Study of Breast Cancer Prevention by Letrozole in High Risk Women

• Sponsor: Carol Fabian, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00579826
• Collaborator: Novartis (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 55
• Location: 1
• Arms: 2
• Duration (Months): 142
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a multi-institution double-blind placebo-controlled trial whose main objective is to determine if 6 months of letrozole (2.5 mg daily) can reduce proliferation as assessed by Ki-67 in high risk postmenopausal women on systemic hormone replacement therapy who have random periareolar fine needle aspiration (RPFNA) evidence of hyperplasia with atypia or borderline atypia, and a minimum Ki-67 of >1.5%.

The primary hypothesis is that proliferation and expression of other estrogen response genes will be favorably modulated by six months of letrozole relative to placebo without substantially increasing hot flashes or worsening overall quality of life.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Letrozole; Drug: Placebo	Phase 2

Detailed Description

Subsequent to the 6 month RPFNA for assessment of biomarkers, toxicity and quality of life assessments, all women may receive optional open-label letrozole for an additional 6 months, followed by a third RPFNA and biomarker

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Study of Breast Cancer Prevention by Letrozole in High Risk Women
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Letrozole Letrozole, 2.5 mg daily for 6 months	Drug: Letrozole; Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.; Other Names: Letrozole(Femara)
Placebo Comparator: Placebo Placebo, daily for 6 months	Drug: Placebo; Placebo tablet daily for 6 months then optional open label letrozole for 6 months.

Outcome Measures

Primary Outcome Measures

1. Change in Proliferation Rate (Ki-67 by Immunocytochemistry) From Baseline to 6 Months [Baseline to 6 Months]

   Change in proliferation rate (percent positively stained cells for Ki-67 antigen by immunocytochemistry) in benign breast epithelial cells acquired by random periareolar fine needle aspiration from women at high risk for the development of breast cancer.

Secondary Outcome Measures

1. Assessment of Change in Morphology by the Masood Score. [Baseline to 6 Months]

   Masood score is a semi-quantitative index of increasing abnormality, thus higher values are worse. Range 6 to 24.

2. Change in Mammographic Density From Baseline to 6 Months.. [Baseline to 6 Months]

   Percent area of the breast considered to be at increased density, as determined by the computer program Cumulus..

3. Change in Biomarkers Associated With Bone and Cardiovascular Health, Adverse Events, Breast Cancer Prevention Trial (BCPT) Symptom Check List, Hot Flash Score, General Fatigue Inventory, the Fibromyalgia Impact Questionnaire. [6 Months, 12 Months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 69 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Post-menopausal women at high risk for development of breast cancer

• On a stable dose of hormone replacement therapy

• have cytomorphologic evidence of hyperplasia +/- atypia and Ki-67 expression >1.5% in benign breast epithelial cells acquired by RPFNA

• Serum level of 25-OH vitamin D of at least 30 ng/ml prior to study entry

• Willing to have a repeat random periareolar fine needle aspiration (RPFNA) and mammogram at 6 months and 12 months (if participating in the open label portion of the study) following initiation of study drug

Exclusion Criteria:

• Prior history of osteoporosis or osteoporotic fracture.

• Prior history of invasive breast cancer or other invasive cancer within five years from date of study entry.

• Current and chronic use of cyclooxygenase-2 (COX-2) specific inhibitors or NSAIDs

• Receiving treatment for rheumatoid arthritis or fibromyalgia

• Current history of poorly controlled migraines or perimenopausal symptoms

• Currently receiving other investigational agents.

• Receipt of more than 6 months of an aromatase inhibitor (anastrozole, exemestane, letrozole, etc.) at any time in the past.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kansas Medical Center	Kansas City	Kansas	United States	66160

Sponsors and Collaborators

• Carol Fabian, MD
• Novartis
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Carol J Fabian, MD, University of Kansas Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 5, 2012

More Information

Publications

None provided.

