Breast Cancer
Conditions
Keywords
breast cancer
Brief summary
RATIONALE: The MAP.3 study was designed to test whether hormone therapy using exemestane may prevent breast cancer by blocking the production of estrogen. PURPOSE: The study protocol was amended in May 2011 and the current purpose of the study is to allow all study participants the opportunity to complete 5 years of exemestane.
Detailed description
OBJECTIVES: Primary Previously: To determine if exemestane reduces the incidence of invasive breast cancer compared with placebo. Currently: To determine the frequency of serious adverse events for post-menopausal women at high-risk of developing breast cancer who choose to receive 5 years of exemestane as preventative therapy. Secondary Previously: (same as is currently listed in PDQ) Currently: To address the Trial Committee and Sponsor's commitment to allow women who are randomized to the MAP.3 trial to receive 5 years of exemestane therapy. OUTLINE: This study was a randomized, double-blind, placebo-controlled, multicentre study. Protocol-specified analyses were performed in April 2011. The results of these analyses are posted in the Results section. Following the amendment of May 2011, the study is now open-label and all eligible patients are receiving exemestane from participating sites for a total of 5 years. After exemestane is stopped, there is no further follow-up. PROJECTED ACCRUAL:There were 4560 women from the United States, Canada, Spain and France who took part in this study.
Interventions
DRUGexemestane
one 25 mg tablet daily in am
Sponsors
Grupo Espanol de Investigacion del Cancer de Mama
UNICANCER
NCIC Clinical Trials Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
35 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* At increased risk of developing breast cancer, due to at least one of the following risk factors: * Gail score ≥ 1.66 * Age ≥ 60 years * Prior atypical ductal hyperplasia, lobular hyperplasia, or lobular carcinoma in situ on breast biopsy * Prior ductal carcinoma in situ (DCIS) treated with total mastectomy with or without tamoxifen (tamoxifen must have been completed ≥ 3 months prior to randomization) * No prior DCIS treated with lumpectomy with or without radiation * No prior invasive breast cancer * Not BRCA1 or BRCA2 carriers PATIENT CHARACTERISTICS: Previous: * 35 and over * Female * Postmenopausal, defined as one of the following: * over 50 years of age with no spontaneous menses for at least 12 months before study entry * 50 years of age or under with no menses (spontaneous or secondary to hysterectomy) for at least 12 months before study entry AND with follicle-stimulating hormone level within postmenopausal range * Underwent prior bilateral oophorectomy * No other malignancies within the past 5 years except adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumors with no evidence of disease for ≥ 5 years * No uncontrolled hypothyroidism or hyperthyroidism * No major medical or psychiatric illness (including substance and alcohol abuse within the past 2 years) that would preclude study participation or compliance * Must be accessible for treatment and follow-up * Willing to complete quality of life questionnaires in either English or French Current: MAP.3 participants who were randomized to the exemestane arm, are currently receiving exemestane as part of the MAP.3 study and who have not completed 5 years of exemestane. OR MAP.3 study participants who were randomized to the placebo arm and who have either completed 5 years of study drug or who are still receiving placebo. Note: this applies only to centres that choose to allow placebo cross-over. PRIOR CONCURRENT THERAPY: Previous: * More than 3 months since prior and no concurrent hormone replacement therapies * More than 3 months since systemic estrogenic, androgenic, or progestational agents * More than 3 months since prior and no concurrent hormonal therapies, including, but not limited to the following: * Luteinizing-hormone releasing-hormone analogs (e.g., goserelin or leuprolide) * Progestogens (e.g., megestrol) * Prolactin inhibitors (e.g., bromocriptine) * Antiandrogens (e.g., cyproterone acetate) * Selective estrogen-receptor modulators (e.g., tamoxifen, toremifene, or raloxifene) * No investigational drug within 30 days or 5 half lives prior to randomization * No concurrent endocrine therapy * No concurrent estrogens, androgens, or progesterones * Concurrent low dose (≤ 100 mg/day) prophylactic aspirin allowed * Concurrent bisphosphonates for prevention or treatment of osteoporosis allowed * No other concurrent medications that may have an effect on study endpoints Current: There are no prior concurrent therapy restrictions for the amended MAP.3 study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Women With Serious Adverse Events | 5 years open-label extension period | Percentage of serious adverse events for women who choose to receive 5 years of exemestane as preventative therapy. |
| Invasive Breast Cancer Incidence (Breast Cancer-Free Survival) | Over randomization period of study (median follow-up 35 months) | Invasive breast cancer incidence was estimated from the breast cancer-free survival (BCFS) which was calculated for all women from the day of the randomization to the earliest date of diagnosis for invasive breast cancer. Women who died from other causes were censored at the time of death. If a woman did not develop an invasive breast cancer, or died, BCFS was censored on the date of the last day the woman was known alive (LKA), which was the latest of the date of assessment. Women who had breast cancer before study entry were also censored at the time of randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Clinical Breast Biopsies | Over randomization period of study (median follow-up 35 months) | — |
| Incidence of All Clinical Fractures | During protocol treatment over randomization period of study (up to 5 years) | — |
| Total Incidence of Invasive and Non-invasive (DCIS) Breast Cancer | Over randomization period of study (median follow-up 35 months) | It was estimated from the Total Breast Cancer-Free Survival (TBCFS), which was calculated for women who developed invasive or non-invasive (DCIS) breast cancer as the time from the date of randomization to the earliest date of diagnosis for invasive or non-invasive (DCIS) breast cancer. Women who died from other causes were censored at the time of death. Women who had breast cancer before entry were censored at the time of randomization. If a woman did not develop an invasive or non-invasive (DCIS) breast cancer, or died, TBCFS will be censored on the date of last known alive. |
| Incidences of Other Malignancies | Over randomization period of study (median follow-up 35 months) | Other malignancies includes any other malignancy which is not in breast. |
| Incidence of Clinically Relevant Cardiac Events | During protocol treatment in randomization period (up to 5 years) | Events including myocardial infarctions and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes and all vascular deaths |
| Incidence of Lobular Carcinoma in Situ, Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia Events | Over randomization period of study (median follow-up 35 months) | — |
Countries
Canada, France, Puerto Rico, United States
Participant flow
Recruitment details
Between February 11, 2004, and March 23, 2010, 4560 women were recruited in medical clinics.
Pre-assignment details
Eligibility of women was first checked before the randomization to the trial.
Participants by arm
| Arm | Count |
|---|---|
| Randomization Period: Exemestane one 25 mg tablet daily in am | 2,285 |
| Randomization Period: Placebo one tablet daily in am | 2,275 |
| Total | 4,560 |
Baseline characteristics
| Characteristic | Randomization Period: Exemestane | Randomization Period: Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 827 Participants | 794 Participants | 1621 Participants |
| Age, Categorical Between 18 and 65 years | 1458 Participants | 1481 Participants | 2939 Participants |
| Age, Continuous | 63.1 years STANDARD_DEVIATION 7.2 | 63.1 years STANDARD_DEVIATION 7 | 63.1 years STANDARD_DEVIATION 7.1 |
| Region of Enrollment Canada | 643 participants | 642 participants | 1285 participants |
| Region of Enrollment France | 9 participants | 10 participants | 19 participants |
| Region of Enrollment Spain | 217 participants | 215 participants | 432 participants |
| Region of Enrollment United States | 1416 participants | 1408 participants | 2824 participants |
| Sex: Female, Male Female | 2285 Participants | 2275 Participants | 4560 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1,963 / 2,240 | 1,901 / 2,248 | 0 / 0 |
| serious Total, serious adverse events | 39 / 2,240 | 26 / 2,248 | 0 / 2,831 |
Outcome results
Primary
Invasive Breast Cancer Incidence (Breast Cancer-Free Survival)
Invasive breast cancer incidence was estimated from the breast cancer-free survival (BCFS) which was calculated for all women from the day of the randomization to the earliest date of diagnosis for invasive breast cancer. Women who died from other causes were censored at the time of death. If a woman did not develop an invasive breast cancer, or died, BCFS was censored on the date of the last day the woman was known alive (LKA), which was the latest of the date of assessment. Women who had breast cancer before study entry were also censored at the time of randomization.
