Breast Cancer
Conditions
Keywords
Her2neu negative breast cancer., Neoadjuvant treatment.
Brief summary
This is an open-label study that includes two substudies of random distribution. First,a sample of the primary tumor will be obtained and will be analyzed by an immunohistochemical technique to determine several markers.Depending on the expression of these markers, the patients will be characterize as group 1 (Luminal A phenotype) or group 2 (Basal phenotype) and a random assignment will be performed to standard or experimental treatment.
Detailed description
Group 1 (Luminal A): * Standard treatment: Epirubicin (E) 90 mg/ m2 intravenous (iv) in combination with Cyclophosphamide (C) 600 mg/ m2 iv every 21 days for 4 cycles, followed by docetaxel (D)100 mg/m2 iv every 21 days for 4 cycles. EC x 4 -\> D x 4 * Selective treatment: Postmenopausal patients: exemestane x 6 months; Premenopausal patients: goserelin x 6 months + exemestane x 6 months Group 2 (Basal): * Standard treatment: EC x 4 -\> D x 4 * Selective treatment: E 90 mg/ m2 iv in combination with C 600 mg/ m2 iv every 21 days for 4 cycles, followed by D (75 mg/m2) and carboplatin (Cb) (area under the curve = 6 mg/mL) iv every 21 days for 4 cycles. EC x 4 -\> DCb x 4
Interventions
DRUGEpirubicin
DRUGCyclophosphamide
DRUGDocetaxel
DRUGExemestane
DRUGGoserelin
DRUGCarboplatin
Sponsors
Pfizer
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
* Written informed consent. * Breast cancer with histological diagnosis. * Negative Human Epidermal Growth Factor Receptor 2 (HER2) tumours defined as immunohistochemistry (IHQ) 0,1+. * No evidence of suspicion of metastatic disease. * Age \>= 18 years old. * Performance status (Karnofsky index) \>= 80 (ECOG 0,1). * Adequate cardiac function by ECG in the previous 12 weeks. * Hematology: neutrophils \>= 1,5 x10\^9/l; platelets \>= 100 x10\^9/l; hemoglobin \>= 10 g/dl. * Adequate hepatic function: total bilirubin \<= 1x Upper Normal Limit (UNL); Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT) \<= 2.5 x UNL; alkaline phosphatase \<= 2.5 x UNL. * Adequate renal function: creatinine \<= 1 x UNL; creatinine clearance \>= 60 ml/min. * Patients able to comply with study treatment and follow-up. * Negative pregnancy test in the previous 14 days.
Exclusion criteria
* HER2 positive tumours (defined as IHQ 3+ or positive fluorescence in situ hybridization \[FISH\]). * Prior systemic therapy for breast cancer (immunotherapy, hormonotherapy, chemotherapy). * Prior treatment with anthracyclines or taxanes (paclitaxel, docetaxel) for any previous malignancy. * Prior radiotherapy for breast cancer. * Bilateral invasive breast cancer. * Pregnant or lactating women. * Previous grade \>= 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria \[NCICTC\]). * Other serious comorbidities: congestive heart failure or unstable angina; prior history of myocardial infarction in previous year; uncontrolled hypertension (HT); high risk arrhythmias; history of significant neurological or psychiatric disorders; uncontrolled active infection; active peptic ulcer; unstable diabetes mellitus; dyspnea at rest; or chronic therapy with oxygen. * Previous or current history of neoplasms different from breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumor curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma. * Chronic treatment with corticosteroids. * Contraindications for administration of corticosteroids. * Concomitant treatment with other therapy for cancer. * Males.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Response for Basal Group 2 | Up to 24 weeks | This primary outcome only applies for the basal group 2 as per protocol. The pathological response in luminal group 1 was not pre-specified even as a Secondary Outcome. Pathological response was assessed after surgery, according to the Miller & Payne criteria, which stratifies the responses based on the proportion of remaining tumor and post-chemotherapy changes, evaluating separately the response in breast and axilla. Grades 1-4 are categorised as a partial pathological response (pPR) and grade 5 was a complete pathological response (cPR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response Rate | Up to week 24 | Clinical Response Rate was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria