The Benefit of Surgery in Stage IV of Breast Cancer

After the diagnosis of primary distant metastatic breast cancer, patients will be randomly allocated into two groups: A. systemic therapy followed by surgery if the disease is not progressive; B. Systemic therapy Patient selection criteria

The eligibility criteria for the study are:

• primary distant metastatic breast cancer (M1); - an anticipated survival of at least 6 months; - a histologically proven diagnosis of the breast tumor; - a known hormonal and HER2Neu status; - TNM classification: T1-T3, resectable T4 status, and N0-N3; - performance status and comorbidity should allow surgery and/or systemic therapy; - age ≥ 18 years;- written informed consent.

Exclusion criteria are:

• primary invasive breast cancer in the medical history; - another malignancy within the last 10 years, besides basal cell carcinoma of the skin or early-stage cervical cancer; - surgical treatment and/or radiotherapy of the breast tumor before randomization; - irresectable T4 breast tumor; - synchronous bilateral breast cancer.

Randomization Centralized randomization will take place immediately after the diagnosis of primary distant metastatic breast cancer, using computer-generated randomization. dominant location of distant metastases (bone, soft tissue (lymph nodes and subcutaneous metastases) and visceral metastases), hormonal receptor status (ER and/ or PR positive or both negative) and HER2Neu status (overexpression yes or no) will be recorded.

Settings and location The study is a randomized controlled trial, which will be conducted at Tehran University of medical sciences, imam Khomeini hospital Treatment options During the study patients can be treated with surgery of the primary tumor (depending on randomization), systemic therapy The different treatment modalities are described below. Patients who are randomized to upfront surgery of the breast tumor will receive a lumpectomy or mastectomy depending on patient and tumor characteristics. Both types of surgery may be conducted as long as the intention is complete resection of the primary tumor, which is defined as having succeeded in obtaining free resection margins for the invasive component. The choice to perform an axillary lymph node dissection is left to the discretion of the treating physician but is highly recommended if palpable and/or tumor positive lymph nodes in the axillary region are present. If patients are randomized for systemic therapy, they may still be candidates for surgery of the primary tumor. In the case of local progression, breast surgery is allowed at any time to gain local control. Surgery for this group is primarily indicated when the treating physician beliefs the tumor may cause wound problems in near future, despite the use of systemic therapy. Patients will be treated with systemic therapy according to the guidelines. The choice of initial chemotherapy, immunotherapy, and endocrine therapy depends-among others-on ER and PR and HER2Neu status, dominant site of distant metastases, age, performance status, and comorbidity; but may also depend on the chance to reach a complete remission for example in minimal metastatic disease. In patients with a hormone receptor-positive tumor, hormonal treatment is indicated. In the case of rapid progression, chemotherapy is the treatment of choice. In HER2Neu positive disease and the use of an aromatase inhibitor, it is possible to add HER2Neu targeted therapy. Chemotherapy is offered to patients with hormone receptor-negative status, with extensive and fast-growing visceral metastases. For this study, we advise using at least an anthracycline, a taxane, and cyclophosphamide for the first 2-3 lines of treatment, if necessary in combination with targeted therapy, such as HER2- Neu targeted therapy, according to local practice.

Primary and secondary outcome measures The primary endpoint is the two-year survival. This is defined as the percentage of patients who survive two years after randomization. Secondary endpoints are quality of life, overall survival, number of unplanned local therapies, i.e. surgery or radiotherapy, number of axillary lymph node dissections or axillary radiotherapy, determination of pathological resection margin (margin status) in patients treated by surgery of the primary tumor.

Statistics Sample size calculation We are planning a randomized controlled trial with an equal number of patients in both treatment arms, an accrual interval of 36 months. Sample size calculation

Step 1: Calculation of the number of events with the following formula:

α=0.05 zα/2= 1.96 β=0.20 Zβ=0.84 π1=π2= 1/2: Equal allocation HR =0.50 Event =66

Step2: Calculation of the number of Patients with the following formula:

In this step, we assume the 40% of patients will die during the 2-years follow-up of the study. So the total number of desired patients will be 212. Therefore we need 106 patients in each group. Considering a 10% loss of patients, we should enter 118 patients in each group.

Following calculations were conducted:

Follow-up period= 2 years Suppose Incidence Rate (IR) = 25 events/person-2 years λt=0.5 at t= 2-year S(t)= exp{-λt}= exp{0.5}=0.60 1-0.60= 0.40 It means 40% of patients will die during 2 years of follow-up.

S1(2)= exp{-0.5}=0.60 S2(2)=exp (-0.5* HR}=0.78 Pr {event} = 1- {(0.60+0.78)/2}=0.31 N= 66/0.31=212 Total number n=106 each group

Number after considering 10% loss =118 /group

Data analysis Investigators will enter the information required by the protocol into the Case Report Forms (CRFs). The data from all investigators will be pooled and summarized with respect to demographic and baseline characteristics and efficacy and safety observations. Data will be presented for the complete intent-to-treat population. The primary endpoint will be analyzed in a Cox regression model, with the minimization factors as covariables. Interim analysis