Clinical trial NCT04568616: Phase II Study of Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)
Official title: Phase II Study of Neoadjuvant ArOMatase Inhibitor Therapy for ER+ Breast Cancer (NAOMI)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
ER Positive Breast Cancer
Keywords: Letrozole
Aromatase Inhibitor
Lead sponsor: Dartmouth-Hitchcock Medical Center
Sponsor class: OTHER
First posted: 2020-09-29
Enrollment: 137
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients receive letrozole orally (PO) once daily (QD) for 4-16 weeks up to the day of surgery in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. After surgery, a subset of patients start a hormone therapy (letrozole, anastrozole, or tamoxifen) and remain in the study for up to 3.5 years.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Tumor CPT1-alpha levels
timeFrame: Baseline to 4-12 Weeks
measure: Determine subject adherence to endocrine therapy as measured via urine analysis
timeFrame: Before surgery (within 14 days before surgery, or on day of surgery); approximately 1 year after surgery; and approximately 3 years after surgery
measure: Treatment Satisfaction Questionnaire for Medication (TSQM) side effects score
timeFrame: Before surgery (approximately 4-24 weeks after the start of letrozole treatment), 1 year after surgery, and 3 years after surgery
Secondary outcomes:
measure: Longest dimension(s) of primary tumor(s) pre- and post-treatment
timeFrame: Baseline and after approximately 4 to 24 weeks of treatment
measure: Altered mitochondrial and fatty acid metabolism in surgical tissue specimen as compared to baseline tissue specimen.
timeFrame: Baseline and at surgery (after approximately 4 to 24 weeks of treatment)
measure: Brief Pain Inventory (BPI) scores
timeFrame: 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
measure: Functional Assessment of Cancer Therapy- Endocrine Symptoms (FACT-ES) scores
timeFrame: 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
measure: Beliefs about Medication Questionnaire (BMQ) score
timeFrame: 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
measure: Treatment Satisfaction Questionnaire for Medication (TSQM) total and domain scores for effectiveness, convenience, global satisfaction, and experience of side effects
timeFrame: Before surgery (approximately 4-24 weeks after the start of letrozole treatment), 1 year after surgery, and 3 years after surgery
measure: Endocrine Therapy adherence pre and post surgery.
timeFrame: Baseline to 4 -12 weeks
measure: Proportion of subjects who experience Clinical Response
timeFrame: 4 to12 Weeks
Other outcomes:
measure: Changes in residual cancer fatty acid.
timeFrame: Baseline to 4 -12 weeks
measure: Changes in tumor cell type
timeFrame: Baseline to 4 -12 weeks
measure: Relationship between duration of endocrine therapy and changes in tumor markers.
timeFrame: Baseline to 4 -12 weeks
Locations:
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
Study officials:
affiliation: Dartmouth-Hitchcock Medical Center
name: Mary D Chamberlin, MD
role: PRINCIPAL_INVESTIGATOR
References: