Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed breast cancer

- Metastatic disease

- Confirmed disease progression after treatment with an aromatase inhibitor (AI)
administered in the adjuvant or metastatic setting

- Must have demonstrated a prior response to AI therapy (i.e., responded after > 2
years of treatment in the adjuvant setting OR complete or partial response or
stable disease after ≥ 24 weeks of treatment in the metastatic setting) AND have
subsequent disease progression after completion of AI therapy

- Meets 1 of the following criteria:

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded) as ≥ 20 mm with conventional
techniques or ≥ 10 mm with spiral CT scan

- Evaluable disease, defined as bone lesions, lytic or mixed (lytic and
sclerotic), evaluable by plain x-ray, CT scan, or MRI

- Lesions identified only by radionucleotide bone scan are not allowed

- No HER2/neu-overexpressing tumor (IHC 3+ or FISH+)

- Hormone receptor status:

- Estrogen receptor- and/or progesterone receptor-positive primary or metastatic
tumor

PATIENT CHARACTERISTICS:

- Female

- Postmenopausal, as defined by any of the following criteria:

- At least 60 years of age

- 45 to 59 years of age and meets ≥ 1 of the following criteria:

- Amenorrhea for ≥ 12 months and intact uterus

- Amenorrhea for < 12 months and follicle-stimulating hormone within the
postmenopausal range (including patients with hysterectomy, prior hormone
replacement therapy, or chemotherapy-induced amenorrhea)

- Patients who received prior luteinizing hormone-releasing hormone
(LHRH) analogues must not have restarted their menses after cessation
of therapy

- Over 18 years of age and bilateral oophorectomy

- WHO performance status 0-2

- Life expectancy ≥ 8 months

- Leukocytes ≥ 3,000/μL

- Absolute neutrophil count ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Total bilirubin normal

- AST/ALT ≤ 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- LVEF normal as measured by ECHO or MUGA

- Able to swallow and retain oral medication

- No ulcerative colitis

- No malabsorption syndrome or disease significantly affecting gastrointestinal
function

- No known history of uncontrolled or symptomatic angina, arrhythmias, or congestive
heart failure

- No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to fulvestrant, aromatase inhibitors, lapatinib tosylate, or
excipients

- No unresolved or unstable serious toxicity from prior therapy

- No active or uncontrolled infection

- No dementia, altered mental status, or any psychiatric condition that would prohibit
the understanding or rendering of informed consent

- No other malignancy within the past 5 years except for adequately treated cervical
carcinoma in situ, melanoma in situ, or basal cell or squamous cell carcinoma of the
skin

- No other concurrent disease or condition that would make the patient inappropriate
for study participation

- No serious medical disorder that would interfere with patient safety

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Prior radiotherapy for the primary or metastatic tumor allowed

- More than 4 months since prior LHRH analogues

- More than 30 days (or 5 half-lives, whichever is longer) since prior investigational
agents

- More than 14 days since prior and no concurrent CYP3A4 inducers*, including any of
the following:

- Rifampin, rifapentine, rifabutin, or other rifamycin class agents

- Phenytoin, carbamazepine, or barbiturates (e.g., phenobarbital)

- Efavirenz or nevirapine

- Oral glucocorticoids (e.g., cortisone [> 50 mg], hydrocortisone [> 40 mg],
prednisone [> 10 mg], methylprednisolone [> 8 mg], or dexamethasone [> 1.5 mg])

- Modafinil

- More than 14 days since prior and no concurrent herbal or dietary supplements*,
including any of the following:

- St. John's wort

- Ginkgo biloba

- Kava

- Grape seed

- Valerian

- Ginseng

- Echinacea

- Evening primrose oil

- More than 7 days since prior and no concurrent CYP3A4 inhibitors*, including any of
the following:

- Clarithromycin, erythromycin, or troleandomycin

- Itraconazole, ketoconazole, fluconazole (> 150 mg daily), or voriconazole

- Delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, or
lopinavir

- Verapamil or diltiazem

- Nefazodone or fluvoxamine

- Cimetidine or aprepitant

- Grapefruit or grapefruit juice

- More than 6 months since prior and no concurrent amiodarone*

- No prior fulvestrant and/or lapatinib tosylate

- No prior resection of the stomach or small bowel

- No other concurrent anticancer therapy, including chemotherapy, immunotherapy, and
biologic therapy

- Concurrent bisphosphonates allowed

- No other concurrent investigational therapy

- No concurrent participation in another clinical trial NOTE: *For patients randomized
to receive lapatinib