Breast Cancer
Conditions
Keywords
stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer
Brief summary
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating in women with breast cancer who have already received 5 years of aromatase inhibitor therapy. PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy.
Detailed description
OBJECTIVES: Primary * To compare the disease-free survival of women with primary breast cancer treated with letrozole vs placebo after completing approximately 5 years (i.e., 4½ - 6 years) of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane). Secondary * To compare the effect of these drugs on overall (all cause specific) mortality of these patients. * To compare the incidence of contralateral breast cancer in patients treated with these drugs. * To evaluate the long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality (e.g., significant coronary artery disease, including myocardial infarction and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes, and all vascular deaths); incidence of all bone fractures (with particular emphasis on hip and wrist fractures as indicators of osteoporosis); changes in bone density; and common toxicities. * To compare overall quality of life (QOL) and menopausal-specific QOL of patients treated with these drugs. OUTLINE: This is a multicenter study. Patients are stratified according to lymph node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and study randomization (\< 6 months vs 6 months to 2 years), and duration of prior tamoxifen citrate use (0 vs \< 2 years vs 2 - 4½ years vs \> 4½ years). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy. * Arm II: Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy. Patients undergo bone mineral density measurement by DEXA scan at baseline (if not done within 12 months of study entry), at 24 and 48 months during study therapy, and at the completion of study therapy. Some patients also complete quality-of-life questionnaires at baseline and at 12, 24, 36, 48, and 60 months. After completion of study therapy, patients are followed annually.
Interventions
DRUGletrozole
Given orally
OTHERplacebo
Given orally
Sponsors
Eastern Cooperative Oncology Group
North Central Cancer Treatment Group
SWOG Cancer Research Network
Alliance for Clinical Trials in Oncology
Canadian Cancer Trials Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
0 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Previously diagnosed with primary breast cancer * Must have received 4½ - 6 years of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane), either as initial therapy or after prior tamoxifen citrate, including treatment received as part of clinical trial CAN-NCIC-MA17 * Completed aromatase inhibitor therapy ≤ 2 years ago * No metastatic or recurrent disease, contralateral breast cancer, or ductal carcinoma in situ in either breast, as determined by the following: * Clinical examination of the breast area, axillae, and neck within the past 60 days * Mammogram within the past 12 months\* * Chest x-ray within the past 60 days * Bone scan, if alkaline phosphatase \> 2 times normal and/or there are symptoms of metastatic disease AND confirmatory x-ray, if bone scan results are questionable, within the past 60 days * Abdominal ultrasound, liver scan, or CT scan of the abdomen within the past 60 days, if ALT, AST, or alkaline phosphatase \> 2 times normal NOTE: \*A baseline mammogram is not required for patients who have undergone bilateral complete mastectomy * Hormone-receptor status: * Estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) primary tumor at the time of diagnosis, defined as a tumor receptor content of \> 10 fmol/mg protein or receptor positive by immunocytochemical assay (for patients not previously enrolled on clinical trial CAN-NCIC-MA17) * ER+ and/or PR+ primary tumor OR hormone receptor status of primary tumor unknown (for patients previously enrolled on clinical trial CAN-NCIC-MA17) PATIENT CHARACTERISTICS: * Menopausal status not specified * ECOG performance status 0-2 * Life expectancy ≥ 5 years * WBC \> 3.0 x 10\^9/L OR granulocyte count (polymorphs + bands) ≥ 1.5 times 10\^9/L * Platelet count \> 100 x 10\^9/L * AST and/or ALT \< 2 times upper limit of normal (ULN)\* * Alkaline phosphatase \< 2 times ULN\* * Able (i.e. sufficiently fluent) and willing to complete quality-of-life questionnaires in either English or French (NCIC CTG participating centers) * Inability to complete questionnaires due to illiteracy in English or French, loss of sight, or other equivalent reason allowed * Accessible for treatment and follow-up * No other prior or concurrent malignancy except adequately treated, superficial squamous cell or basal cell skin cancer, carcinoma in situ of the cervix, or other cancer treated \> 5 years ago that is presumed cured NOTE: \*Elevated levels allowed provided imaging examinations have ruled out metastatic disease PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No concurrent selective estrogen receptor modulator (e.g., raloxifene, idoxifene) * No other concurrent anticancer therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) | Unitil the end of study with a median follow up of 75 months | It is defined as the months from the day of randomization to the earliest date when a recurrence of the primary disease (recurrence in the breast, chest wall and nodal sites or the development of metastatic disease) or a contralateral breast cancer was observed. Subjects who died without recurrence of the primary disease or the development of the contralateral breast cancer were censored at their death date. If a patient has not recurred, developed a contralateral breast cancer, or died, disease-free survival was censored on the date of the last day the patient was known to be alive. Probability of disease free survival at 5 years is estimated and reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Contralateral Breast Cancer | 10 years | The annual incidence rate was estimated based on the time to the development of contralateral breast cancer, which was calculated in months from the day of randomization to the diagnosis date of contralateral breast cancer for subjects who had developed the contralateral breast cancer, to the time of death for the patient who died, or to the last day the patient was known alive for subjects without contralateral breast cancer |
| Overall Survival (OS) | Until the end of study with a median follow-up of 75 months | For subjects who died, overall survival was calculated in months from the day of randomization to the date of death. Otherwise, survival was censored at the last day the patient was known to be alive. Probability of overall survival at 5 years is estimated and reported. |
| Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey | 8 years | Difference between post baseline scores and baseline score of role function-physical scale on SF-36 Health Survey (scale range between 0 and 100 with higher score indicating better quality of life). |
Countries
Canada, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Letrozole Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
letrozole: Given orally | 959 |
| Placebo Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
placebo: Given orally | 959 |
| Total | 1,918 |
Baseline characteristics
| Characteristic | Total | Placebo | Letrozole |
|---|---|---|---|
| Age, Continuous | 65.1 years | 64.8 years | 65.6 years |
| ECOG Performance Status Grade 0 | 1708 Participants | 856 Participants | 852 Participants |
| ECOG Performance Status Grade 1 | 195 Participants | 95 Participants | 100 Participants |
| ECOG Performance Status Grade 2 | 15 Participants | 8 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 13 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1879 Participants | 939 Participants | 940 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 7 Participants | 8 Participants |
| Region of Enrollment Canada | 561 Participants | 285 Participants | 276 Participants |
| Region of Enrollment United States | 1357 Participants | 674 Participants | 683 Participants |
| Sex: Female, Male Female | 1918 Participants | 959 Participants | 959 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 100 / 959 | 100 / 954 |
| other Total, other adverse events | 863 / 959 | 841 / 954 |
| serious Total, serious adverse events | 15 / 959 | 19 / 954 |
Outcome results
Primary
Disease-free Survival (DFS)
It is defined as the months from the day of randomization to the earliest date when a recurrence of the primary disease (recurrence in the breast, chest wall and nodal sites or the development of metastatic disease) or a contralateral breast cancer was observed. Subjects who died without recurrence of the primary disease or the development of the contralateral breast cancer were censored at their death date. If a patient has not recurred, developed a contralateral breast cancer, or died, disease-free survival was censored on the date of the last day the patient was known to be alive. Probability of disease free survival at 5 years is estimated and reported.
Time frame: Unitil the end of study with a median follow up of 75 months
Population: All women randomized were included in the analysis based on treatment arm they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letrozole | Disease-free Survival (DFS) | 0.95 probability of DFS at 5 years |
| Placebo | Disease-free Survival (DFS) | 0.91 probability of DFS at 5 years |
p-value: 0.0195% CI: [0.48, 0.91]Log Rank
Secondary
Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey
Difference between post baseline scores and baseline score of role function-physical scale on SF-36 Health Survey (scale range between 0 and 100 with higher score indicating better quality of life).
Time frame: 8 years
Population: All randomized patients.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey | -7.74 score on a scale | Standard Error 1.09 |
| Placebo | Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey | -6.28 score on a scale | Standard Error 1.08 |
p-value: <0.01Mixed Models Analysis
Secondary
Incidence of Contralateral Breast Cancer
The annual incidence rate was estimated based on the time to the development of contralateral breast cancer, which was calculated in months from the day of randomization to the diagnosis date of contralateral breast cancer for subjects who had developed the contralateral breast cancer, to the time of death for the patient who died, or to the last day the patient was known alive for subjects without contralateral breast cancer
Time frame: 10 years
Population: All women randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letrozole | Incidence of Contralateral Breast Cancer | 2.1 Number of new case per 1000 person years |
| Placebo | Incidence of Contralateral Breast Cancer | 4.9 Number of new case per 1000 person years |
p-value: 0.007Log Rank
Secondary
Overall Survival (OS)
For subjects who died, overall survival was calculated in months from the day of randomization to the date of death. Otherwise, survival was censored at the last day the patient was known to be alive. Probability of overall survival at 5 years is estimated and reported.
Time frame: Until the end of study with a median follow-up of 75 months
Population: All women randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letrozole | Overall Survival (OS) | 0.93 probability of OS at 5 years |
| Placebo | Overall Survival (OS) | 0.94 probability of OS at 5 years |
p-value: 0.8395% CI: [0.73, 1.28]Log Rank