Letrozole in Treating Postmenopausal Women With Stage I, II or III Breast Cancer That Can Be Removed by Surgery

OBJECTIVES:

Primary To determine that in breast tumors that continue to exhibit high proliferation (i.e.,
Ki67) upon hormone deprivation (with letrozole), their gene expression and/or a mutational or
proteomic signatures will harbor molecules or 'pathways' that are biomarkers of resistance to
endocrine therapy or a cause of it.

The ultimate goal of these aims is to identify clinically-targetable pathways which can be
exploited to enhance responses and survival in patients with ER+ breast cancer.

OUTLINE: Patients receive oral letrozole once daily for 7-21 days in the absence of disease
progression or unacceptable toxicity. Within 24 hours after the last dose of letrozole,
patients undergo total mastectomy or segmental resection with lymph node evaluation.

Pre-treatment diagnostic breast tissue is obtained. Patients undergo treatment and then
undergo standard of care mastectomy or lumpectomy. Pre and post treatment tumor tissue
samples are analyzed for Ki67, P-ER, ER, progesterone receptor (PR), and caspase 3 by
immunohistochemistry; and RNA microarray.

DISEASE CHARACTERISTICS:

- Diagnosis of invasive breast cancer

- Clinical stage I, II, or III disease

- Resectable disease

- Measurable disease, defined as a mass that can be reproducibly measured by physical
examination and/or ultrasound and is at least 1 cm in size by ultrasound

- Patients with measurable residual tumor at the primary site allowed

- Estrogen receptor-positive tumor by immunohistochemistry (IHC)

- HER2-negative tumor by Herceptest (0 or +1) OR HER2 not overexpressed by fluorescence
in situ hybridization (FISH)

- Planning to undergo surgical treatment with either segmental resection or total
mastectomy with or without lymph node evaluation

- Must have core biopsies from the time of diagnosis available (may include sections of
paraffin-embedded material)

- Prior contralateral breast cancer allowed provided there is no evidence of recurrence
of the initial primary breast cancer

- Patients with locally advanced disease who are candidates for preoperative
chemotherapy at the time of initial evaluation are not eligible

- Locally advanced disease is defined by any of the following:

- Primary tumor ≥ 5 cm (T3)

- Tumor of any size with direct extension to the chest wall or skin (T4a-c)

- Inflammatory breast cancer (T4d)

- Fixed axillary lymph node metastases (N2)

- Metastasis to ipsilateral internal mammary node (N3)

- No locally recurrent disease

- No evidence of distant metastatic disease (i.e., lung, liver, bone, or brain
metastases)

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Postmenopausal, as defined by any of the following:

- 55 years of age and over

- Under 55 years of age and meets 1 of the following criteria:

- Amenorrheic for at least 12 months

- Follicle-stimulating hormone (FSH) ≥ 40 IU/L and estradiol levels ≤ 20 IU/L

- Has undergone prior bilateral oophorectomy or radiation castration AND has been
amenorrheic for at least 6 months

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- SGOT and SGPT ≤ 1.5 times ULN

- Creatinine ≤ 1.5 t times ULN

- Able to swallow and retain oral medication

- No serious medical illness that, in the judgment of the treating physician, places the
patient at high risk for operative mortality

- No malabsorption syndrome, ulcerative colitis, or other disease significantly
affecting gastrointestinal function

- No other malignancy within the past 5 years except for completely resected nonmelanoma
skin cancer or successfully treated in situ carcinoma

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

- No severe uncontrolled malabsorption condition or disease (i.e., grade II/III
diarrhea, severe malnutrition, or short gut syndrome)

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 21 days since prior tamoxifen or raloxifene as a preventive agent

- At least 7 days since prior hormone replacement therapy (e.g., conjugated estrogens
[Premarin])

- No prior resection of the stomach or small bowel

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

- No prior chemotherapy for this primary breast cancer

- No other concurrent investigational agents

- No other concurrent anticancer therapy (e.g., chemotherapy, radiotherapy,
immunotherapy, hormonal therapy, or any other biologic therapy)