Letrozole in Preventing Breast Cancer in Postmenopausal Women (WISE)

A Pilot Study of Aromatase Inhibitors for Women at Increased Risk of Breast Cancer Based on Estradiol Levels

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Letrozole may be effective in preventing the development or recurrence of breast cancer in postmenopausal women who are at increased risk of developing breast cancer because of elevated estradiol levels.

PURPOSE: This randomized phase II trial is studying how well letrozole works in preventing breast cancer in postmenopausal women with elevated estradiol levels.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Other: Placebo; Drug: Letrozole

Detailed Description

OBJECTIVES:

Primary

• The primary outcome of the study is the change in bone mineral density following a year on letrozole vs. a year on placebo.

Secondary

• Compare the safety, acceptability, and adherence to letrozole vs placebo in postmenopausal women at increased risk for the development or recurrence of breast cancer based on elevated plasma estradiol levels through evaluation of menopausal symptoms (including hot flushes, weight changes, sexual functioning, and genitourinary effects), blood lipid levels, markers of bone turnover, and multidimensional quality of life.
• Determine the effect of letrozole-induced reduction of plasma estradiol levels on mammographic percent breast density.
• Obtain background information for a future large chemoprevention trial to address the question of whether a reduction in plasma estradiol levels can reduce the risk of breast cancer in postmenopausal women.

OUTLINE: This is a pilot, randomized, double-blind, placebo-controlled, multicenter study. Patients are randomized to 2:1 (experimental treatment: placebo arms).

PROJECTED ACCRUAL: A total of 110 patients (73 for arm I and 37 for arm II) will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Abramson Cancer Center of the University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • Dan L. Duncan Cancer Center at Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• At increased risk for the development or recurrence of breast cancer, defined as an estradiol level ≥ 9 pg/mL

• No evidence of suspicious or malignant disease, based on the following examinations:

  • Clinical bilateral breast examination within the past 6 months
  • Bilateral* mammogram within 3 months before randomization OR within 30 days after randomization
  • Pelvic exam normal within the past 5 years
  • General physical exam within the past 6 months NOTE: *Unilateral mammogram of the uninvolved breast for patients with prior invasive breast cancer or ductal carcinoma in situ (DCIS)

• Bone density scan within 2 standard deviations from normal within the past 30 days

  • Bone density scan ≥ 2 standard deviations below normal allowed if approved by the study physician
• At least 1 breast that has not been previously treated with radiotherapy or surgery (for patients with prior invasive breast cancer or DCIS)

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 35 and over

Sex

• Female

Menopausal status

• Postmenopausal, defined by any of the following criteria:

  • At least 12 months without spontaneous menstrual bleeding
  • Prior hysterectomy and bilateral salpingo-oophorectomy
  • ≥ 55 years of age with a prior hysterectomy with or without oophorectomy
  • < 55 years of age with a prior hysterectomy without oophorectomy OR the status of the ovaries is unknown AND follicle-stimulating hormone (FSH) level is in the postmenopausal range

Performance status

• Normal activity must not be restricted for a significant portion of the day

Life expectancy

• At least 10 years

Hematopoietic

• Complete blood count with differential normal

  • Prior benign neutropenia allowed provided the granulocyte count is ≥ 1,500/mm^3

Hepatic

• Bilirubin normal
• Alkaline phosphatase normal
• SGOT and SGPT normal

Renal

• Creatinine normal

Cardiovascular

• No uncontrolled cardiovascular disease

Other

• Not pregnant
• No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No osteoporosis
• No hyperlipidemia
• No mental health status resulting in cognitive or emotional impairment that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• More than 30 days since prior AND no concurrent use of any of the following hormonal agents:

  • Estrogen or progesterone replacement therapy
  • Oral contraceptives
  • Raloxifene or other plasma estrogen receptor modulators (SERMs)
  • Androgens (e.g., danazol)
  • Luteinizing hormone-releasing hormone (LHRH) analogs (e.g., goserelin or leuprolide)
  • Prolactin inhibitors (e.g., bromocriptine)
  • Antiandrogens (e.g., cyproterone)
• More than 60 days since prior AND no concurrent tamoxifen
• No prior aromatase inhibitors (for patients with prior invasive breast cancer or DCIS)