for target lesions before surgery: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Breast Conservative Surgery Rate | Up to 24 weeks | All patients will undergo surgery within the expected period from the end of treatment with neoadjuvant therapy. The chosen surgical option will be collected in the Case Report Form (CRF) before starting the neoadjuvant treatment, depending on the characteristics Clinics of the patient at that time (conservative surgery or mastectomy). This information will be compared with definitive surgery, to analyze whether neoadjuvant treatment has contributed to increase the rate of conservative surgery. |
| Axillary Node Status at the Time of Surgery | Up to 24 weeks | All the patients underwent lymphadenectomy in the foreseen term from the end of the treatment with neoadjuvant therapy, except for patients who underwent the technique of Sentinel lymph node with negative result before the start of the study treatment. Clinical lymph node involvement were collected in the CRF. Behind the lymphadenectomy, the rate of patients with affected lymph nodes, regardless of the type of response in the breast. To help find out if the cancer has spread outside the breast, one or more of the lymph nodes in the axilla (axillary lymph nodes) are removed for examination under a microscope. This is an important part of the determination of the stage. When the lymph nodes have cancer cells, there is a greater chance that the cancer cells have spread to other parts of the body. Decisions about treatment will depend on whether there is cancer in the lymph nodes. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (Luminal A) Standard Treatment Epirubicin (E) 90 mg/ m2 intravenous (iv) in combination with Cyclophosphamide (C) 600 mg/ m2 iv every 21 days for 4 cycles, followed by docetaxel (D)100 mg/m2 iv every 21 days for 4 cycles. | 47 |
| Group 1 (Luminal A) Selective Treatment Postmenopausal patients: exemestane x 6 months Premenopausal patients: goserelin x 6 months + exemestane x 6 months | 48 |
| Group 2 (Basal) Standard Treatment Epirubicin (E) 90 mg/ m2 intravenous (iv) in combination with Cyclophosphamide (C) 600 mg/ m2 iv every 21 days for 4 cycles, followed by docetaxel (D)100 mg/m2 iv every 21 days for 4 cycles. | 46 |
| Group 2 (Basal) Selective Treatment Epirubicin (E) 90 mg/ m2 intravenous (iv) in combination with Cyclophosphamide (C) 600 mg/ m2 iv every 21 days for 4 cycles, followed by docetaxel (D)100 mg/m2 iv and carboplatin (Cb) (area under the curve = 6 mg/mL) iv every 21 days for 4 cycles. | 48 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 4 | 3 |
| Overall Study | Disease progression | 0 | 2 | 5 | 1 |
| Overall Study | No treatment received | 2 | 2 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Group 1 (Luminal A) Standard Treatment | Group 1 (Luminal A) Selective Treatment | Group 2 (Basal) Standard Treatment | Group 2 (Basal) Selective Treatment | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51 years | 50.5 years | 47 years | 47 years | 49 years |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 0 | 43 Participants | 47 Participants | 38 Participants | 44 Participants | 172 Participants |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 1 | 4 Participants | 1 Participants | 7 Participants | 4 Participants | 16 Participants |
| Eastern Cooperative Oncology Group (ECOG) status ECOG Unknown | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Histological grade Grade 1 | 11 Participants | 11 Participants | 1 Participants | 2 Participants | 25 Participants |
| Histological grade Grade 2 | 30 Participants | 27 Participants | 9 Participants | 13 Participants | 79 Participants |
| Histological grade Grade 3 | 6 Participants | 10 Participants | 36 Participants | 33 Participants | 85 Participants |
| Histologic type Ductal | 38 Participants | 39 Participants | 39 Participants | 41 Participants | 157 Participants |
| Histologic type Lobular | 4 Participants | 5 Participants | 0 Participants | 0 Participants | 9 Participants |
| Histologic type Other | 5 Participants | 4 Participants | 7 Participants | 7 Participants | 23 Participants |
| Menopausal status Postmenopausal | 23 Participants | 21 Participants | 13 Participants | 19 Participants | 76 Participants |
| Menopausal status Premenopausal | 24 Participants | 27 Participants | 33 Participants | 29 Participants | 113 Participants |
| Nodal status N0 | 24 Participants | 28 Participants | 21 Participants | 24 Participants | 97 Participants |
| Nodal status N1 | 22 Participants | 19 Participants | 22 Participants | 20 Participants | 83 Participants |
| Nodal status N2 | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Female | 47 Participants | 48 Participants | 46 Participants | 48 Participants | 189 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor size T1 | 1 Participants | 1 Participants | 3 Participants | 6 Participants | 11 Participants |
| Tumor size T2 | 36 Participants | 34 Participants | 34 Participants | 31 Participants | 135 Participants |
| Tumor size T3 | 10 Participants | 13 Participants | 8 Participants | 10 Participants | 41 Participants |
| Tumor size T4 | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 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 | 0 / 45 | 0 / 46 | 0 / 46 | 0 / 47 |
| other Total, other adverse events | 45 / 45 | 46 / 46 | 46 / 46 | 47 / 47 |
| serious Total, serious adverse events | 5 / 45 | 0 / 46 | 16 / 46 | 9 / 47 |
Outcome results
Primary
Pathological Response for Basal Group 2
This primary outcome only applies for the basal group 2 as per protocol. The pathological response in luminal group 1 was not pre-specified even as a Secondary Outcome. Pathological response was assessed after surgery, according to the Miller & Payne criteria, which stratifies the responses based on the proportion of remaining tumor and post-chemotherapy changes, evaluating separately the response in breast and axilla. Grades 1-4 are categorised as a partial pathological response (pPR) and grade 5 was a complete pathological response (cPR).
Time frame: Up to 24 weeks
Population: For Group 2 (Basal) selective treatment: there was one patient who did not receive treatment, because of this is not included on the final analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 2 (Basal) Standard Treatment | Pathological Response for Basal Group 2 | Grade 5 | 16 Participants |
| Group 2 (Basal) Standard Treatment | Pathological Response for Basal Group 2 | Grade 4 | 5 Participants |
| Group 2 (Basal) Standard Treatment | Pathological Response for Basal Group 2 | Grade 3 | 11 Participants |
| Group 2 (Basal) Standard Treatment | Pathological Response for Basal Group 2 | Grade 2 | 8 Participants |
| Group 2 (Basal) Standard Treatment | Pathological Response for Basal Group 2 | Grade 1 | 5 Participants |
| Group 2 (Basal) Standard Treatment | Pathological Response for Basal Group 2 | Not available | 1 Participants |
| Group 2 (Basal) Selective Treatment | Pathological Response for Basal Group 2 | Grade 1 | 4 Participants |
| Group 2 (Basal) Selective Treatment | Pathological Response for Basal Group 2 | Grade 5 | 14 Participants |
| Group 2 (Basal) Selective Treatment | Pathological Response for Basal Group 2 | Grade 2 | 9 Participants |
| Group 2 (Basal) Selective Treatment | Pathological Response for Basal Group 2 | Grade 4 | 11 Participants |
| Group 2 (Basal) Selective Treatment | Pathological Response for Basal Group 2 | Not available | 1 Participants |
| Group 2 (Basal) Selective Treatment | Pathological Response for Basal Group 2 | Grade 3 | 8 Participants |
Secondary
Axillary Node Status at the Time of Surgery
All the patients underwent lymphadenectomy in the foreseen term from the end of the treatment with neoadjuvant therapy, except for patients who underwent the technique of Sentinel lymph node with negative result before the start of the study treatment. Clinical lymph node involvement were collected in the CRF. Behind the lymphadenectomy, the rate of patients with affected lymph nodes, regardless of the type of response in the breast. To help find out if the cancer has spread outside the breast, one or more of the lymph nodes in the axilla (axillary lymph nodes) are removed for examination under a microscope. This is an important part of the determination of the stage. When the lymph nodes have cancer cells, there is a greater chance that the cancer cells have spread to other parts of the body. Decisions about treatment will depend on whether there is cancer in the lymph nodes.
