Selective Neoadjuvant Treatment According to Immunohistochemical Subtype for HER2 Negative Breast Cancer Patients

Study Overview
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Brief Summary
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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
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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

Official Title
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A Randomized Multicenter Phase II Trial to Evaluate the Effectiveness of Selective Neoadjuvant Treatment According to Immunohistochemical Subtype for HER2 Negative Breast Cancer Patients

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: Docetaxel
* Drug: Exemestane
* Drug: Goserelin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1 (Luminal A) Standard treatment<br>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. | Drug: Epirubicin<br> <br> * Other names: Ellence;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: Docetaxel<br> <br> * Other names: Taxotere;|
| Experimental: Group 1 (Luminal A) Selective treatment<br>Selective treatment: Postmenopausal patients: exemestane x 6 months Premenopausal patients: goserelin x 6 months + exemestane x 6 months | Drug: Exemestane<br> <br> * Other names: aromasil;Drug: Goserelin<br> <br> * Other names: Zoladex;|
| Active Comparator: Group 2 (Basal) Standard treatment<br>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. | Drug: Epirubicin<br> <br> * Other names: Ellence;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: Docetaxel<br> <br> * Other names: Taxotere;|
| Experimental: Group 2 (Basal) Selective treatment<br>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. | Drug: Epirubicin<br> <br> * Other names: Ellence;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: Docetaxel<br> <br> * Other names: Taxotere;Drug: Carboplatin<br> <br> * Other names: Paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to week 24 | 
| 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. | Up to 24 weeks | 
| 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. | Up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Her2neu negative breast cancer., Neoadjuvant treatment.