Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase II Study of Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)

Conditions
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Breast Cancer, ER Positive Breast Cancer

Intervention / Treatment
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* Drug: Letrozole 2.5mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. The invasive cancer must be estrogen receptor alpha (ER)-positive, with ER staining present in greater than 50% of invasive cancer cells by IHC. 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). 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. 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. 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. 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. Ability to give informed consent. Exclusion Criteria: 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. Any other neoadjuvant therapy for breast cancer. Bisphosphonate treatment for bone symptoms is allowed. Women who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Letrozole 2.5mg tablet administered once daily for 4 to  12 weeks (window of + 4 weeks for surgical scheduling flexibility) final dose taken the day of surgery. | Drug: Letrozole 2.5mg<br>* Aromatase Inhibitor<br>* Other names: Femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tumor CPT1-alpha levels | Determine whether residual cancer cells exhibit upregulation of the fatty acid transport CPT1-alpha (compared to baseline) | Baseline to 4-12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects who experience Clinical Response | Determine the proportion of subjects who experience clinical response, defined as a ≥50% decrease in the longest dimension of the primary tumor. The longest dimension(s) of the primary tumor(s) will be measured from radiological images acquired as per standard of care before (up to 4 wk prior to) neoadjuvant letrozole treatment, and after neoadjuvant letrozole treatment (prior to surgery). If multiple primary tumors are detected, the sum of the longest diameters will be used to provide a single measurement at each time point for each subject. Pre- and post-treatment tumor lengths will be compared. | 4 to12 Weeks | 
| Change in tumor CPT1-alpha histoscore | Determine whether residual cancer cells exhibit altered levels of CPT1-alpha compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against CPT1-alpha. CPT1-alpha histoscore levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells. | Baseline to 4 -12 weeks | 
| Change in tumor mitochondrial content per cell | Determine whether residual cancer cells exhibit altered mitochondrial length compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against TOM20. TOM20-stained organelle length per cell will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased mitochondrial content compared to baseline cancer cells. | Baseline to 4 -12 weeks | 
| Change in tumor ACC histoscore | Determine whether residual cancer cells exhibit altered levels of ACC compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against ACC. ACC levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells. | Baseline to 4 -12 weeks | 
| Change in tumor FASN histoscore | Determine whether residual cancer cells exhibit altered levels of FASN compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against FASN. FASN levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells. | Baseline to 4 -12 weeks | 
| Change in tumor CD36 histoscore | Determine whether residual cancer cells exhibit altered levels of CD36 compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against CD36. CD36 levels will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased levels compared to baseline cancer cells. | Baseline to 4 -12 weeks | 
| Change in tumor lipid droplet content per cell | Determine whether residual cancer cells exhibit altered lipid droplet content compared to baseline tumors. Specimens will be immunofluorescently stained using an antibody against perilipin. Perilipin-stained organelle content per cell will be measured using Halo software to determine whether post-neoadjuvant therapy cancer cells exhibit increased lipid droplet content compared to baseline cancer cells. | Baseline to 4 -12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Letrozole, Aromatase Inhibitor