RCT of Fixed vs Titrated Letrozole in Breast Cancer Patient Undergoing IVF

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01035099
• Collaborator: (none)
• Enrollment: 41
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 154.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to compare two different ways to administer Letrozole to determine their effectiveness in blocking estrogen production during ovarian stimulation in patients with breast cancer prior to chemotherapy/radiotherapy so that oocytes or embryos can be cryopreserved and patients can possibly achieve a pregnancy after the treatment of breast cancer.

During standard ovulation stimulation, the estrogen levels will exceed normal levels and may reach 10 times the normal level for a 2 week period. This may not be desirable in breast cancer patients. The study hopes to determine if the investigators can stimulate oocyte development in the conventional way and administer different doses of Letrozole as the oocytes develop, to keep estradiol levels low, increase the number of oocytes the investigators are able to recover, and improve the quality of those oocytes.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Infertility	Drug: Letrozole; Drug: Letrozole	Phase 4

Detailed Description

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.

Patients will have serum blood tests for bHCG, FSH, AMH, Estradiol, and LH and vaginal sonogram on the second day of menstrual bleeding. Start of stimulation medication will proceed only with documentation of a serum negative pregnancy test. Patients will only be eligible to participate in the study for one cycle of in vitro fertilization.

Patients who elect to participate in the study will be provided with gonadotropin medications.

The starting dose of gonadotropins for both study groups would be determined by the patients' age and by antral follicle counts assessed by transvaginal ultrasound at the time of initial consultation. See below:

Age <35 , Antral follicle Count >15 gonadotropin dose 225 IU (150 IU FSH + 75 IU HMG; Age <35, Antral follicle Count <15 gonadotropin dose 300 IU (150 IU FSH + 150 IU HMG; Age 35-39, Antral follicle Count >10 gonadotropin dose 300 IU (150 IU FSH + 150 IU HMG; Age 35-39, Antral follicle Count <10 gonadotropin dose 450 IU (225 IU FSH + 225 IU HMG; Age>40 Independent of antral follicle count, gonadotropin dose 450 IU (225 FSH + 225 IU HMG);

All patients would also be given a daily medication to prevent them from ovulating (Ganirelix), no later than cycle day #7 and continuing until HCG administration.

Group#1-Fixed Letrozole Group: Provided their blood tests and sonograms were within normal limits, patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle (Current Letrozole protocol at CRMI). Patients will be monitored with daily blood tests for estradiol and LH and sonogram every 1-3 days. Adjustments to gonadotropin dosing will be made as per usual protocol for IVF. Letrozole dose will not change and will continue for two weeks after egg retrieval.

Group #2-Titrated Letrozole Group: Provided their blood tests and sonograms were within normal limits, patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen:

Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;

The maximal starting dose of Letrozole will be 5 mg, regardless of the initial estradiol level. The Letrozole dose may be reduced if the appropriate suppression of estradiol occurs. The maximal increase or decrease in Letrozole dose will be 2.5 mg/ day. Patients will be monitored with blood tests for estradiol and LH and sonograms starting on the second day of gonadotropin stimulation and every 1-3 days to monitor response and adjust medication dose as per our usual IVF protocol. Letrozole will be stopped for both groups on the day that HCG is given and resumed after egg retrieval. All patients will stay on the same dose of Letrozole that was required for their last day of ovarian stimulation for 2 weeks after stimulation to keep estradiol levels at a minimum. In addition, patients will have serum estradiol levels drawn weekly for 2 weeks after stimulation. Follow-up vital signs will be recorded along with CBC, liver function panel, and cholesterol panel 2 weeks after stimulation. They will also be asked to return 6 months to 1 year after completion of chemotherapy for AMH and FSH levels to evaluate ovarian reserve, and then followed on a yearly basis by phone/mail questionnaire or in person with an annual gynecological examination.

All study patients will be provided with an emergency 24-hour phone number to reach a physician to report adverse reactions to medications, and these physicians will file adverse event report forms to the principal investigator and data safety monitoring board. In addition, they will be asked to report any adverse reactions to medications during follicular monitoring sonograms. All decisions regarding daily medication doses will be determined by the study principal investigator. Otherwise, the treatment of ovarian stimulation, egg retrieval, and cryopreservation is identical to non-study patients undergoing ovarian stimulation, oocyte retrieval, and embryo/oocyte cryopreservation.

