Breast Cancer
Conditions
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.
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
Interventions
DRUGLetrozole
Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.
DRUGPlacebo
Placebo tablet daily for 6 months then optional open label letrozole for 6 months.
Sponsors
Novartis
National Cancer Institute (NCI)
Carol Fabian, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
30 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
* Post-menopausal women at high risk for development of breast cancer * 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-hydroxyvitamin 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 (RPFNA) from women at high risk for the development of breast cancer. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. Based on Masood S, Frykberg ER, McLellan GL, Scalapino MC, Mitchum DG, Bullard JB. Prospective evaluation of radiologically directed fine-needle aspiration biopsy of nonpalpable breast lesions. Cancer 1990; 66:1480-7. |
| 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.. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Fibromyalgia Impact Questionnaire (FIQ) Score. | Baseline to 6 months | Assessment of impact of fibromyalgia on everyday living activities. Composite score ranges from 0 (best, no interference or impact on activities) to 104 (worst, maximum interference with activities). |
| Change in Brief Fatigue Inventory (BFI) Score. | baseline to 6 months | Assessment of the extent to which fatigue interferes in normal everyday living activities. Change over 6 months of treatment is assessed. Range from 0 (best, no fatigue) to 10 (worst). Increase in score indicates greater intensity of fatigue and/or greater interference with activities due to fatigue. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Letrozole Letrozole, 2.5 mg daily for 6 months
Letrozole: Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months. | 29 |
| Placebo Placebo, daily for 6 months
Placebo: Placebo tablet daily for 6 months then optional open label letrozole for 6 months. | 26 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Letrozole | Placebo | Total |
|---|---|---|---|
| Age at first live birth | 20.5 years STANDARD_DEVIATION 10.1 | 21.7 years STANDARD_DEVIATION 11.1 | 21.4 years STANDARD_DEVIATION 10.2 |
| Age at menarche | 12.6 years STANDARD_DEVIATION 1.3 | 12.6 years STANDARD_DEVIATION 1.2 | 12.6 years STANDARD_DEVIATION 1.2 |
| Age, Continuous | 58.2 years STANDARD_DEVIATION 8.3 | 44.7 years STANDARD_DEVIATION 7.4 | 57.0 years STANDARD_DEVIATION 7.9 |
| Body Mass Index | 26.3 kg/m^2 STANDARD_DEVIATION 5 | 27.9 kg/m^2 STANDARD_DEVIATION 9.1 | 27.0 kg/m^2 STANDARD_DEVIATION 7.2 |
| Cytology Hyperplasia | 4 participants | 4 participants | 8 participants |
| Cytology Hyperplasia with Atypia | 20 participants | 17 participants | 37 participants |
| Cytology Hyperplasia with borderline atypia | 5 participants | 5 participants | 10 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 25 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gail risk of developing breast cancer within 5 years | 4.2 percent STANDARD_DEVIATION 3.9 | 3.4 percent STANDARD_DEVIATION 1.8 | 3.8 percent STANDARD_DEVIATION 3.1 |
| Height | 1.63 m STANDARD_DEVIATION 0.09 | 1.64 m STANDARD_DEVIATION 0.08 | 1.63 m STANDARD_DEVIATION 0.08 |
| History of prior breast biopsy History of biopsy | 19 participants | 16 participants | 35 participants |
| History of prior breast biopsy No history of biopsy | 10 participants | 10 participants | 20 participants |
| History of prior Ductal Carcinoma In Situ (DCIS) or Lobular Carcinoma in Situ (LCIS) History | 3 participants | 1 participants | 4 participants |
| History of prior Ductal Carcinoma In Situ (DCIS) or Lobular Carcinoma in Situ (LCIS) No History | 26 participants | 25 participants | 51 participants |
| Immunocytochemical expression of Ki-67 | 4.5 percent STANDARD_DEVIATION 3.1 | 4.0 percent STANDARD_DEVIATION 2.8 | 4.2 percent STANDARD_DEVIATION 3 |
| Masood Score | 15 units on a scale STANDARD_DEVIATION 0.9 | 15 units on a scale STANDARD_DEVIATION 1.1 | 15 units on a scale STANDARD_DEVIATION 1 |
| Number of relatives with breast cancer No relatives | 11 participants | 6 participants | 17 participants |
| Number of relatives with breast cancer With relatives | 18 participants | 20 participants | 38 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 25 Participants | 54 Participants |
| Region of Enrollment United States | 29 participants | 26 participants | 55 participants |
| Sex: Female, Male Female | 29 Participants | 26 Participants | 55 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 69.0 kg STANDARD_DEVIATION 11.2 | 73.6 kg STANDARD_DEVIATION 15.9 | 71.2 kg STANDARD_DEVIATION 13.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 29 | 3 / 26 |
| serious Total, serious adverse events | 0 / 29 | 0 / 26 |
Outcome results
Primary
Change in Proliferation Rate (Ki-67 by Immunocytochemistry) From 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 (RPFNA) from women at high risk for the development of breast cancer.
