Please select the eligibility criteria that correspond to the clinical trial below.
Title: Systemic Therapy With or Without Up Front Surgery of the Primary Tumor in Breast Cancer Patients With Distant Metastases at Initial presenTation
Brief Summary: SUBMIT is a clinical trial that intends to answer the question whether up front breast surgery in patients with primary distant metastatic breast cancer will result in an improvement of the 2-year survival compared to the survival achieved with systemic therapy and delayed local treatment or systemic therapy alone.

Randomization will take place immediately after the diagnosis of primary distant metastatic breast cancer. Patients either randomize for up front surgery of the breast tumor (UFS) followed by systemic therapy or for systemic therapy (ST) potentially followed by delayed local treatment of the breast tumor.

The primary endpoint of this trial is the 2-years survival. Quality of life is one of the most important secondary endpoints.


Options:
A: Inclusion Criteria:

* Women with metastatic breast cancer at the initial diagnosis

Exclusion Criteria:

* Women needs breast surgery at the time of initial diagnosis (such as bleeding, necrosis, etc)
* who have systemic morbidity that do not allows her to be in the trial,
* who have synchronous breast cancer at the contralateral breast,
* who have a previous cancer history or another primary cancer history and metastasis at the past,
* who have palpable lymph node/nodes at the contralateral axilla,
* who do not agree to participate the trial
B: Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and candidate for chemotherapy. Participants with measurable and non-measurable disease are eligible (locally recurrent disease must not be amenable to resection with curative intent; participants with de novo Stage IV disease are eligible)
* Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC)
* Left ventricular ejection fraction (LVEF) ≥50 percent (%) at baseline (within 42 days of randomization)
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
* For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective form of contraception and to continue its use for the duration of study treatment and for at least 7 months after the last dose of study treatment

Exclusion Criteria:

* History of anti-cancer therapy for MBC (with the exception of one prior hormonal regimen for MBC, which must be stopped prior to randomization)
* History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting
* History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of less than (\<)12 months
* History of persistent Grade ≥2 hematologic toxicity resulting from previous adjuvant therapy
* Current peripheral neuropathy of National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0, Grade ≥3 at randomization
* History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent
* Current clinical or radiographic evidence of central nervous system (CNS) metastases
* Computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain is mandatory in cases of clinical suspicion of brain metastases
* History of exposure to cumulative doses of anthracyclines
* Current uncontrolled hypertension or unstable angina
* History of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (exception: atrial fibrillation or paroxysmal supraventricular tachycardia)
* History of myocardial infarction within 6 months of randomization
* History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy
* Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy
* Inadequate organ function, as defined in the protocol, within 28 days prior to randomization
* Current severe, uncontrolled systemic disease
* Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment
* Pregnant or lactating women
* History of receiving any investigational treatment within 28 days of randomization
* Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
* Receipt of IV antibiotics for infection within 14 days of randomization
* Current chronic daily treatment with corticosteroids (excluding inhaled steroids)
* Known hypersensitivity to any of the study drugs
* Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
C: Inclusion Criteria:

* Metastatic breast cancer at first presentation with an expected survival of at least one year

Exclusion Criteria:

1. Patients who are not fit to receive anthracycline based chemotherapy.
2. More than two visceral organ involvement.
3. Multiple liver metastases with deranged liver function tests (SGOT/SGPT more than four times the upper normal limit).
4. Locally static or progressive disease or systemically progressive disease as shown by repeat staging investigations guided by worsening symptoms.
5. Ulceration/ fungation/ bleeding after completion of chemotherapy, which mandates surgery.
6. Expected survival of less than six months after completion of chemotherapy.
7. Unfit for anaesthesia due to metastatic disease.
D: Inclusion Criteria:

* Newly diagnosed primary distant metastatic breast cancer (M1)
* Anticipated survival of at least 6 months
* Histologically proven breast cancer
* Hormonal and HER2Neu status should be known
* T1-T3, resectable T4 status, N0-N3
* Performance status of the patient should allow surgery / systemic therapy
* Co-morbidity of the patient should allow surgery / systemic therapy
* Age \> 18 years
* Written informed consent

Exclusion Criteria:

* Primary invasive breast cancer in medical history
* Other malignancy within the last 10 years, besides basal cell carcinoma of the skin or early stage cervical cancer
* Surgical treatment / radiotherapy of this breast tumor before randomization
* Irresectable T4 breast tumor
* Synchronous bilateral breast cancer

Answer: D