• No concurrent phytoestrogenic dietary supplements (e.g., soy, ginseng, or other natural products)

  • Dietary soy allowed

Radiotherapy

• See Disease Characteristics

Surgery

• See Disease Characteristics
• No prior bilateral mastectomy

Other

• More than 60 days since prior treatment for invasive breast cancer or DCIS
• More than 30 days since prior bisphosphonates or calcitonin
• No prior or concurrent participation on a treatment study for invasive breast cancer or DCIS
• No concurrent participation in any other cancer prevention study or osteoporosis prevention study involving pharmacologic agents
• No concurrent calcitonin
• No concurrent bisphosphonate therapy
• Concurrent cholecalciferol (vitamin D) and calcium to augment bone mineral density allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Letrozole; Participants in this arm received 2.5 mg of letrozole per day for a duration of 12 months; followed by an optional 4 years. Treatment continued in the absence of unacceptable toxicity or diagnosis of invasive breast cancer, ductal carcinoma in situ, or any non-breast primary cancer.	Drug: Letrozole; Other Names: Femara
Placebo Comparator: Placebo; Participants in this arm received 1 tablet per day which contained the inert ingredients from the letrozole tablet, for a duration of 12 months; followed by an optional 5 years of letrozole.Treatment continued in the absence of unacceptable toxicity or diagnosis of invasive breast cancer, ductal carcinoma in situ, or any non-breast primary cancer.	Other: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Lumbar Density From Baseline to 12 Months	The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip.	Evaluation occurred at treatment initiation (BL) and after 12-months of treatment.
Change in Femoral Neck Density From Baseline to 12 Months	The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip.	Evaluation occurred at treatment initiation (BL) and after 12-months of treatment.
Change in Trochanter Density From Baseline to 12 Months	The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip.	Evaluation occurred at treatment initiation (BL) and after 12-months of treatment.
Change in Hip Density From Baseline to 12 Months	The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip.	Evaluation occurred at treatment initiation (BL) and after 12-months of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Worst Grade Hot Flashes	Participants reported worst grade hot flashes: 01: mild (<1qd) or 02: moderate (>1qd) during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.
Worst Grade Muscle Aches/Pains	Participants reported worst grade muscle aches/pains defined as grade 01: mild, 02: moderate, 03: severe (CTCAEv3) or 04: disabling (CTCAEv3) during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.
Worst Grade Nausea	Participants reported worst grade nausea grade 01: able to eat, 02: oral intake significantly decreased, 03: no significant intake, requiring IV fluids during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.
Worst Grade Vomiting	Participants reported worst grade vomiting grade 01: 1x in 24 hours, 02: 2-5x in 24 hours, 03: >/= 6x in 24 hours, grade 04: requiring parenteral nutrition/intensive care during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.
Worst Grade Abdominal Pain	Participants reported worst grade abdominal pain: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.
Worst Grade Bone Pain	Participants reported worst grade bone pain: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.
Worst Grade Headache	Participants reported worst grade headache: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.
Worst Grade Fatigue	Participants reported worst grade fatigue: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment.	Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months.

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: National Cancer Institute (NCI); Jonsson Comprehensive Cancer Center
• Investigators: Principal Investigator: Judy Garber, MD, Dana-Farber Cancer Institute; Principal Investigator: Patricia A. Ganz, MD, Jonsson Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2002
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: September 7, 2004
• First Submitted That Met QC Criteria: September 7, 2004
• First Posted (Estimate): September 8, 2004

Study Record Updates

• Last Update Posted (Actual): March 30, 2018
• Last Update Submitted That Met QC Criteria: March 5, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: stage IV breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; breast cancer; stage II breast cancer; stage IIIC breast cancer; stage I breast cancer; breast cancer in situ; ductal breast carcinoma in situ
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: DFCI-00024; P50CA089393 (U.S. NIH Grant/Contract); P30CA006516 (U.S. NIH Grant/Contract); UCLA-0210012-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO