Letrozole in Post-Menopausal Patients With Operable Hormone-Sensitive Breast Cancer

Patients will receive a prescription for letrozole to be taken orally at a dose of 2.5 mg/day
for 7-56 days to allow for variations in surgical scheduling. Patients are to undergo
surgical resection of their tumor the day after the last dose of letrozole.

Post-treatment tumor biopsies (a goal of 4-6 cores) will be obtained following 7-56 days of
letrozole treatment on the day of surgery. Frozen AND formalin fixed core biopsies will be
obtained whenever possible. The tissue will be used for study-specific assays as well as
routine histopathology. Post-treatment core needle biopsy tissue will be obtained, whenever
possible, by the surgeon intraoperatively at the time of routine surgical resection. A
formalin-fixed paraffin embedded tumor block from the patient's surgical resection is also
requested. This block will be used for a subset of the correlative studies if no tumor is
obtained by the post treatment core biopsies. This block will be returned to pathology
promptly after the correlative studies are completed.

Surgical treatment (total mastectomy or segmental resection with lymph node evaluation if
clinically indicated) will occur the day after completion of therapy.

The primary lesion obtained at the time of the definitive surgical procedure (partial or
total mastectomy) will be sent for standard of care histopathologic analysis; wherever
possible intra-opearative cores from the central portion of the tumor will be obtained for
study-specific assays. All specimens will be handled according to established institutional
guidelines to maintain the accuracy of the analysis of tumor size and margin status.

Following standard of care histopathologic analysis, additional paraffin-embedded sections
will be submitted at a later time to the Simmons Cancer Tissue Core to determine tumor
proliferation with Ki67 (MIB1Ab, Dako Cytomation) IHC. These tests are of no clinical utility
and will be done for research purposes only.

Frozen cores and/or peels from the formalin-fixed paraffin-embedded (FFPE) tumor blocks from
the surgical specimen will be selected and/or macrodissected - when needed - based on ≥20%
tumor cellularity as assessed by Dr. Sahoo, expert breast pathologist in the trial. These
will be sent to Dr. Carlos Arteaga's laboratory for further testing.

Inclusion Criteria:

1. Eligibility waivers are not permitted. Subjects must meet all of the inclusion and
exclusion criteria to be registered to the study. Study treatment may not begin until
a subject is registered.

2. Patients must provide informed written consent

3. ECOG performance status 0-1.

4. Clinical stage operable I, II or III invasive mammary carcinoma, which is ER-positive
by IHC and HER2-negative by Herceptest (0 or 1+) or not amplified by FISH as per
routine clinical testing Patients who have measurable residual tumor at the primary
site Patients who will undergo surgical treatment with either segmental resection or
total mastectomy

5. Measurable tumor i. Measurable disease: a mass that can be reproducibly measured by
physical exam and calipers or ultrasound and is at least 1 cm in size

6. The pathology report from the initial diagnosis has been reviewed by either UTSW or
Parkland Hospital, Department of Pathology and meets eligibility criteria. Available
core biopsies from the time of diagnosis have been requested. These may include the
paraffin block or sections from the paraffin-embedded tumor blocks.

7. Post-menopausal female subjects ≥18 years of age, as defined by any of the following:

- Subjects at least 55 years of age;

- Subjects under 55 years of age and amenorrhoeic for at least 12 months or
follicle-stimulating hormone (FSH) values ≥40 IU/L and estradiol levels ≤20 IU/L;

- Prior bilateral oophorectomy or prior radiation castration with amenorrhea for at
least 6 months.

- (There is no upper age limit for enrollment to this study)

8. No prior chemotherapy for this primary breast cancer.

9. Patients with a prior history of contralateral breast cancer are eligible if they have
no evidence of recurrence of their initial primary breast cancer.

10. Women may have been taking tamoxifen or raloxifene as a preventive agent prior to
study entry but must have discontinued the drug for at least 21 days prior to study
enrollment.

11. Subjects must have ended hormone replacement therapy (HRT) (e.g., conjugated estrogens
tablets, USP, [Premarin]), at least 7 days prior to receiving the first dose of
randomized therapy.

12. Patients must have adequate hepatic and renal function. All tests must be obtained
less than 4 weeks from study entry. This includes:

1. Creatinine <1.5X upper limits of normal

2. Bilirubin, SGOT, SGPT <1.5X upper limits of normal

13. Able to swallow and retain oral medication

Exclusion Criteria:

1. Patients with locally advanced disease who are candidates for other preoperative
chemotherapy at the time of initial evaluation. This may include patients with locally
advanced disease such as:

- Inflammatory breast cancer (T4d)

- Fixed axillary lymph node metastases (N2)

- Metastasis to ipsilateral internal mammary node (N3)

2. Locally recurrent breast cancer

3. Evidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.)

4. Serious medical illness that in the judgment of the treating physician places the
patient at high risk of operative mortality.

5. Severe uncontrolled malabsorption condition or disease (i.e. grade II/III diarrhea,
severe malnutrition, short gut syndrome)

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

7. Use of an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of letrozole.