• Responsible Party: Carol Fabian, MD, Professor, Director Breast Cancer Prevention Unit, University of Kansas Medical Center
• ClinicalTrials.gov Identifier: NCT00579826
• Other Study ID Numbers: 10587; CFEM345AUS45; 5R01CA122577-03
• First Posted: Dec 24, 2007
• Last Update Posted: Jan 19, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Breast Neoplasms; Letrozole

Study Results

Participant Flow

Arm/Group Title	Letrozole	Placebo
Arm/Group Description	Letrozole, 2.5 mg daily for 6 months Letrozole: Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.	Placebo, daily for 6 months Placebo: Placebo tablet daily for 6 months then optional open label letrozole for 6 months.
Period Title: Overall Study
STARTED	29	26
6 Months	28	25
COMPLETED	24	23
NOT COMPLETED	5	3

Baseline Characteristics

Arm/Group Title	Letrozole	Placebo	Total
Arm/Group Description	Letrozole, 2.5 mg daily for 6 months Letrozole: Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.	Placebo, daily for 6 months Placebo: Placebo tablet daily for 6 months then optional open label letrozole for 6 months.	Total of all reporting groups
Overall Participants	29	26	55
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.2 (8.3)	44.7 (7.4)	57.0 (7.9)
Sex: Female, Male (Count of Participants)
Female	29 100%	26 100%	55 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 3.8%	1 1.8%
Not Hispanic or Latino	29 100%	25 96.2%	54 98.2%
Unknown or Not Reported	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%	1 3.8%	1 1.8%
White	29 100%	25 96.2%	54 98.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	29 100%	26 100%	55 100%
Height (m) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m]	1.63 (0.09)	1.64 (0.08)	1.63 (0.08)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	69.0 (11.2)	73.6 (15.9)	71.2 (13.7)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.3 (5.0)	27.9 (9.1)	27.0 (7.2)
Age at menarche (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.6 (1.3)	12.6 (1.2)	12.6 (1.2)
Age at first live birth (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	20.5 (10.1)	21.7 (11.1)	21.4 (10.2)
History of prior breast biopsy (participants) [Number]
History of biopsy	19 65.5%	16 61.5%	35 63.6%
No history of biopsy	10 34.5%	10 38.5%	20 36.4%
History of prior Ductal Carcinoma In Situ (DCIS) or Lobular Carcinoma in Situ (LCIS) (participants) [Number]
History	3 10.3%	1 3.8%	4 7.3%
No History	26 89.7%	25 96.2%	51 92.7%
Number of relatives with breast cancer (participants) [Number]
With relatives	18 62.1%	20 76.9%	38 69.1%
No relatives	11 37.9%	6 23.1%	17 30.9%
Gail risk of developing breast cancer within 5 years (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	4.2 (3.9)	3.4 (1.8)	3.8 (3.1)
Immunocytochemical expression of Ki-67 (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	4.5 (3.1)	4.0 (2.8)	4.2 (3.0)
Cytology (participants) [Number]
Hyperplasia	4 13.8%	4 15.4%	8 14.5%
Hyperplasia with borderline atypia	5 17.2%	5 19.2%	10 18.2%
Hyperplasia with Atypia	20 69%	17 65.4%	37 67.3%
Masood Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	15 (0.9)	15 (1.1)	15 (1.0)

Outcome Measures

1. Primary Outcome

Title	Change in Proliferation Rate (Ki-67 by Immunocytochemistry) From Baseline to 6 Months
Description	Change in proliferation rate (percent positively stained cells for Ki-67 antigen by immunocytochemistry) in benign breast epithelial cells acquired by random periareolar fine needle aspiration from women at high risk for the development of breast cancer.
Time Frame	Baseline to 6 Months

Outcome Measure Data

Analysis Population Description

Subjects who complete initial 6-month period and have repeat RPFNA.

