Neoadjuvant Aromatase Inhibitor(AI) With Ovarian Suppression Versus Chemotherapy in Premenopausal Breast Cancer Patients

Study Overview
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Brief Summary
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To compare the efficacy and safety of neoadjuvant aromatase inhibitor plus ovarian suppression with chemotherapy in premenopausal patients with hormone receptor-positive breast cancer.

Detailed Description
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Neoadjuvant therapy is nowadays the standard treatment for both early stage and locally advanced breast cancer, and exhibited similar benefit compared with adjuvant therapy in terms of disease free and overall survival. Patients achieved pathological complete response(pCR) after neoadjuvant chemotherapy have superior outcome compared with those with residual tumors in breast and/or axilla. pCR is now the most wildly accepted surrogate marker for long-term survival of patients, especially in those with triple negative or human epidermal growth factor receptor-2(HER2)-positive breast cancer. However, in luminal HER2-negative breast cancer, neoadjuvant chemotherapy is not as effective as in other subtypes of breast cancer, pCR is less noted and seems barely correlated to long-term survival benefit. In postmenopausal patients with hormone receptor-positive breast cancer, neoadjuvant endocrine therapy of aromatase inhibitor achieved similar clinical response rate compared with neoadjuvant chemotherapy, and in premenopausal hormone receptor-positive, HER2-negative breast cancer patients, neoadjuvant aromatase inhibitor plus ovarian function suppression(OFS) has showed more pronounced efficacy than tamoxifen plus OFS. In adjuvant setting, aromatase inhibitor combined with OFS in premenopausal patients with hormone receptor-positive breast cancer has demonstrated superior benefit in terms of disease free survival, and has been established as one of the routine options of adjuvant endocrine therapy. Notwithstanding the remarkable performance of combination of aromatase inhibitor and OFS in adjuvant therapy, the role of this treatment strategy in neoadjuvant setting has yet not been proved when compared with neoadjuvant chemotherapy. The aim of this study is to prospectively compare the efficacy and safety of neoadjuvant aromatase inhibitor plus OFS with chemotherapy in premenopausal patients with hormone receptor-positive HER2-negative breast cancer.

Official Title
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Comparison of Neoadjuvant Aromatase Inhibitors With Ovarian Suppression Versus Chemotherapy in Premenopausal Patients With Hormone Receptor-positive Breast Cancer (COMPETE): a Randomized Phase 3 Trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Neoadjuvant endocrine therapy
* Drug: Neoadjuvant chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Women aged ≥ 18 years Histologically confirmed invasive breast cancer American Joint Committee on Cancer (AJCC) stage: ⅡA-ⅢC, no evidence of metastasis At least one measurable disease in breast and/or axilla ER and/or progesterone receptor(PgR) positive(≥10% of the cells by IHC) HER2 negative(by IHC and/or FISH) Premenopause status (estradiol in premenopausal range or with normal menstrual cycle in the past 6 months with no use of hormonal drugs) Eastern Cooperative Oncology Group（ECOG）score 0-1, an estimated life expectancy of at least 12 months Adequate bone marrow function: Leukocyte ≥ 3.0*109/L; Neutrophil ≥ 1.5*109/L; Hb ≥ 100g/L; Platelet(PLT） ≥ 80*109/L Adequate liver, renal function and coagulation function: Alanine transaminase（ALT） and/or Aspartate transaminase（AST）≤ 1.5 upper normal limit（UNL）, total bilirubin ≤upper normal limit, creatinine ≤ 110umol/L, Creatinine clearance > 60ml/min, blood urea nitrogen（BUN） ≤ 7.1mmol/L, activated partial thromboplastin time（APTT） ≤ 1.5 upper normal limit（UNL） Women with child-bearing potential must have a negative pregnancy test (urine or serum) within 7 days of drug administration and agree to use an acceptable method of birth control to avoid pregnancy for the duration of the study Serological records of hepatitis B virus（HBV）and hepatitis C virus（HCV） testing. Exclusion Criteria: Stage IV breast cancer Prior systemic or loco-regional treatment of breast cancer Any anti-neoplastic treatment within 28 days before the beginning of study Known severe hypersensitivity to any drugs in this study History of malignancy within 5 years except carcinoma in situ of cervix or skin basal cell carcinoma that had received adequate treatment Peripheral neuropathy ≥ 2°, according to National Cancer Institute(NCI) Common Terminology Criteria for Adverse Events(CTCAE)(Version 4.0) Any cardiac or pulmonary dysfunction defined as following: (1) ≥ 3° symptomatic congestive heart failure (CHF) according to NCI CTCAE(Version 4.0) or ≥ 2° CHF according to New York Heart Association（NYHA） (2) Angina that needs anti-anginal drugs, advanced conduction abnormality or significant vascular disease (3) Uncontrolled high-risk arrhythmia: atrial tachycardia that silent heart rate >100/min, significant ventricular arrythmia or advanced atrioventricular block(2° type II atrioventricular or 3° atrioventricular block) (4) Poorly controlled hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg) (5) Transmural myocardial infarction in EKG (6) Long-term oxygen therapy 8. Uncontrolled severe systemic disease(clinically significant cardiovascular disease，pulmonary disease or metabolic disease, wound healing disorder, ulcer, severe infection) 9. Pregnant or breast feeding 10. Major operation, obvious trauma within 28 days before randomization or planned major operation during the study 11. Known active hepatic disease due to hepatitis B virus, hepatitis C virus, auto-immune liver disease or sclerosing cholangitis 12. Known HIV infection 13. Any reasons investigators consider that not suitable for the study

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 |
| --- | --- |
| Experimental: Neoadjuvant endocrine therapy<br>Six months of exemestane or anastrozole plus goserelin. | Drug: Neoadjuvant endocrine therapy<br>* Goserelin: 3.6mg, d1, hypodermic injection , q28d*7 plus exemestane: 25mg, po, qd*24w, or anastrozole: 1mg, po, qd*24w<br>* Other names: Goserelin and AI;|
| Active Comparator: Neoadjuvant chemotherapy<br>Six cycles of docetaxel plus epirubicin and cyclophosphamide(TEC). | Drug: Neoadjuvant chemotherapy<br>* Docetaxel: 75mg/m2, d1, q3w*6, Epirubicin 75mg/m2, d1, q3w*6 and Cyclophosphamide: 500mg/m2, d1, q3w*6<br>* Other names: TEC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate(ORR) | Overall response rate(ORR) is defined as complete response rate plus partial response rate. | up to 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response(pCR) |  | up to 7 months | 
| Breast conserving surgery(BCS) rate |  | up to 7 months | 
| Incidence of neutropenia fever |  | participants will be followed during the six months of neoadjuvant therapy | 
| Incidence of hot flushes/flashes |  | participants will be followed during the six months of neoadjuvant therapy | 
| Incidence of osteoporosis |  | participants will be followed during the six months of neoadjuvant therapy | 
| Incidence of grade 3-4 adverse events |  | participants will be followed during the six months of neoadjuvant therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Neoplasms, Neoadjuvant Endocrine Therapy, Ovarian Function Suppression, Neoadjuvant chemotherapy