Phase II Study of Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI) (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 24 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. Subjects will be evaluated for treatment adherence and provide feedback via survey questionnaires to identify potential causes of non-adherence.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer; ER Positive Breast Cancer
• Intervention / Treatment: Drug: Letrozole 2.5mg

Detailed Description

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, antiestrogen 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.

• Study Type: Interventional
• Enrollment (Actual): 178
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologic documentation of invasive breast cancer by core needle or incisional biopsy. Subjects without excess baseline tumor tissue are eligible and evaluable for Primary Objective #2 (re: adherence). Excess baseline biopsy tumor tissue sufficient to make ten 5- micron sections must be available for research use for a subject to be evaluable for Primary Objective #1 (re: molecular analyses).
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 ≥0.5 cm. For the optional research biopsy (from 5 subjects), tumor must be

   ≥1 cm.

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 (A) neoadjuvant treatment with an aromatase inhibitor would be clinically indicated, and (B) adjuvant treatment with one of the following would be clinically indicated: tamoxifen; anastrozole; letrozole. Women must be postmenopausal, defined as last menstrual period >2 years prior to registration, or >1 yearer prior to registration with FSH and estradiol in post-menopausal range.

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 or prevention of breast cancer in the last 10 years is not allowed.
2. Any other neoadjuvant therapy for breast cancer. Bisphosphonate or denosumab treatment for metabolic bone issues are allowed.
3. Women who are pregnant or lactating.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; 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; Aromatase Inhibitor; Other Names: Femara

What is the study measuring?

