Study objectives
(1) Primary Objective: Time To Progression(TTP)
(2) Secondary Objectives: 
a)Overall response rate as measured by RECIST 1.1
b) Clinical benefit rate(CBR)
c) Overall survival  
d) Qualitative and quantitative toxicity as assessed by NCI CTCAE v3.0
e) Predictive markers
f) Determination of adequacy of estrogen suppression(estradiol)and related endocrine function(LH and FSH)

Study rationale
Endocrine treatment should be offered as first option to most women with hormone-sensitive MBC. This recommendation is based upon lower toxicity of endocrine treatment and generally longer durations of response in this subset as compared with cytotoxic chemotherapy, with no difference in OS. The selection of endocrine agents takes account of the menopausal status of the patients, the type of previous adjuvant endocrine treatment, the disease free interval and past medical history. In general, endocrine treatment should be offered as first option to most women with hormone-sensitive MBC. 
The goal of endocrine treatment is to block or interfere with the function of estrogen or progesterone. The major source of estrogen in premenopausal women is the ovaries; in postmenopausal women, estrogen arises from the aromatization of peripheral androgens catalysed by the enzyme aromatase. In premenopausal patients with endocrine-dependent MBC, tamoxifen, ovarian function suppression or a combination of those have been used. For postmenopausal women, aromatase inhibitor, tamoxifen or fulvestrant have been used. In a difference from Western countries, the age distribution of breast cancer peaked in the late forties in Korea. Thus, premenopausal women comprised of higher portion(up to 60%) than in Western countries. 
Historically, tamoxifen has been the standard first-line therapy for estrogen receptor (ER) positive metastatic breast cancer. Tamoxifen is a selective ER-modulator (SERM) that acts primarily as an antagonist, binding to the ER, thereby preventing the subsequent binding of estrogen. However, tamoxifen also displays some estrogen agonist effects that are thought to be partially responsible for treatment failures. Resistance to tamoxifen does not necessarily imply resistance to other endocrine therapies. Patients experiencing disease progression with a first-line hormonal therapy may benefit from other endocrine agents. Treatment options for women whose tumors are resistant to tamoxifen include discontinuation of tamoxifen, an alternative endocrine therapy, or systemic chemotherapy. Sequential second- and third-line endocrine treatment is often effective, although typically for shorter durations than initial therapy.
For the premenopausal women with metastatic breast cancer patients who failed to tamoxifen treatment, there are few endocrine treatment options except LH-RH agonist even though their diseases are still candidates for second-line endocrine treatment.

Treatment plan
Arm I: Patients receive fulvestrant 500 mg IM (1st cycle, loading; 500mg IM on D1, 15, then every 4 weeks, 2nd cycle is going to be received on D29) with goserelin 3.6 mg SC in every 4 weeks till documentation of disease progression.
Arm II: Patients receive anastrozole 1 mg p.o. daily undergoing goserelin 3.6 mg SC in every 4 weeks till disease progression.
Arm III: Patients receive goserelin 3.6 mg SC in every 4 weeks till disease progression

Statistical considertation 
The initial sample size of the present study was determined based on the data derived from a previous trial on goserelin, tamoxifen cross-over design;6-month TTP is 15% for goserelin arm. Based on this estimate, we will recruit a total of N=132 patients (44 per arm). Following are design assumptions this sample size recalculation is based on. 
(1) 6-months TTP=50% for the control arm; =65% for each experimental arm
(2) one side alpha=15%, power=85% for the comparison of each experimental arm to the control 
(3) Additional follow-up period of 1.5 years after the completion of accrual

Treatment

Arm I: Patients receive fulvestrant 500 mg IM (1st cycle, loading; 500mg IM on D1, 15, then every 4 weeks, 2nd cycle is going to be received on D29) with goserelin 3.6 mg SC in every 4 weeks till documentation of disease progression.
Arm II: Patients receive anastrozole 1 mg p.o. daily undergoing goserelin 3.6 mg SC in every 4 weeks till disease progression.
Arm III: Patients receive goserelin 3.6 mg SC in every 4 weeks till disease progression.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Patients receive fulvestrant 500 mg IM (1st cycle, loading; 500mg IM on D1, 15, then every 4 weeks, 2nd cycle is going to be received on D29) with goserelin 3.6 mg SC in every 4 weeks till documentation of disease progression.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Patients receive anastrozole 1 mg p.o. daily undergoing goserelin 3.6 mg SC in every 4 weeks till disease progression.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Patients receive goserelin 3.6 mg SC in every 4 weeks till disease progression.

