A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study Comparing GW572016 and Letrozole Versus Letrozole in Subjects With Estrogen/Progesterone Receptor-Positive Advanced or Metastatic Breast Cancer

Inclusion Criteria:

- Signed informed consent;

- Subjects must have histologically confirmed invasive breast cancer with stage IV
disease at primary diagnosis or at relapse after curative-intent surgery [Singletary,
2002];

- Tumors that are ER+ and/or PgR+;

- Subjects will be considered ER+ or PgR+ if any assay [cytochemical, immunochemical,
immunohistochemistry (IHC), or radioimmunoassay] of primary or secondary tumor tissue
is positive;

- Post-menopausal female subjects =18 years of age;

- ECOG Performance Status of 0 or 1;

- Subjects must have archived tumor tissue available to compare tumor response with
intra-tumoral expression of ErbB1 and ErbB2. Archived tumor tissue will also be used
to confirm estrogen receptor (ER) and/or progesterone receptor (PgR) positivity.
Results will not be used to determine subject eligibility for the study;

- Adjuvant therapy with an aromatase inhibitor is allowed; however, treatment must have
ended more than 1 year prior (>12 months) to the first dose of randomized therapy;

- Adjuvant therapy with trastuzumab is allowed; however, treatment must have ended more
than 1 year prior (>12 months) to the first dose of randomized therapy;

- Subjects who received neo-adjuvant/adjuvant therapy and now present with newly
relapsed advanced or metastatic disease are eligible; however, prior
neo-adjuvant/adjuvant therapy is not required for study entry; 11. Subjects must have
ended hormone replacement therapy (HRT) (e.g., conjugated estrogens tablets, USP,
[Premarin]), at least 1 month (30 days) prior to receiving the first dose of
randomized therapy;

- Radiotherapy prior to initiation of randomized therapy is allowed to a limited area
(e.g., palliative treatment for painful bone metastases), if it is not the sole site
of disease. Subject must have completed treatment and recovered from all treatment
related toxicities, in particular bone marrow suppression;

- Able to swallow and retain oral medication;

- Cardiac ejection fraction within the institutional range of normal as measured by
echocardiogram (or MUGA scan if an echocardiogram cannot be performed or is
inconclusive);

- Subjects must complete all screening assessments as outlined in the protocol;

- Adequate organ function

Exclusion Criteria:

- Pre-menopausal, pregnant, or lactating;

- Received prior chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or
anti-ErbB1/ErbB2 therapy for advanced or metastatic disease;

- Bisphosphonate therapy for bone metastases is allowed; however, treatment must be
initiated prior to the first dose of randomized therapy. Prophylactic use of
bisphosphonates in subjects without bone disease, except for the treatment of
osteoporosis, is not permitted;

- Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with ulcerative colitis are also
excluded;

- History of other malignancy. Subjects who have been disease-free for 5 years, or
subjects with a history of completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible;

- Concurrent disease or condition that would make the subject inappropriate for study
participation, or any serious medical disorder that would interfere with the
subject's safety;

- Subjects who have not recovered from toxicities related to prior adjuvant therapy
(e.g., surgery, radiotherapy, chemotherapy, hormonal therapy, immunotherapy, biologic
therapy, and investigational agents);

- Subjects who have received anthracyclines in the neo-adjuvant and/or adjuvant
setting, which exceeded the following doses: 360 mg/m2 of Doxorubicin, 720 mg/m2 of
Epirubicin, and 72 mg/m2 of Mitoxantrone;

- Subjects with extensive symptomatic visceral disease including hepatic involvement
and pulmonary lymphangitic spread of tumor, or the disease is considered by the
investigator to be rapidly progressing or life threatening;

- Active or uncontrolled infection;

- Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent;

- Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart
failure;

- Known history of, or clinical evidence of, central nervous system (CNS) metastases or
leptomeningeal carcinomatosis;

- Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
immunotherapy, hormonal therapy, targeted therapy, biologic therapy, or tumor
embolization) other than letrozole;

- Concurrent treatment with an investigational agent or participation in another
clinical trial;

- Used an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of randomized therapy (GW572016 or placebo);

- The subject has a known immediate or delayed hypersensitivity reaction or
idiosyncrasy to drugs chemically related to randomized therapy (GW572016 or placebo)
or to excipients of randomized therapy (GW572016 or placebo); 18. Subject has known
hypersensitivity to Femara or excipients of Femara