Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)
Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)
This is a single-arm, open-label study testing the effects of neoadjuvant therapy with the
 aromatase inhibitor letrozole in post-menopausal women with Stage I-III ER+, HER2- breast
 cancer. Eligible subjects will be treated with letrozole therapy for 4 to 12 weeks prior to
 surgical resection of the tumor. Tumor specimens obtained at baseline (diagnostic biopsy) and
 at surgery (surgical specimen) will be compared using molecular analyses. A subset of
 subjects will be asked to provide an optional research tumor biopsy prior to treatment for
 molecular analysis.
Approximately 70% of breast cancers express estrogen receptor alpha (ER), which is activated
 by estrogens and typically drives cancer cell growth. Adjuvant therapy with anti-estrogens
 such as tamoxifen and aromatase inhibitors (AIs) is commonly used to inhibit ER to prevent
 cancer (re)growth after early-stage breast tumors are surgically removed. However, ~33% of
 such patients (~300,000 new cases per year worldwide) will eventually develop
 anti-estrogen-resistant breast cancer that is metastatic or locally advanced; at this stage,
 the disease is almost never cured using available therapies and is uniformly fatal.
 Therefore, more effective treatment early in the course of disease (i.e., in the adjuvant
 setting, shortly after surgical removal of a tumor) has huge potential to prevent cancer
 regrowth.

 Most often, ER+ breast cancers re-emerge in the years after the end of the standard five-year
 anti-estrogen treatment regimen (called 'late recurrence'). Recent data indicate that
 continued anti-estrogen therapy in patients who remain "disease-free" after five years of
 anti-estrogen therapy modestly prevents cancer recurrence. However, tumor cells are
 detectable in bone marrow of patients who are "disease-free." Thus, anti-estrogen therapy in
 "disease-free" patients likely suppresses the growth of undetectable tumor cells, keeping
 them in a "clinically dormant" state (i.e., undetectable by standard clinical methods).
 Little is known about how such dormant cancer cells survive. This clinical study will help
 identify the signaling pathways essential for the survival of clinically dormant ER+ breast
 cancer cells to enable the development of more effective therapies to eradicate such cells
 and prevent cancer recurrence.
Inclusion Criteria:

 1. Histologic documentation of invasive breast cancer by core needle or incisional
 biopsy. Excess baseline biopsy tumor tissue sufficient to make ten 5-micron sections
 must be available for research use as part of this study.

 2. The invasive cancer must be estrogen receptor alpha (ER)-positive, with ER staining
 present in greater than 50% of invasive cancer cells by IHC.

 3. The invasive cancer must be HER2-negative (IHC 0-1+, or with a FISH ratio of <1.8 if
 IHC is 2+ or if IHC has not been done).

 4. Clinical Stage I-III invasive breast cancer with the intent to treat with surgical
 resection of the primary tumor. Baseline tumor must be ≥1 cm to provide adequate
 tissue.

 5. Patients with multicentric or bilateral disease are eligible if the subject is a
 candidate for clinically indicated neoadjuvant endocrine therapy. Samples from all
 available tumors are requested for research purposes.

 6. Women over 18 years of age, for whom neoadjuvant treatment with an aromatase inhibitor
 would be clinically indicated. Women must be surgically, medically, or naturally
 post-menopausal.

 7. Patients must meet the following clinical laboratory criteria:

 -  Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.

 -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

 8. Ability to give informed consent.

 Exclusion Criteria:

 1. Prior endocrine therapy for any histologically-confirmed cancer is not allowed. Prior
 endocrine therapy that was administered ≥5 years ago for the prevention of breast
 cancer in patients with no history of breast cancer is allowed.

 2. Any other neoadjuvant therapy for breast cancer. Bisphosphonate treatment for bone
 symptoms is allowed.

 3. Women who are pregnant or lactating.