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) following neoadjuvant endocrine therapy in patients with ER+ breast cancer.	Baseline to 4-12 Weeks
Determine subject adherence to endocrine therapy as measured via urine analysis	Urine analysis for drug metabolites will be used to determine subject adherence to endocrine therapy at three time points. (Protocol section 6.16.e) The outcome measure is percent of participants with adherence vs non-adherence as measured by urine samples tested for metabolites of adjuvant endocrine agents: tamoxifen, letrozole, anastrozole or exemestane. Urine tests will be recorded as positive or negative. Positive urine test = adherence.	Before surgery (within 14 days before surgery, or on day of surgery); approximately 1 year after surgery; and approximately 3 years after surgery
Treatment Satisfaction Questionnaire for Medication (TSQM) side effects score	The Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4 assesses subjects' satisfaction with their breast cancer medication over the past 2-3 weeks, or since last use. A modified 12-item questionnaire will address 4 domains: effectiveness (Item 1), side effects (Items 2-6), convenience (Items 7-9), and global satisfaction (Items 10-12). Item 2 (experience of side effects; yes/no) will be evaluated independently. Subjects will be dichotomized at the median score for analysis.	Before surgery (approximately 4-24 weeks after the start of letrozole treatment), 1 year after surgery, and 3 years after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longest dimension(s) of primary tumor(s) pre- and post-treatment	The longest dimension(s) of the primary tumor(s) will be measured from radiological images acquired as per standard of care before 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.	Baseline and after approximately 4 to 24 weeks of treatment
Altered mitochondrial and fatty acid metabolism in surgical tissue specimen as compared to baseline tissue specimen.	Sections of baseline and post-neoadjuvant therapy tumor tissue specimens will be immunofluorescently stained using antibodies against TOM-20, ACC, FASN, CD36, and perilipin. Mitochondrial number and length (per cancer cell) will be measured using Halo software to determine whether neoadjuvant therapy cancer cells exhibit increased mitochondrial content compared to baseline cancer cells. Other markers will be scored by Histoscoring. Correlations between A) the duration of neoadjuvant letrozole, and B) expression of metabolic markers (CPT1-alpha, TOM-20, FASN, CD36, perilin) will be determined.	Baseline and at surgery (after approximately 4 to 24 weeks of treatment)
Brief Pain Inventory (BPI) scores	The Brief Pain Inventory (BPI) asks subjects to rate pain (modified to also include stiffness) over the prior week and the degree to which it interferes with activities on a 0 to 10 scale, where higher scores indicate more pain or interference. We will examine items reflecting worst pain, least pain, average pain, pain right now, and pain interference. Pain interference will be calculated as the mean score across 7 items (in Question 9). Subjects will be dichotomized at the median score using each of the above metrics, and rates of non-adherence will be calculated for subjects below vs. above the median.	Baseline (within 28 days prior to start of letrozole), Before surgery (approximately 4-24 weeks after the start of letrozole treatment), 1 year after surgery, and 3 years after surgery
Functional Assessment of Cancer Therapy- Endocrine Symptoms (FACT-ES) scores	The Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) contains (A) the Functional Assessment of Cancer Therapy- General (FACT-G) to measure physical, social, family, emotional, and functional well-being through 4 subscales, and (B) a fifth 18-item subscale to measure endocrine-related symptoms. In FACT-G, 6-7 items are queried in each subscale. FACT scales have 5 response levels ("not at all" to "very much"), where higher scores reflect increased wellness. The sum of item scores in each subscale will be calculated, multiplied by the number of items in the subscale, and divided by the number of items answered to derive a subscale score for each subject. The sum of subscale scores will yield the total FACT-G and FACT-ES score for each subject. Subjects will be dichotomized at the median scores for analysis.	Baseline (within 28 days prior to start of letrozole), Before surgery (approximately 4-24 weeks after the start of letrozole treatment), 1 year after surgery, and 3 years after surgery
Beliefs about Medication Questionnaire (BMQ) score	The Beliefs about Medication Questionnaire (BMQ) assesses patients' beliefs about their prescribed medication. BMQ items were adapted to reflect medication prescribed for cancer. Subjects will indicate their degree of agreement with each statement on a 5-point Likert scale ("strongly disagree" to "strongly agree"). The sum of scores for all items will be calculated for each subject. Subjects will be dichotomized at the median score for analysis.	Baseline (within 28 days prior to start of letrozole), Before surgery (approximately 4-24 weeks after the start of letrozole treatment), 1 year after surgery, and 3 years after surgery
Treatment Satisfaction Questionnaire for Medication (TSQM) total and domain scores for effectiveness, convenience, global satisfaction, and experience of side effects	Change in Treatment Satisfaction Questionnaire for Medication (TSQM) total; Change in Treatment Satisfaction Questionnaire for Medication (TSQM) for effectiveness; Change in Treatment Satisfaction Questionnaire for Medication (TSQM) for convenience; Change in Treatment Satisfaction Questionnaire for Medication (TSQM) for global satisfaction	Before surgery (approximately 4-24 weeks after the start of letrozole treatment), 1 year after surgery, and 3 years after surgery
Endocrine Therapy adherence pre and post surgery.	Determine the proportion of subjects who receive ≥1 wk of neoadjuvant endocrine therapy and remain adherent with prescribed adjuvant endocrine therapy at 1 and 3 years post surgery.	Baseline to 4 -12 weeks
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(s) measured from the start of treatment to right before surgery.	4 to12 Weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in residual cancer fatty acid.	Compare values of CPT1-alpha histoscores in pre and post neoadjuvant endocrine therapy samples to show the number of samples with residual disease that exhibit upregulation of the fatty acid transporter CPT1-alpha compared to pre-treatment samples.	Baseline to 4 -12 weeks
Changes in tumor cell type	Using fresh tumor tissue at baseline, tumor cell type proportions before and after neoadjuvant endocrine therapy will be measured per 10X Genomics manufacturer's protocol. Data will be bioinformatically analyzed using dimensionality reduction with t-distributed stochastic neighbor embedding (t-SNE) to visualize data in two dimensions and measure: Percent of each cell type before and after neoadjuvant endocrine therapy; Change in cell type proportions via t-SNE	Baseline to 4 -12 weeks
Relationship between duration of endocrine therapy and changes in tumor markers.	Determine whether duration of neoadjuvant letrozole treatment is correlated with changes in markers of altered mitochondrial and fatty acid metabolism	Baseline to 4 -12 weeks

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Mary D Chamberlin, MD, Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2021
• Primary Completion (Estimated): April 2, 2028
• Study Completion (Estimated): August 13, 2029

Study Registration Dates

• First Submitted: September 22, 2020
• First Submitted That Met QC Criteria: September 24, 2020
• First Posted (Actual): September 29, 2020

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Letrozole; Aromatase Inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Nitriles; Triazoles; Letrozole
• Other Study ID Numbers: D20148; NCI-2022-02378 (Other Identifier: NCI ID)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes