Breast Cancer
Conditions
Keywords
stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer
Brief summary
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole may fight breast cancer by lowering the amount of estrogen the body makes. Fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Given the lack of clinical data on fulvestrant in patients with large operable or locally advanced hormone-receptor-positive breast cancer, and the potential to identify differences in the mechanism of resistance using the neoadjuvant model,we decided to perform a multicentre randomised phase II clinical trial of anastrozole and fulvestrant. PURPOSE: The aim of this study was to assess the efficacy of neoadjuvant anastrozole and fulvestrant treatment of large operable or locally advanced hormone-receptor-positive breast cancer not eligible for initial breast-conserving surgery, and to identify genomic changes occurring after treatment.
Detailed description
OBJECTIVES: Primary * Evaluate clinical tumor response at 6 months in patients with hormone-sensitive non-metastatic breast cancer treated with neoadjuvant anastrozole and fulvestrant. Secondary * Evaluate tumor regression by mammography and ultrasound in these patients. * Evaluate the rate of breast conservation at 6 months of treatment in these patients. * Evaluate the tolerability of these regimens. * Estimate the relapse-free survival at 5 years. * Identify molecular signatures predictive of response in these patients. * Identify genes implicated in response in these patients. * Identify changes in mRNA splicing of genes involved in breast tumorigenesis. OUTLINE: This is a non-comparative multicentre randomised phase II study in which patients from three French centres were randomly assigned in a 1 : 1 ratio to receive either anatrozole or fulvestrant. All patients undergo biopsy at baseline. Patients are randomized between the two treatment arms. * Arm I: Patients receive oral anastrozole once daily for 6 months. * Arm II: Patients receive fulvestrant intramuscularly on days 1, 14, and 28 and then once a month at 2-6 months. Within 8 days after completion of hormone therapy, all patients undergo surgical resection of the residual lesion followed by radiotherapy. Patients then receive oral anastrozole once daily for 5 years. Tissue samples from biopsy and surgery are analyzed to assess molecular signatures and sensitivity to treatment, and to compare gene expression variation with response.
Interventions
DRUGanastrozole
Given orally
DRUGfulvestrant
Given intramuscularly
Sponsors
National Cancer Institute, France
Institut Bergonié
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed invasive breast cancer, meeting 1 of the following criteria: * SBR grade I-II disease (patients \< 65 years of age) * SBR grade I-III disease (patients \> 65 years of age) * T2 (2-5 cm), T3, or T4B, and N0-1 disease * No metastatic disease * Breast lesion not amenable to breast-conserving resection * No inflammatory breast cancer * No prior breast cancer * Hormone receptor status: * Estrogen receptor- and/or progesterone receptor-positive PATIENT CHARACTERISTICS: * Postmenopausal * No other cancer within the past 5 years except for adequately treated skin carcinoma or carcinoma in situ of the cervix * No contraindication to anti-hormonal treatment * No psychological, familial, social, or geographical reasons that would preclude follow up PRIOR CONCURRENT THERAPY: * At least 8 days since prior hormone replacement therapy * No concurrent anti-vitamin K treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Determined by Clinical Palpation | 6 months | Objective response rate is defined as the rate of participants with partial or complete responses according to RECIST V1.0. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Determined by Ultrasound | 6 months | Objective response rate is defined as the rate of participants with partial or complete responses according to RECIST V1.0. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.). |
| Objective Response Rate (ORR) Determined by Mammography | 6 months | Objective response rate is defined as the rate of participants with partial or complete responses according to RECIST V1.0. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.). |
| Rate of Breast-conserving Surgery | 6 months | breast-conserving surgery concerns patients who did not undergo mastectomy. |
| Percentage of Participants With 5-year Relapse-Free Survival | 5 years | Relapse-Free survival (RFS) is measured from the date of randomization to the date of the following events, whichever occurs first according to the DATECAN recommendations for breast cancer: * Invasive ipsilateral breast tumor recurrence/ progression ; * Local invasive recurrence/progression ; * Regional invasive recurrence/progression (N+: regional progression) ; * Appearance/Occurrence of Metastatic recurrence; * Death whatever the cause. Participants who did not experience events were censored at the date of last follow-up. RFS was estimated using the Kaplan-Meier method. No comparison test was performed between the two arms as this study is non-comparative. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A (ANA) Patients receive oral anastrozole as 1 mg film-coated tablets, once daily for 6 months.
anastrozole: Given orally | 61 |
| Arm B (FULV) Patients receive fulvestrant intramuscularly ( 250 mg/5 ml solution) on days 1, 14, and 28 and then once a month thereafter until 6 months.
fulvestrant: Given intramuscularly | 59 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Arm A (ANA) | Arm B (FULV) | Total |
|---|---|---|---|
| Age, Continuous | 69.1 years | 70.5 years | 69.8 years |
| Region of Enrollment France | 61 participants | 59 participants | 120 participants |
| Sex: Female, Male Female | 61 Participants | 59 Participants | 120 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 | 6 / 60 | 6 / 58 |
| other Total, other adverse events | 48 / 60 | 43 / 58 |
| serious Total, serious adverse events | 2 / 60 | 3 / 58 |
Outcome results
Primary
Objective Response Rate (ORR) Determined by Clinical Palpation
Objective response rate is defined as the rate of participants with partial or complete responses according to RECIST V1.0. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.).
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (ANA) | Objective Response Rate (ORR) Determined by Clinical Palpation | 58.9 percentage of participants |
| Arm B (FULV) | Objective Response Rate (ORR) Determined by Clinical Palpation | 53.8 percentage of participants |
Secondary
Objective Response Rate (ORR) Determined by Mammography
Objective response rate is defined as the rate of participants with partial or complete responses according to RECIST V1.0. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.).
Time frame: 6 months
Population: Out of 108 patients (56 arm A + 52 arm B) evaluable for efficacy (completed in flow chart) : 33 patients in Arm A and 34 in arm B with missing size at mammography.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (ANA) | Objective Response Rate (ORR) Determined by Mammography | 26.1 percentage of participants |
| Arm B (FULV) | Objective Response Rate (ORR) Determined by Mammography | 27.8 percentage of participants |
Secondary
Objective Response Rate (ORR) Determined by Ultrasound
Objective response rate is defined as the rate of participants with partial or complete responses according to RECIST V1.0. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.).
Time frame: 6 months
Population: Out of 108 patients (56 arm A + 52 arm B) evaluable for efficacy (completed in flow chart) : 19 patients in Arm A and 31 in arm B with missing size at ultrasound examination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (ANA) | Objective Response Rate (ORR) Determined by Ultrasound | 35.1 percentage of participants |
| Arm B (FULV) | Objective Response Rate (ORR) Determined by Ultrasound | 52.4 percentage of participants |
Secondary
Percentage of Participants With 5-year Relapse-Free Survival
Relapse-Free survival (RFS) is measured from the date of randomization to the date of the following events, whichever occurs first according to the DATECAN recommendations for breast cancer: * Invasive ipsilateral breast tumor recurrence/ progression ; * Local invasive recurrence/progression ; * Regional invasive recurrence/progression (N+: regional progression) ; * Appearance/Occurrence of Metastatic recurrence; * Death whatever the cause. Participants who did not experience events were censored at the date of last follow-up. RFS was estimated using the Kaplan-Meier method. No comparison test was performed between the two arms as this study is non-comparative.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (ANA) | Percentage of Participants With 5-year Relapse-Free Survival | 82.8 Percentage of participants |
| Arm B (FULV) | Percentage of Participants With 5-year Relapse-Free Survival | 74.7 Percentage of participants |
Secondary
Rate of Breast-conserving Surgery
breast-conserving surgery concerns patients who did not undergo mastectomy.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (ANA) | Rate of Breast-conserving Surgery | 60.7 percentage of participants |
| Arm B (FULV) | Rate of Breast-conserving Surgery | 50.0 percentage of participants |