Breast Cancer
Conditions
Keywords
luminal, anastrozole, fulvestrant, early breast cancer, HR+/HER2-
Brief summary
Postmenopausal women with hormone receptor positive and negative Her2 tumours. Before randomization, the patients will be stratified according to the center, positive nodes (0 vs. 1-3 vs. ≥4), previous chemotherapy (yes vs no) and hormonal receptors status.
Detailed description
It is expected that disease-free survival for patients receiving Anastrozole alone for 5 years will be up to 90%. An increase of 3% in disease-free survival (DFS) is expected in the arm of Fulvestrant plus Anastrozole, i.e a DFS of up to 93%. They will be required 1358 patients per treatment group (i.e, 2716 patients in total) to give 80% power, alfa bilateral 0.05, and OR 0.6888. Assuming 5% screening failures 2852 patients are required to enter the study. In Jun-2010 the recruitment was stopped due to lack of support of the financier based on the result of Faslodex® and Arimidex® in Combination Trial (FACT-trial), comparing Fulvestrant + Anastrozole vs Anastrozole alone in 1st relapse showed no difference in time to progression at more than 40 months follow-up.
Interventions
DRUGFulvestrant
500 mg Im Fulvestrant day 0, 250 mg days 14 and 28(charge dose); later 250 mg each 28 days during 3 years plus 1 mg oral Anastrozole per day during 5 years.
DRUGAnastrozole
1 mg oral Anastrozole per day during 5 years.
Sponsors
AstraZeneca
Spanish Breast Cancer Research Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histological documentation of breast cancer. 2. Stage I, II, IIIA and IIIC\* invasive breast cancer. One of these two characteristics must be fulfilled: * N+ * T \> 1cm \*Eligible patients T1-T3 and pN3a (patients with metastasis in infraclavicular nodes would not be eligible) 3. Local treatment with curative intention: * mastectomy or tumour excision with free margins + radiotherapy * axillary lymphadenectomy or sentinel node biopsy 4. Positive hormone receptors (Estrogen Receptor \[ER\]+ and/or Progesterone Receptor \[PR\]+) in primary tumour tissue as measured by a central laboratory 5. Human Epidermal Growth Factor Receptor 2 (HER2) negative breast cancer, defined as immunohistochemistry (IHC) 0 or 1+ or negative fluorescence in situ hybridization (FISH) (in the event of IHC 2+ or 3+) 6. Postmenopausal women, defined as women meeting any of the following criteria: * Age ≥ 60 years * Age ≥ 45 years with amenorrhea ≥ 12 months in the moment of breast cancer diagnosis and an intact uterus * Prior bilateral ovariectomy * In case previous hysterectomy, follicle stimulating hormone (FSH) and estradiol levels within the postmenopausal range (using local laboratory ranges)\* \* In patients previously treated with a luteinizing hormone releasing hormone (LH-RH) analogue, the last extended release formulation should have been administered more than 6 months before randomisation, and menses must not have reappeared. 7. A World Health Organization (WHO) performance status of 0, 1, or 2. 8. Age \> 18 years
Exclusion criteria
1. Presence of metastatic disease or bilateral invasive cancer 2. ER and Progesterone Receptor (PR) negative breast cancer 3. HER2-positive breast cancer, defined as FISH+ 4. Treatment with a non-approved or experimental drug within 4 months of randomisation 5. Current malignancy or previous malignancy in the past 5 years (other that breast cancer or basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) 6. Pregnant or nursing patients 7. Any of the following laboratory values within 3 months of randomisation: * Platelets \< 100 x 109/L * Total bilirubin \> 1.5 x Upper limit of reference range (ULRR)\*\* \*\* Patients with documented Gilbert syndrome may be included in this trial * Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) \> 2.5 x ULRR * A history of: * hemorrhagic diathesis (i.e. Disseminated Intravascular Coagulation \[DIC\], coagulation factor deficiency) or * long-term anticoagulant treatment (except for anti-platelet aggregants and low-dose warfarin; see section 3.7) 8. A history of hypersensitivity to the active ingredient or inactive excipients of fulvestrant, aromatase inhibitors, or castor oil 9. Any concomitant severe disease advising against patient participation in the trial o that may jeopardize compliance with the trial protocol, such as uncontrolled heart disease, uncontrolled diabetes mellitus, or uncontrolled severe infections 10. Hormone replacement therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival (DFS) Events | Up to 5 years | Disease-free survival (DFS) has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. DFS event is defined as the evidence of local and/or distant recurrence, new primary breast tumour, or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Breast Cancer Specific Survival (BCsS) Events | Up to 5 years | BCsS events has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to BCsS in patients treated with anastrozole for 5 years. BCsS event is defined as the death from breast cancer. |
| Overall Survival (OS) Event | Up to 5 years | OS event has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. OS event is defined as the death from any cause. |
| Time to Recurrence (TR) Event | Up to 5 years | TR event has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. TR event is defined as the evidence of breast cancer recurrence (local and/or distant recurrence of breast cancer, does not include second primary malignancies or deaths from any cause). |
Countries
Spain
Participant flow
Recruitment details
870 patients were recruited, from them, 437 were randomized to Anastrozole (A) and 433 to A plus Fulvestrant (F), but 18 patients (3 in A arm and 15 in arm A+F) never received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Fulvestrant + Anastrozole Fulvestrant + Anastrozole: 500 mg Im Fulvestrant day 0, 250 mg days 14 and 28(charge dose); later 250 mg each 28 days during 3 years plus 1 mg oral Anastrozole per day during 5 years. | 433 |
| Anastrozole Anastrozole: 1 mg oral Anastrozole per day during 5 years. | 437 |
| Total | 870 |
Baseline characteristics
| Characteristic | Anastrozole | Total | Fulvestrant + Anastrozole |
|---|---|---|---|
| Age, Continuous | 62 years | 62 years | 62 years |
| Axillary surgery Axillary dissection | 281 Participants | 539 Participants | 258 Participants |
| Axillary surgery Sentinel Node Biopsy | 155 Participants | 329 Participants | 174 Participants |
| Axillary surgery Unknown | 1 Participants | 2 Participants | 1 Participants |
| Breast Surgery Conservative | 310 Participants | 613 Participants | 303 Participants |
| Breast Surgery Mastectomy | 127 Participants | 257 Participants | 130 Participants |
| Final diagnosis tumor size T1 | 243 Participants | 463 Participants | 220 Participants |
| Final diagnosis tumor size T2 | 179 Participants | 368 Participants | 189 Participants |
| Final diagnosis tumor size T3-T4 | 14 Participants | 36 Participants | 22 Participants |
| Final diagnosis tumor size TX | 1 Participants | 3 Participants | 2 Participants |
| Histologic grade Grade 1 | 82 Participants | 170 Participants | 88 Participants |
| Histologic grade Grade 2 | 235 Participants | 451 Participants | 216 Participants |
| Histologic grade Grade 3 | 83 Participants | 177 Participants | 94 Participants |
| Histologic grade Grade X | 37 Participants | 72 Participants | 35 Participants |
| Histopathologic type Invasive Ductal Carcinoma | 346 Participants | 683 Participants | 337 Participants |
| Histopathologic type Invasive Lobular Carcinoma | 71 Participants | 142 Participants | 71 Participants |
| Histopathologic type Other | 20 Participants | 45 Participants | 25 Participants |
| Nodal status N0 | 200 Participants | 414 Participants | 214 Participants |
| Nodal status N1 | 164 Participants | 321 Participants | 157 Participants |
| Nodal status N2 | 52 Participants | 94 Participants | 42 Participants |
| Nodal status N3 | 18 Participants | 32 Participants | 14 Participants |
| Nodal status NX | 3 Participants | 9 Participants | 6 Participants |
| Previous chemotherapy Adjuvant | 261 Participants | 517 Participants | 256 Participants |
| Previous chemotherapy Neoadjuvant | 34 Participants | 71 Participants | 37 Participants |
| Previous chemotherapy Neoadjuvant + Adjuvant | 2 Participants | 5 Participants | 3 Participants |
| Previous chemotherapy None | 140 Participants | 277 Participants | 137 Participants |
| Previous radiotherapy NO | 90 Participants | 175 Participants | 85 Participants |
| Previous radiotherapy YES | 347 Participants | 695 Participants | 348 Participants |
| Sex: Female, Male Female | 437 Participants | 870 Participants | 433 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tumor size | 2 cm | 2 cm | 2 cm |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 192 / 415 | 197 / 437 |
| serious Total, serious adverse events | 40 / 415 | 61 / 437 |
Outcome results
Primary
Disease Free Survival (DFS) Events
Disease-free survival (DFS) has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. DFS event is defined as the evidence of local and/or distant recurrence, new primary breast tumour, or death from any cause.
Time frame: Up to 5 years
Population: Primary statistical analyses of the efficacy outcome variables will be based on an intent-to-treat (ITT) method and will include all randomised patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fulvestrant + Anastrozole | Disease Free Survival (DFS) Events | 49 Participants |
| Anastrozole | Disease Free Survival (DFS) Events | 62 Participants |
Secondary
Breast Cancer Specific Survival (BCsS) Events
BCsS events has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to BCsS in patients treated with anastrozole for 5 years. BCsS event is defined as the death from breast cancer.
Time frame: Up to 5 years
Population: Analyses of the efficacy outcome variables will be based on an intent-to-treat (ITT) method and will include all randomised patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fulvestrant + Anastrozole | Breast Cancer Specific Survival (BCsS) Events | 17 Participants |
| Anastrozole | Breast Cancer Specific Survival (BCsS) Events | 18 Participants |
Secondary
Overall Survival (OS) Event
OS event has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. OS event is defined as the death from any cause.
Time frame: Up to 5 years
Population: Statistical analyses of the efficacy outcome variables will be based on an intent-to-treat (ITT) method and will include all randomised patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fulvestrant + Anastrozole | Overall Survival (OS) Event | 28 Participants |
| Anastrozole | Overall Survival (OS) Event | 34 Participants |
Secondary
Time to Recurrence (TR) Event
TR event has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. TR event is defined as the evidence of breast cancer recurrence (local and/or distant recurrence of breast cancer, does not include second primary malignancies or deaths from any cause).
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fulvestrant + Anastrozole | Time to Recurrence (TR) Event | 36 Participants |
| Anastrozole | Time to Recurrence (TR) Event | 46 Participants |