Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed breast cancer

- Not amenable to curative therapy

- HER-2 positive disease allowed

- Disease relapse or progression after aromatase inhibitor as adjuvant therapy or for
advanced stage disease

- Bilateral breast cancer allowed provided tumor endocrine sensitivity has been proven
on both sides

- Measurable disease according to RECIST criteria v1.1 or other lesions assessable by
radiological exams (i.e., bone-only disease or small but unequivocal liver or lung
metastases)

- Received no more than 1 line of chemotherapy for advanced stage disease

- Estrogen receptor- and/or progesterone receptor-positive (≥ 10% tumor cells positive
by immunohistochemistry or ≥ 10 fmol/mg cytosol protein by ligand binding assay)

- No known CNS metastases

- Patients with brain metastases treated with radiotherapy and without any sign of
brain progression after ≥ 3 months since the end of radiotherapy may be
considered eligible after trial chair approval)

PATIENT CHARACTERISTICS:

- WHO performance status 0-2

- Postmenopausal

- Hemoglobin ≥ 90 g/L

- Platelet count ≥ 100 x 10^9/L

- Absolute neutrophil count ≥ 1.5 x 10^9/L

- Creatinine clearance ≥ 30 mL/min

- ALT ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN in patients with liver
metastases)

- Bilirubin ≤ 1.5 times ULN

- INR < 1.6

- PTT normal

- LVEF ≥ 50%

- Able to swallow AZD6244/placebo capsules

- Capable of understanding information given by the investigator on the trial

- Must adhere to and be geographically proximal to allow for proper staging, treatment,
and follow up

- No contraindication for intramuscular injections

- No bleeding diathesis

- No current or prior malignancy other than breast cancer within the past 5 years,
except carcinoma in situ of the cervix or basal cell carcinoma of the skin treated
curatively

- No serious underlying medical condition that, in the judgment of the investigator,
would impair the ability of the patient to participate in the trial (e.g., active
autoimmune disease or uncontrolled diabetes)

- No refractory nausea and vomiting, chronic gastrointestinal disease (e.g.,
inflammatory bowel disease), or significant bowel resection that preclude adequate
absorption

- No psychiatric disorder precluding understanding of information on trial-related
topics, giving informed consent, or interfering with adherence for oral drug intake

- No uncontrolled hypertension (systolic BP > 150 mm Hg and/or diastolic BP > 100 mm
Hg, measured repeatedly at more than two visits despite adequate treatment with at
least two different antihypertensive drugs)

- No clinically significant (i.e., active) cardiovascular disease, including any of the
following:

- Cerebrovascular accident/stroke or myocardial infarction within the past 6
months

- Unstable angina

- NYHA class III-IV congestive heart failure

- Serious cardiac arrhythmia or AV-block > 1, requiring medication during the
trial and which might interfere with regularity of the trial treatment, or not
controlled by medication

- No known hypersensitivity to trial drugs or any other component of the trial drugs

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 30 days since other prior experimental drugs or participation in another
clinical trial

- No prior fulvestrant, AZD6244, MEK inhibitors, RAF inhibitors, or endocrine therapies
other than aromatase inhibitors (e.g., anastrazole, letrozole, or exemestane) or
tamoxifen

- No more than 1 line of aromatase inhibitors (steroidal and nonsteroidal aromatase
inhibitors are considered two different lines)

- No concurrent full-dose anticoagulation therapy (e.g., low molecular weight heparin,
acenocoumarol, phenprocoumon, or analogues)

- Prophylactic doses of anticoagulation or antiplatelet may be allowed

- No concurrent radiotherapy

- No other concurrent anticancer therapy or experimental drugs

- Concurrent bisphosphonate allowed provided the investigator rules out tumor
progression