Time frame: Over randomization period of study (median follow-up 35 months)
Population: intention to treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Extension: Exemestane | Invasive Breast Cancer Incidence (Breast Cancer-Free Survival) | 0.19 percentage of cases/follow-up person-yr |
| Randomization Period: Placebo | Invasive Breast Cancer Incidence (Breast Cancer-Free Survival) | 0.55 percentage of cases/follow-up person-yr |
Comparison: The null hypothesis was no difference between two groups. The sample size estimate was based on an assumption of annual invasive breast cancer rate of 0.60% in the placebo group and 0.21% in exemestane group, a relative reduction of 65% with exemestane. To detect this with a two-sided 5% level and 90% power, a total of 38 cases of invasive breast cancer were required, projected to occur when 4560 women were randomly assigned in a 3-year period and then followed for an additional 1.2 years.p-value: 0.00295% CI: [0.18, 0.7]Log Rank
Primary
Percentage of Women With Serious Adverse Events
Percentage of serious adverse events for women who choose to receive 5 years of exemestane as preventative therapy.
Time frame: 5 years open-label extension period
Population: Postmenopausal women who were randomized to exemestane in original MAP.3 study and chose to continue to receive exemestane for up to 5 years and those randomized to placebo and decided to start 5 years of exemestane.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Extension: Exemestane | Percentage of Women With Serious Adverse Events | 0.0 percentage of women |
Secondary
Incidence of All Clinical Fractures
Time frame: During protocol treatment over randomization period of study (up to 5 years)
Population: Women who have received treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Extension: Exemestane | Incidence of All Clinical Fractures | 149 participants |
| Randomization Period: Placebo | Incidence of All Clinical Fractures | 143 participants |
Secondary
Incidence of Clinically Relevant Cardiac Events
Events including myocardial infarctions and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes and all vascular deaths
Time frame: During protocol treatment in randomization period (up to 5 years)
Population: Women who received treatment during randomization period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Extension: Exemestane | Incidence of Clinically Relevant Cardiac Events | 106 participants |
| Randomization Period: Placebo | Incidence of Clinically Relevant Cardiac Events | 111 participants |
Secondary
Incidence of Lobular Carcinoma in Situ, Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia Events
Time frame: Over randomization period of study (median follow-up 35 months)
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Extension: Exemestane | Incidence of Lobular Carcinoma in Situ, Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia Events | 0.07 percentage of cases/follow-up person-yr |
| Randomization Period: Placebo | Incidence of Lobular Carcinoma in Situ, Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia Events | 0.20 percentage of cases/follow-up person-yr |
p-value: 0.0795% CI: [0.11, 1.12]Log Rank
Secondary
Incidences of Other Malignancies
Other malignancies includes any other malignancy which is not in breast.
Time frame: Over randomization period of study (median follow-up 35 months)
Population: Women who have received treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Extension: Exemestane | Incidences of Other Malignancies | 50 participants |
| Randomization Period: Placebo | Incidences of Other Malignancies | 42 participants |
Secondary
Number of Clinical Breast Biopsies
Time frame: Over randomization period of study (median follow-up 35 months)
Population: Women who had at least one clinical breast biopsy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open-label Extension: Exemestane | Number of Clinical Breast Biopsies | 1 number of clinical breast biopsies |
| Randomization Period: Placebo | Number of Clinical Breast Biopsies | 1 number of clinical breast biopsies |
Secondary
Total Incidence of Invasive and Non-invasive (DCIS) Breast Cancer
It was estimated from the Total Breast Cancer-Free Survival (TBCFS), which was calculated for women who developed invasive or non-invasive (DCIS) breast cancer as the time from the date of randomization to the earliest date of diagnosis for invasive or non-invasive (DCIS) breast cancer. Women who died from other causes were censored at the time of death. Women who had breast cancer before entry were censored at the time of randomization. If a woman did not develop an invasive or non-invasive (DCIS) breast cancer, or died, TBCFS will be censored on the date of last known alive.
Time frame: Over randomization period of study (median follow-up 35 months)
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label Extension: Exemestane | Total Incidence of Invasive and Non-invasive (DCIS) Breast Cancer | 0.35 percentage of cases/follow-up person-yr |
| Randomization Period: Placebo | Total Incidence of Invasive and Non-invasive (DCIS) Breast Cancer | 0.77 percentage of cases/follow-up person-yr |
p-value: 0.00495% CI: [0.27, 0.79]Log Rank