in many tissues, including the granulosa cells of ovarian follicles. Letrozole competitively inhibits the activity of the aromatase enzyme and has a half-life of approximately 48 hours. Because of its potent, sustained suppression in the plasma levels of estradiol, this drug has been recently found to be superior to tamoxifen in the treatment of advanced-stage post-menopausal breast cancer. Conventional ovarian stimulation often results in very high estrogen levels. Since the high estrogen levels are often unsafe for breast cancer patients, fixed dose aromatase inhibitor protocols with Letrozole were developed, to achieve effective ovarian stimulation with reduced estrogen levels to prevent tumor progression and short-term cancer recurrence.

A fixed dose of Letrozole has been used off-label as an ovulation induction agent in many centers to stimulate egg development for infertile couples and patients prior to undergoing chemotherapy for estrogen sensitive cancers.

The purpose of our study is to determine if titrated dose Letrozole in comparison to fixed dose Letrozole during gonadotropin stimulation in IVF in breast cancer patients results in lower estradiol levels and higher mature oocyte yield.

In patients who are scheduled to undergo treatment with IVF for fertility preservation due to breast cancer, we would like to prospectively randomize them to fixed dose vs. titrated dose of Letrozole. Due to time restraints for chemotherapy patients may present for ovarian stimulation prior to Day 2 of their menstrual cycle. If this were to occur, Ganirelix may be started to suppress the pituitary hormones for down regulation prior to starting stimulation medications until day 2 of menstrual bleeding. Eligible subjects will be fully informed about the nature of the trial. Subjects could be enrolled for IVF treatment at any point after breast cancer diagnosis following surgery but before the initiation of chemotherapy, if chemotherapy has been prescribed by their oncologist. After obtaining written informed consent, the subjects will be screened based on inclusion/exclusion criteria, medical and infertility history, Day 2/3 FSH and estradiol, physical and gynecological examination, oncology clearance and the Center's standard screening evaluations for IVF patients. A thorough gynecologic and endocrinologic evaluation will be performed before the start of any treatment. Laboratory assessments will include CBC, chemistry and lipid profile (see attached history and physical form). Vital signs including blood pressure, pulse, and weight will be assessed at baseline (prior to start of stimulation medication), with preoperative evaluation, on day of egg retrieval, and with post retrieval visits.