Breast Cancer
Conditions
Keywords
Austrian Breast & Colorectal Cancer Study Group (ABCSG), 12, Phase 3, breast cancer, anastrozole, tamoxifen, zoledronic acid, premenopausal, hormone receptor-positive, Stage I, Stage II, bone mineral density, BMD, bisphosphonate, zoledronate
Brief summary
The primary objective is, first, the comparison of tamoxifen and anastrozole and, second, the comparison of zoledronate added to standard adjuvant therapy with controls according to disease-free survival (DFS) in premenopausal patients with non-metastatic breast cancer treated with tamoxifen or anastrozole. To assess whether zoledronate added to standard adjuvant therapy can decrease or even prevent bone loss in patients treated with hormonal blockade combined with an antiestrogen or aromatase inhibitor.
Detailed description
The trial is conducted as an open multi-center phase III study, in a two-factorial study design and according to Good Clinical Practice (GCP) guidelines. Patients will be randomly assigned to a total of 4 study groups in a 1:1:1:1 assignment ratio. Several stratification criteria will be used in order to ensure balanced distribution of known risk factors. A total of 1.803 patients will be enrolled in 4 arms. Patients will either be treated with anastrozole (1mg daily for 3 years) or tamoxifen (20mg daily for 3 years), and will additionally receive either zoledronate (8mg q4 weeks for 3 years) or no zoledronate (arm A: Nolvadex alone; arm B: Nolvadex plus zoledronate; arm C: Arimidex alone; arm D: Arimidex plus zoledronate). Zoledronate will be administered by i.v. injection at a dose of 4 mg/month for the treatment period of 3 years. Five Bone Mineral Density (BMD) measurements will be performed in a subgroup of patients (404 patients, enrolled in 3 centres).
Interventions
DRUGtamoxifen
20 mg/d
DRUGanastrozole
1 mg/d
DRUGzoledronic acid
4 mg q6m
OTHERgoserelin
3.6 mg goserelin subcutaneously every 28 days
Sponsors
AstraZeneca
Novartis Pharmaceuticals
Austrian Breast & Colorectal Cancer Study Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
19 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* Premenopausal, hormone receptor-positive patient * Histologically verified (minimally) invasive breast cancer, local radical treatment * 0-9 involved axillary lymph nodes (≥ 10 histologically examined nodes) * Tumor stage: pT1b-3, yT0 or yT1a
Exclusion criteria
* T1a, T4d, yT4; M1 * Previous breast tumor irradiation * Previous or concurrent chemotherapy (except for preoperative chemotherapy) * Serum creatinine \> 1.5 x UNL or creatinine clearance \< 60 ml/min
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months. | DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause |
| Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months. | DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months. | RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer |
| Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months. | RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer |
| Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months. | OS is defined as time from randomization to death from any cause |
| Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months. | OS is defined as time from randomization to death from any cause |
Countries
Austria, Germany
Participant flow
Recruitment details
The first patient was randomized June 17, 1999, the last patient was randomized May 17, 2006. Randomization took place in 66 Austrian and 10 German clinical sites. In total, 1.803 patients were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| AZ (Arimidex+Zoledronate) Study Drugs Arimidex (Anastrozole), Zometa (Zoledronate; zoledronic acid)
anastrozole: 1 mg/d
zoledronic acid: 4 mg q6m
goserelin: 3.6 mg goserelin subcutaneously every 28 days | 450 |
| TZ (Tamoxifen+Zoledronate) Study Drugs Nolvadex (Tamoxifen), Zometa (Zoledronate; zoledronic acid)
tamoxifen: 20 mg/d
zoledronic acid: 4 mg q6m
goserelin: 3.6 mg goserelin subcutaneously every 28 days | 450 |
| AC (Arimidex Control) Study Drug Arimidex (Anastrozole)
anastrozole: 1 mg/d
goserelin: 3.6 mg goserelin subcutaneously every 28 days | 453 |
| TC (Tamoxifen Control) Study Drug Nolvadex (Tamoxifen)
tamoxifen: 20 mg/d
goserelin: 3.6 mg goserelin subcutaneously every 28 days | 450 |
| Total | 1,803 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 9 | 7 | 18 | 8 |
| Overall Study | Lost to Follow-up | 0 | 5 | 1 | 5 |
| Overall Study | Protocol Violation | 18 | 20 | 20 | 18 |
| Overall Study | Withdrawal by Subject | 8 | 9 | 11 | 14 |
Baseline characteristics
| Characteristic | TZ (Tamoxifen+Zoledronate) | AZ (Arimidex+Zoledronate) | Total | TC (Tamoxifen Control) | AC (Arimidex Control) |
|---|---|---|---|---|---|
| Age, Continuous | 45 years | 44 years | 45 years | 45 years | 44 years |
| Estrogen receptor status Negative | 20 Participants | 17 Participants | 67 Participants | 16 Participants | 14 Participants |
| Estrogen receptor status Positive | 416 Participants | 424 Participants | 1694 Participants | 423 Participants | 431 Participants |
| Estrogen receptor status Unknown | 14 Participants | 9 Participants | 42 Participants | 11 Participants | 8 Participants |
| Histologic grade G1/G2 | 347 Participants | 341 Participants | 1381 Participants | 346 Participants | 347 Participants |
| Histologic grade G3 | 85 Participants | 93 Participants | 352 Participants | 85 Participants | 89 Participants |
| Histologic grade GX | 4 Participants | 7 Participants | 28 Participants | 8 Participants | 9 Participants |
| Histologic grade Unknown | 14 Participants | 9 Participants | 42 Participants | 11 Participants | 8 Participants |
| pN-stage Negative | 298 Participants | 304 Participants | 1211 Participants | 305 Participants | 304 Participants |
| pN-stage Positive | 138 Participants | 137 Participants | 550 Participants | 134 Participants | 141 Participants |
| pN-stage Unknown | 14 Participants | 9 Participants | 42 Participants | 11 Participants | 8 Participants |
| Preoperative chemotherapy No | 382 Participants | 386 Participants | 1536 Participants | 379 Participants | 389 Participants |
| Preoperative chemotherapy Unknown | 45 Participants | 38 Participants | 170 Participants | 46 Participants | 41 Participants |
| Preoperative chemotherapy Yes | 23 Participants | 26 Participants | 97 Participants | 25 Participants | 23 Participants |
| Progesterone receptor status Negative | 32 Participants | 36 Participants | 143 Participants | 40 Participants | 35 Participants |
| Progesterone receptor status Positive | 404 Participants | 405 Participants | 1617 Participants | 399 Participants | 409 Participants |
| Progesterone receptor status Unknown | 14 Participants | 9 Participants | 43 Participants | 11 Participants | 9 Participants |
| pT-stage pT1 | 339 Participants | 343 Participants | 1375 Participants | 341 Participants | 352 Participants |
| pT-stage pT2/pT3 | 97 Participants | 98 Participants | 386 Participants | 98 Participants | 93 Participants |
| pT-stage Unknown | 14 Participants | 9 Participants | 42 Participants | 11 Participants | 8 Participants |
| Sex: Female, Male Female | 450 Participants | 450 Participants | 1803 Participants | 450 Participants | 453 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 450 | 7 / 450 | 18 / 453 | 8 / 450 |
| other Total, other adverse events | 355 / 450 | 320 / 450 | 340 / 453 | 290 / 450 |
| serious Total, serious adverse events | 67 / 450 | 103 / 450 | 55 / 453 | 93 / 450 |
Outcome results
Primary
Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS)
DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause
Time frame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Population: Intent-to-treat population: All participants assigned to one of the four treatment arms were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZ (Arimidex+Zoledronate) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
| TZ (Tamoxifen+Zoledronate) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
| AC (Arimidex Control) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
| TC (Tamoxifen Control) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
Comparison: To determine the effect of arimidex (AZ and AC) compared to tamoxifen (TZ and TC) in terms of disease-free survival. Disease-free survival (DFS) is defined as the time from randomization to the first occurrence of a local or regional recurrence, cancer in the contralateral breast, distant metastasis, second primary carcinoma, or death from any cause.p-value: 0.5995% CI: [0.78, 1.53]Log Rank
Primary
Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS)
DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause
Time frame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Population: Intent-to-treat population: All participants assigned to one of the four treatment arms were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZ (Arimidex+Zoledronate) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
| TZ (Tamoxifen+Zoledronate) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
| AC (Arimidex Control) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
| TC (Tamoxifen Control) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS) | NA years |
Comparison: To determine the effect of Zoledronic Acid (AZ and TZ) compared to no Zoledronic Acid (AC and TC) in terms of disease-free survival. Disease-free survival (DFS) is defined as the time from randomization to the first occurrence of a local or regional recurrence, cancer in the contralateral breast, distant metastasis, second primary carcinoma, or death from any cause.p-value: 0.0195% CI: [0.46, 0.91]Log Rank
Secondary
Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS)
OS is defined as time from randomization to death from any cause
Time frame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Population: Intent-to-treat population: All participants assigned to one of the four treatment arms were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZ (Arimidex+Zoledronate) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
| TZ (Tamoxifen+Zoledronate) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
| AC (Arimidex Control) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
| TC (Tamoxifen Control) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
Comparison: To determine the effect of anastrozole (AZ and AC) compared to tamoxifen (TZ and TC) in terms of overall survival. Overall survival is defined as the time from randomization to death from any cause.p-value: 0.0795% CI: [0.96, 3.38]Log Rank
Secondary
Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS)
RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer
Time frame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Population: Intent-to-treat population: All participants assigned to one of the four treatment arms were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZ (Arimidex+Zoledronate) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
| TZ (Tamoxifen+Zoledronate) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
| AC (Arimidex Control) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
| TC (Tamoxifen Control) | Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
Comparison: To determine the effect of arimidex (AZ and AC) compared to tamoxifen (TZ and TC) in terms of recurrence-free survival. Recurrence-free survival is defined as the time from randomization to the first occurrence of a local or regional recurrence, cancer in the contralateral breast, distant metastasis, second primary carcinoma, or death related to breast cancer.p-value: 0.5395% CI: [0.8, 1.56]Log Rank
Secondary
Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS)
OS is defined as time from randomization to death from any cause
Time frame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Population: Intent-to-treat population: All participants assigned to one of the four treatment arms were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZ (Arimidex+Zoledronate) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
| TZ (Tamoxifen+Zoledronate) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
| AC (Arimidex Control) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
| TC (Tamoxifen Control) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS) | NA years |
Comparison: To determine the effect of Zoledronic Acid (AZ and TZ) compared to no Zoledronic Acid (AC and TC) in terms of overall survival. Overall survival is defined as the time from randomization to death from any cause.p-value: 0.195% CI: [0.32, 1.11]Log Rank
Secondary
Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS)
RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer
Time frame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Population: Intent-to-treat population: All participants assigned to one of the four treatment arms were included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZ (Arimidex+Zoledronate) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
| TZ (Tamoxifen+Zoledronate) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
| AC (Arimidex Control) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
| TC (Tamoxifen Control) | Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS) | NA years |
Comparison: To determine the effect of Zoledronic Acid (AZ and TZ) compared to no Zoledronic Acid (AC and TC) in terms of recurrence-free survival. Recurrence-free survival is defined as the time from randomization to the first occurrence of a local or regional recurrence, cancer in the contralateral breast, distant metastasis, second primary carcinoma, or death related to breast cancer.p-value: 0.0195% CI: [0.46, 0.92]Log Rank