Time frame: Up to 24 weeks
Population: For Group 2 (Basal) selective treatment: there was one patient who did not receive treatment, because of this is not included on the final analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 2 (Basal) Standard Treatment | Axillary Node Status at the Time of Surgery | Negative nodes | 15 Participants |
| Group 2 (Basal) Standard Treatment | Axillary Node Status at the Time of Surgery | Not available | 3 Participants |
| Group 2 (Basal) Standard Treatment | Axillary Node Status at the Time of Surgery | No Negative nodes | 29 Participants |
| Group 2 (Basal) Selective Treatment | Axillary Node Status at the Time of Surgery | Negative nodes | 14 Participants |
| Group 2 (Basal) Selective Treatment | Axillary Node Status at the Time of Surgery | Not available | 6 Participants |
| Group 2 (Basal) Selective Treatment | Axillary Node Status at the Time of Surgery | No Negative nodes | 28 Participants |
| Group 2 (Basal) Standard Treatment | Axillary Node Status at the Time of Surgery | No Negative nodes | 13 Participants |
| Group 2 (Basal) Standard Treatment | Axillary Node Status at the Time of Surgery | Negative nodes | 31 Participants |
| Group 2 (Basal) Standard Treatment | Axillary Node Status at the Time of Surgery | Not available | 2 Participants |
| Group 2 (Basal) Selective Treatment | Axillary Node Status at the Time of Surgery | Negative nodes | 32 Participants |
| Group 2 (Basal) Selective Treatment | Axillary Node Status at the Time of Surgery | Not available | 2 Participants |
| Group 2 (Basal) Selective Treatment | Axillary Node Status at the Time of Surgery | No Negative nodes | 13 Participants |
Secondary
Breast Conservative Surgery Rate
All patients will undergo surgery within the expected period from the end of treatment with neoadjuvant therapy. The chosen surgical option will be collected in the Case Report Form (CRF) before starting the neoadjuvant treatment, depending on the characteristics Clinics of the patient at that time (conservative surgery or mastectomy). This information will be compared with definitive surgery, to analyze whether neoadjuvant treatment has contributed to increase the rate of conservative surgery.
Time frame: Up to 24 weeks
Population: For Group 2 (Basal) selective treatment: there was one patient who did not receive treatment, because of this is not included on the final analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 2 (Basal) Standard Treatment | Breast Conservative Surgery Rate | Breast conservative surgery | 22 Participants |
| Group 2 (Basal) Standard Treatment | Breast Conservative Surgery Rate | Not available | 2 Participants |
| Group 2 (Basal) Standard Treatment | Breast Conservative Surgery Rate | Non Breast conservative surgery | 23 Participants |
| Group 2 (Basal) Selective Treatment | Breast Conservative Surgery Rate | Breast conservative surgery | 27 Participants |
| Group 2 (Basal) Selective Treatment | Breast Conservative Surgery Rate | Not available | 4 Participants |
| Group 2 (Basal) Selective Treatment | Breast Conservative Surgery Rate | Non Breast conservative surgery | 17 Participants |
| Group 2 (Basal) Standard Treatment | Breast Conservative Surgery Rate | Non Breast conservative surgery | 15 Participants |
| Group 2 (Basal) Standard Treatment | Breast Conservative Surgery Rate | Breast conservative surgery | 31 Participants |
| Group 2 (Basal) Standard Treatment | Breast Conservative Surgery Rate | Not available | 0 Participants |
| Group 2 (Basal) Selective Treatment | Breast Conservative Surgery Rate | Breast conservative surgery | 34 Participants |
| Group 2 (Basal) Selective Treatment | Breast Conservative Surgery Rate | Not available | 0 Participants |
| Group 2 (Basal) Selective Treatment | Breast Conservative Surgery Rate | Non Breast conservative surgery | 13 Participants |
Secondary
Clinical Response Rate
Clinical Response Rate was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria for target lesions before surgery: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to week 24
Population: For Group 2 (Basal) selective treatment: there was one patient who did not receive treatment, because of this is not included on the final analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Basal) Standard Treatment | Clinical Response Rate | 31 Participants |
| Group 2 (Basal) Selective Treatment | Clinical Response Rate | 23 Participants |
| Group 2 (Basal) Standard Treatment | Clinical Response Rate | 32 Participants |
| Group 2 (Basal) Selective Treatment | Clinical Response Rate | 36 Participants |