Two weeks after retrieval, follow-up instructions will be reviewed. Patients will be advised to refrain from embryo transfer for a minimum of 2 years after chemotherapy. Patients will not be permitted to undergo embryo transfer for a minimum of one year after completing chemotherapy and only after clearance for pregnancy has been obtained from their medical oncologist. Patients will be followed for five years on an annual basis with a follow-up telephone call from one of the investigators inquiring about health status (see patient follow-up data sheet). A pregnancy registry will be created for any pregnancy occurring following enrollment in the study. Detailed pregnancy outcome will be collected between age 2-5 years (see baby follow-up data sheet attached).

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jul 23, 2019
• Anticipated Study Completion Date: Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Titrated dose Letrozole Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen.	Drug: Letrozole; Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg; Other Names: Femara- trade name
Active Comparator: Fixed dose Letrozole Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle.	Drug: Letrozole; Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle; Other Names: Femara- trade name

Outcome Measures

Primary Outcome Measures

1. Mature Oocyte Yield [1 to 2 months]

   Mature oocyte yield in each group

2. Percent of Mature Oocyte Yield [1 to 2 months]

   The percentage of mature oocyte obtained will be compared from both arms. Calculated as number of mature oocytes divided by number of oocytes retrieved (per patient).

Secondary Outcome Measures

1. Participant Cycle Cancellation Rate [1 to 2 months]

   Cycle cancellation rate- participant

2. Breast Cancer Recurrence Rate [5 years]

   5 year follow-up breast cancer recurrence rate

3. Peak Serum Estradiol Level [1 to 2 months]

   Peak Serum Estradiol Level (pg/ml)

4. FSH ng/ml (Cycle Day 2) [1 to 2 months]

   FSH ng/ml on Cycle Day 2

5. AMH ng/ml (Cycle Day 2) [1 to 2 months]

   AMH ng/ml on Cycle Day 2

6. AF Count [1 to 2 months]

   Antral follicle count

7. Total Days Stimulation Medications [1 to 2 months]

   Total days of stimulation medications

8. Total Medication Dose [1 to 2 months]

   Total medication dose given

9. Total Number of Oocytes [1 to 2 months]

   Total number of oocytes retrieved

10. Number of Follicles on Day of HCG [1 to 2 months]

    Number of follicles on day of Human Chorionic Gonadotrophin (HCG)

11. Number of Fertilized Oocytes [1 to 2 months]

    Number of fertilized oocytes among participants

12. Number of Good Quality Embryos [1 to 2 months]

    Number of good quality embryos among participants

13. Breast Cancer Recurrence at Year 1-2 [1 to 2 years]

    Number of Subjects with Breast Cancer Recurrence at Year 1-2

14. Breast Cancer Recurrence at Year 2-3 [2- 3 years]

    Number of Subjects with Breast Cancer Recurrence at year 2-3

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female breast cancer patient with breast cancer diagnosis after surgery and before undergoing chemotherapy desiring fertility preservation with oocyte or embryo cryopreservation

• Healthy subject according to documented medical history and physical examination who has been diagnosed with breast cancer (estrogen and progesterone receptor positive and/or negative)

• Age less that 45 years at time of informed consent

• Verbal or written clearance from medical or surgical oncologist to undergo controlled ovarian hyperstimulation-IVF

• Delay to chemotherapy treatment will not jeopardize cancer treatment outcome

• Ovarian stimulation will not affect cancer treatment plan

• Transvaginal ultrasound scan (US) within one month of starting stimulation with no clinically significant pelvic mass

• Serum FSH level (Day 2-4) less than 25

• Negative pregnancy test prior to beginning Letrozole or gonadotropin therapy

• Willing and able to comply with the protocol

• Voluntary provision of written informed consent, prior to any study related procedure that was not part of normal medical care, with the understanding that the subject can withdraw consent at any time without prejudice to her future medical care

• Willingness to provide follow-up information on herself and babies born as part of this study

Exclusion Criteria:

• Patients not medically cleared by their oncologist

• Patients with stage IV breast cancer based on the poor prognosis, general health of the patient, and higher uncertainty with delaying chemotherapy