Gender

Age

Description

1)	All patients must be female and premenopausal. Premenopausal is defined as either: 
① last menstrual period within 3 months, or 
② post-hysterectomy without bilateral oophorectomy and with FSH in the premenopausal range (≤ 30 mIU/mL), or, 
③ if on tamoxifen within the past 3 months, a plasma estradiol in the premenopausal range (≥20 pg/mL), 
④ if in case of chemotherapy induced amenorrhea, a plasma estradiol in the premenopausal range (≥20 pg/mL). 
2)	Patients must have either positive estrogen and/or progesterone receptor determination by IHC or competitive binding assay on metastatic disease, or if not performed on their metastatic disease a positive result on their primary breast cancer specimen (Positivity is defined as an Allred score from 3 to 8 by IHC or at least 1% positive tumor nuclei in the sample in the presence of expected reactivity of internal and external controls [36]).
3)	No HER2 overexpressing breast cancer by IHC 3+ or FISH. 
4)	Patients who recurred after 5 years of tamoxifen use or would not be considered for resume to tamoxifen treatment as physician/s discretion or if patients who could not use tamoxifen for 5 years, the duration of tamoxifen treatment should be at least 12 weeks or more.
5)	Patients who showed progressive disease on tamoxifen treatment as a palliative hormonal therapy or an adjuvant endocrine treatment
6)	No prior treatment with an aromatase inhibitor or inactivator or fulvestrant.
7)	Prior treatment with an LH/RH agonist for adjuvant and/or palliative treatment are allowed if the last treatment has finished before 1 year of study entry. 
8)	No adjuvant chemotherapy within 1 year of study entry. 
9)	The patients who progressed after achieving response or disease control to previous 1st line chemotherapy for metastatic disease are allowed.
10)	Patients must have an ECOG performance status of 0, 1, or 2. 
11)	Adequate organ function as determined by the following laboratory results, within approximately 14 days prior to randomization: 
① Absolute neutrophil count ≥ 1500 cells/㎣, 
② Platelet count ≥ 100,000 cells/㎣, 
③ Hemoglobin ≥ 9.0 g/dL; patients may receive red blood cell transfusions to obtain this level, 
④ Total bilirubin ≤ 1.5 ⅹupper limit of normal (ULN) unless the patient has documented Gilbert’s syndrome, 
⑤ SGOT (AST), SGPT (ALT), and alkaline phosphatase (ALP) ≤ 2.5 ⅹ ULN, or ALP, AST and ALT ≤ 5.0ⅹULN if judged by the investigator to be related to liver metastases. 
⑥ International normalized ratio (INR) and activated partial thromboplastin time (aPTT) < 1.5 ⅹULN (unless on therapeutic anti-coagulation).
12)	Patients must not have received tamoxifen therapy for at least 2 weeks prior to enrollment. 
13)	Concomitant irradiation to any bony sites of disease for pain control or for prevention of fracture is allowed at the time of randomization. Radiation therapy for documented disease progression is not allowed.    
14)	Bisphosphonates for the treatment of bone metastases should not be initiated following the first dose of randomized therapy. It must be initiated prior to day of treatment (cycle 1, day 1). Patients may continue on bisphosphonates who already established on bisphophonate therapy for bone metastases.
15)	Patients who are pregnant or lactating are ineligible. A negative pregnancy test must be available for all subject of the study.
16)	For women of childbearing potential and men with partners of childbearing potential, agreement to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for 6 months after the last dose of study treatment. 
17)	Patients must not have had an active malignancy other than breast cancer, in situ carcinoma of the cervix, curatively resected thyroid papillary carcinoma or non-melanomatous skin cancers in the past 5 years. 
18)	No active, unresolved infection. 
19)	All patients must give signed written informed consent

1)	No prior treatment with an LH/RH agonist/antagonist within 1 year ofstudy entry for adjuvant or palliative endocrine therapy. 
2)	Patients must not have received more than 1 prior chemotherapy regimen for metastatic disease.
3)	Lymphangitic pulmonary metastases
4)	Symptomatic hepatic metastases 
5)	Documented parenchymal or leptomeningeal brain metastasis
6)	HER-2 overexpressing breast cancer and concomitant trastuzumab treatment is not allowed
7)	Serious uncontrolled intercurrent infections
8)	Serious intercurrent medical or psychiatric illness, including active cardiac disease
9)	Pregnancy or breast feeding
10)	Second primary malignancy (except in situ carcinoma of the cervix or resected papillary thyroid carcinoma or adequately treated nonmelanomatous carcinoma of the skin or other malignancy treated at least 5 years previously with no evidence of recurrence)

Time To Progression(TTP)

The time from the day 1 of first hormon therapy to the time of first documented disease progression of breast cancer

Overall response rate as measured by RECIST 1.1

Within 4 weeks of randomization and must be re-assessed at each subsequent tumor evaluation (every 3 months, regardless dose delays and/or interruptions)

Overall survival

As the time from the day 1 of hormonal therapy to the date of deathof any cause

Qualitative and quantitative toxicity as assessed by NCI CTCAE v3.0

The time from the day 1 of first hormon therapy to end of treatment

Biochemical response - estradiol (E2), LH, and FSH levels

At baseline and followed-up every 3 cycles