Arm/Group Title	Letrozole	Placebo
Arm/Group Description	Letrozole, 2.5 mg daily for 6 months Letrozole: Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.	Placebo, daily for 6 months Placebo: Placebo tablet daily for 6 months then optional open label letrozole for 6 months.
Measure Participants	28	25
Mean (Standard Deviation) [percentage of cells stained positive]	-1.5 (2.8)	-1.1 (3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Assessment of Change in Morphology by the Masood Score.
Description	Masood score is a semi-quantitative index of increasing abnormality, thus higher values are worse. Range 6 to 24.
Time Frame	Baseline to 6 Months

Outcome Measure Data

Analysis Population Description

Subjects who complete initial 6-month intervention and have a repeat RPFNA, thus a change from baseline to 6-months can be computed.

Arm/Group Title	Letrozole	Placebo
Arm/Group Description	Letrozole, 2.5 mg daily for 6 months Letrozole: Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.	Placebo, daily for 6 months Placebo: Placebo tablet daily for 6 months then optional open label letrozole for 6 months.
Measure Participants	28	25
Mean (Standard Deviation) [units on a scale]	-1.1 (1.5)	-1.1 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Change in Mammographic Density From Baseline to 6 Months..
Description	Percent area of the breast considered to be at increased density, as determined by the computer program Cumulus..
Time Frame	Baseline to 6 Months

Outcome Measure Data

Analysis Population Description

Subjects who complete the initial 6-months intervention and have mammograms available for analysis at baseline and 6 months, thus a change can be computed.

Arm/Group Title	Letrozole	Placebo
Arm/Group Description	Letrozole, 2.5 mg daily for 6 months Letrozole: Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.	Placebo, daily for 6 months Placebo: Placebo tablet daily for 6 months then optional open label letrozole for 6 months.
Measure Participants	23	24
Mean (Standard Deviation) [percentage of breast at high densit]	-3.8 (12.8)	0.2 (11.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Change in Biomarkers Associated With Bone and Cardiovascular Health, Adverse Events, Breast Cancer Prevention Trial (BCPT) Symptom Check List, Hot Flash Score, General Fatigue Inventory, the Fibromyalgia Impact Questionnaire.
Time Frame	6 Months, 12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	duration of study agent
Arm/Group Title	Letrozole, 2.5 mg Daily for 12 Months		Placebo for 6 Months; Open Label Letrozole 2.5 mg Daily
Arm/Group Description	Letrozole, 2.5 mg daily for 6 months Letrozole: Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.		Placebo, daily for 6 months Placebo: Placebo tablet daily for 6 months then optional open label letrozole for 6 months.
All Cause Mortality
	Letrozole, 2.5 mg Daily for 12 Months		Placebo for 6 Months; Open Label Letrozole 2.5 mg Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Letrozole, 2.5 mg Daily for 12 Months		Placebo for 6 Months; Open Label Letrozole 2.5 mg Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Letrozole, 2.5 mg Daily for 12 Months		Placebo for 6 Months; Open Label Letrozole 2.5 mg Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/29 (37.9%)		3/26 (11.5%)
Cardiac disorders
Atrial Tachycardia	1/29 (3.4%)	1	0/26 (0%)	0
Eye disorders
Cataract	1/29 (3.4%)	2	0/26 (0%)	0
Gastrointestinal disorders
Vomiting/nausea	1/29 (3.4%)	3	0/26 (0%)	0
Hepatobiliary disorders
Gallbladder necrosis	1/29 (3.4%)	1	0/26 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	5/29 (17.2%)	5	3/26 (11.5%)	3
Nervous system disorders
Dizziness	1/29 (3.4%)	1	0/26 (0%)	0
Headache	1/29 (3.4%)	2	0/26 (0%)	0
Renal and urinary disorders
Kidney pain	0/29 (0%)	0	1/26 (3.8%)	1
Reproductive system and breast disorders
Vaginal mucositis/ cervical infection	1/29 (3.4%)	2	0/26 (0%)	0
Skin and subcutaneous tissue disorders
Wound complication	1/29 (3.4%)	1	0/26 (0%)	0
Skin infection	1/29 (3.4%)	1	0/26 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.