• Any clinically relevant abnormal laboratory value (FSH >25 miu/ml, renal function, (greater than two times normal value), hepatic function (greater than two times normal value), blood biochemistry, hematology (elevated white blood count greater than 1.5 times the normal value, hemoglobin <10mg/dL, thrombocytopenia), abnormal cholesterol profile (total cholesterol ≥ 300mg/dL, abnormal LDL greater than 2 times normal value,) based on a fasting sample during the screening phase

• Contraindications for the use of gonadotropins (i.e. Tumors other than breast cancer, pregnancy, lactation, undiagnosed vaginal bleeding)

• Recent or current medical conditions where the patient is not medically stable to undergo stimulation or egg retrieval, HIV infection, diabetes, cardiovascular disease, gastrointestinal, hepatic disease, undiagnosed pelvic mass, renal or pulmonary disease

• History or presence of alcohol or drug abuse within 12 months of signing consent

• History of severe allergic or anaphylactic reactions or hypersensitivity to any of the concomitant medication prescribed as part of the treatment regimen in this protocol

• Administration of investigational drugs within three months prior to signing the informed consent

• Use of insulin sensitizing agents at least one month prior to signing informed consent

• Any patient who is not a candidate for IVF

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College	New York	New York	United States	10021

Sponsors and Collaborators

• Weill Medical College of Cornell University

Investigators

• Principal Investigator: Glenn Schattman, MD, Weill Cornell Medical Cornell

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 20, 2018

More Information

Additional Information:

• The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT01035099
• Other Study ID Numbers: 0811010075
• First Posted: Dec 18, 2009
• Last Update Posted: Nov 23, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Weill Medical College of Cornell University: Letrozole; IVF (in vitro fertilization); Cryopreservation; Fertility Preservation; Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Infertility; Letrozole

Study Results

Participant Flow

Pre-assignment Detail	41 subjects were enrolled; One subject 1 later withdrew consent prior to randomization.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Period Title: Overall Study
STARTED	18	22
COMPLETED	18	22
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole	Total
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.	Total of all reporting groups
Overall Participants	18	22	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 100%	22 100%	40 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	18 100%	22 100%	40 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	18 100%	21 95.5%	39 97.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 4.5%	1 2.5%
Region of Enrollment (Count of Participants)
United States	18 100%	22 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Mature Oocyte Yield
Description	Mature oocyte yield in each group
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 39 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization; 1 subject in the Fixed dose group had no oocytes harvested, so this measure could not be calculated for that patient).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	18	21
Mean (Standard Deviation) [oocytes]	5.1 (8.4)	7.9 (8.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

2. Primary Outcome

Title	Percent of Mature Oocyte Yield
Description	The percentage of mature oocyte obtained will be compared from both arms. Calculated as number of mature oocytes divided by number of oocytes retrieved (per patient).
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 39 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization; 1 subject in the Fixed dose group had no oocytes harvested, so this measure could not be calculated for that patient).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	18	21
Mean (Standard Deviation) [percentage of mature oocytes]	0.29 (0.38)	0.46 (0.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

3. Secondary Outcome

Title	Participant Cycle Cancellation Rate
Description	Cycle cancellation rate- participant
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

This information was not recorded.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle
Measure Participants	0	0

4. Secondary Outcome

Title	Breast Cancer Recurrence Rate
Description	5 year follow-up breast cancer recurrence rate
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

This information was not recorded.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	0	0

5. Secondary Outcome

Title	Peak Serum Estradiol Level
Description	Peak Serum Estradiol Level (pg/ml)
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 40 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	18	22
Mean (Standard Deviation) [pg/ml]	603.1 (213.4)	771.1 (401.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

6. Secondary Outcome

Title	FSH ng/ml (Cycle Day 2)
Description	FSH ng/ml on Cycle Day 2
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 37 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization; Three subjects in Titrated group did not have FSH recorded).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	15	22
Mean (Standard Deviation) [ng/ml]	5.9 (2.0)	5.8 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

7. Secondary Outcome

Title	AMH ng/ml (Cycle Day 2)
Description	AMH ng/ml on Cycle Day 2
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 33 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization; Three subjects in Titrated group did not have AMH recorded and 4 patients in the Fixed group did not have AMH recorded).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	15	18
Mean (Standard Deviation) [ng/ml]	2.1 (1.6)	2.4 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

8. Secondary Outcome

Title	AF Count
Description	Antral follicle count
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

This information was not recorded.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	0	0

9. Secondary Outcome

Title	Total Days Stimulation Medications
Description	Total days of stimulation medications
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 40 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	18	22
Mean (Standard Deviation) [days]	10.1 (1.7)	11.2 (2.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

10. Secondary Outcome

Title	Total Medication Dose
Description	Total medication dose given
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 40 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	18	22
Mean (Standard Deviation) [mg]	34.0 (7.0)	55.3 (14.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

11. Secondary Outcome

Title	Total Number of Oocytes
Description	Total number of oocytes retrieved
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 40 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	18	22
Mean (Standard Deviation) [oocytes]	17.1 (10.3)	19.0 (11.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

12. Secondary Outcome

Title	Number of Follicles on Day of HCG
Description	Number of follicles on day of Human Chorionic Gonadotrophin (HCG)
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

This information was not recorded.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	0	0

13. Secondary Outcome

Title	Number of Fertilized Oocytes
Description	Number of fertilized oocytes among participants
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

Only 39 subjects analyzed of 41 (1 subject later withdrew consent prior to randomization; One subject in Fixed group did not have this information recorded).

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	18	21
Mean (Standard Deviation) [fertlized oocytes]	3.7 (5.8)	5.3 (6.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Titrated Dose Letrozole, Fixed Dose Letrozole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	t-test, 2 sided
	Comments	Nonparametric Wilcoxon rank-sum test confirmed these results.

14. Secondary Outcome

Title	Number of Good Quality Embryos
Description	Number of good quality embryos among participants
Time Frame	1 to 2 months

Outcome Measure Data

Analysis Population Description

This information was not recorded.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	0	0

15. Secondary Outcome

Title	Breast Cancer Recurrence at Year 1-2
Description	Number of Subjects with Breast Cancer Recurrence at Year 1-2
Time Frame	1 to 2 years

Outcome Measure Data

Analysis Population Description

This information was not recorded.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	0	0

16. Secondary Outcome

Title	Breast Cancer Recurrence at Year 2-3
Description	Number of Subjects with Breast Cancer Recurrence at year 2-3
Time Frame	2- 3 years

Outcome Measure Data

Analysis Population Description

This information was not recorded.

Arm/Group Title	Titrated Dose Letrozole	Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;	Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
Measure Participants	0	0

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	Only 40 subjects analyzed out of 41 (1 subject was not included because they withdrew consent prior to randomization).
Arm/Group Title	Titrated Dose Letrozole		Fixed Dose Letrozole
Arm/Group Description	Patients who are randomized to the titrated dose of Letrozole, will start gonadotropins in the evening of day #2 of their menstrual cycle with injectable follicle stimulating hormone (FSH) and human menopausal gonadotropin (HMG). Oral Letrozole will be added to the stimulation in the following titrated regimen. Letrozole: Letrozole titrated regimen may be started on day 2 of menstrual cycle: Serum Estradiol level <150 pg/ml- No Letrozole; Serum Estradiol Level 150-250 pg/ml- 2.5mg; Serum Estradiol Level 251-350 pg/ml- 5 mg; Serum Estradiol Level >350 pg/ml - 7.5 mg;		Patients who are randomized to fixed dose Letrozole will start Letrozole 5mg daily (orally) on the second day of their menstrual cycle and then gonadotropins on the fourth day of their menstrual cycle. Letrozole: Fixed dose of 5 mg per day Letrozole will be started on the second day of their menstrual cycle.
All Cause Mortality
	Titrated Dose Letrozole		Fixed Dose Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)
Serious Adverse Events
	Titrated Dose Letrozole		Fixed Dose Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Titrated Dose Letrozole		Fixed Dose Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)		4/22 (18.2%)
Gastrointestinal disorders
abdominal pain	6/18 (33.3%)	6	4/22 (18.2%)	4
Reproductive system and breast disorders
OHSS	2/18 (11.1%)	2	1/22 (4.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.