Time frame: Baseline to 6 Months
Population: Subjects who complete initial 6-month period and have repeat RPFNA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Proliferation Rate (Ki-67 by Immunocytochemistry) From Baseline to 6 Months | -1.5 percentage of cells stained positive | Standard Deviation 2.8 |
| Placebo | Change in Proliferation Rate (Ki-67 by Immunocytochemistry) From Baseline to 6 Months | -1.1 percentage of cells stained positive | Standard Deviation 3.9 |
p-value: 0.92Wilcoxon (Mann-Whitney)
Secondary
Assessment of Change in Morphology by the Masood Score.
Masood score is a semi-quantitative index of increasing abnormality, thus higher values are worse. Range 6 to 24. Based on Masood S, Frykberg ER, McLellan GL, Scalapino MC, Mitchum DG, Bullard JB. Prospective evaluation of radiologically directed fine-needle aspiration biopsy of nonpalpable breast lesions. Cancer 1990; 66:1480-7.
Time frame: Baseline to 6 Months
Population: Subjects who complete initial 6-month intervention and have a repeat RPFNA, thus a change from baseline to 6-months can be computed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Assessment of Change in Morphology by the Masood Score. | -1.1 units on a scale | Standard Deviation 1.5 |
| Placebo | Assessment of Change in Morphology by the Masood Score. | -1.1 units on a scale | Standard Deviation 1.8 |
p-value: 0.96Wilcoxon (Mann-Whitney)
Secondary
Change in Mammographic Density From Baseline to 6 Months..
Percent area of the breast considered to be at increased density, as determined by the computer program Cumulus..
Time frame: Baseline to 6 Months
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Mammographic Density From Baseline to 6 Months.. | -3.8 percent of breast area at high density | Standard Deviation 12.8 |
| Placebo | Change in Mammographic Density From Baseline to 6 Months.. | 0.2 percent of breast area at high density | Standard Deviation 11.8 |
p-value: 0.73Wilcoxon (Mann-Whitney)
Other Pre-specified
Change in Brief Fatigue Inventory (BFI) Score.
Assessment of the extent to which fatigue interferes in normal everyday living activities. Change over 6 months of treatment is assessed. Range from 0 (best, no fatigue) to 10 (worst). Increase in score indicates greater intensity of fatigue and/or greater interference with activities due to fatigue.
Time frame: baseline to 6 months
Population: Subjects who complete a 6-months visit and a 6-months BFI questionnaire, such that change in score can be computed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Brief Fatigue Inventory (BFI) Score. | 0.6 score on a scale | Standard Deviation 1.9 |
| Placebo | Change in Brief Fatigue Inventory (BFI) Score. | 0.4 score on a scale | Standard Deviation 1.6 |
p-value: 0.73Wilcoxon (Mann-Whitney)
Other Pre-specified
Change in Fibromyalgia Impact Questionnaire (FIQ) Score.
Assessment of impact of fibromyalgia on everyday living activities. Composite score ranges from 0 (best, no interference or impact on activities) to 104 (worst, maximum interference with activities).
Time frame: Baseline to 6 months
Population: subjects who complete 6 month visit and provide a 6-month FIQ score, such that the change in score (6-month - baseline) can be computed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Fibromyalgia Impact Questionnaire (FIQ) Score. | 3.7 score on scale | Standard Deviation 9.6 |
| Placebo | Change in Fibromyalgia Impact Questionnaire (FIQ) Score. | 3.9 score on scale | Standard Deviation 10.3 |
p-value: 0.64Wilcoxon (Mann-Whitney)