This early phase I trial tests whether letrozole with simvastatin works better than letrozole alone to stop tumor cell proliferation in patients with stage I-III hormone receptor positive, HER2 negative invasive breast cancer. Letrozole and simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. The addition of simvastatin to letrozole may be more effective at stopping the growth of cancer cells than letrozole alone.
PRIMARY OBJECTIVE: I. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in a decrease of Ki67, a biomarker of tumor proliferation, in postmenopausal women with stage I-III, hormone receptor positive, HER2 negative breast cancer following 14 days of pre-surgical therapy. SECONDARY OBJECTIVES: I. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased immune activation from pre- to post-treatment, based on the evaluation of the immune subtype composition in the tissue via multiplex immunofluorescence. II. To determine if changes (from pre- to post-treatment) in immune activation correlate with changes in antiproliferative response, based on Ki-67 (from pre- to post-treatment). III. To identify an association between response defined per percent change in Ki-67 and the percentage of tissue immune biomarkers CD8 and FOXp3. IV. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased pain based on Patient-Reported Outcomes Measurement Information System (PROMIS) from pre- to post-treatment. V. To describe the safety and tolerability of letrozole +/- simvastatin in the pre-surgical setting. EXPLORATORY OBJECTIVES: I. In both arms of the trial, assess the levels of blood-based biomarkers (CRP, IL-6, IL-10, TGF-beta, and TNF-alpha) in pre- and post-treatment blood samples. Ia. Determine if changes (from pre- to post-treatment) in the levels of these blood-based biomarkers correlate with changes in antiproliferative response, based on Ki67 (from pre- to post-treatment). Ib. Determine if changes (from pre- to post-treatment) in the levels of these blood-based biomarkers correlate with changes in immune activation, based on the evaluation of the immune subtype composition in the tissue via multiplex immunofluorescence (from pre- to post-treatment). II. In both arms of the trial, assess fasting total cholesterol levels in pre- and post-treatment blood samples to determine if there is a correlation with changes in antiproliferative response, based on Ki67 (from pre- to post-treatment). III. In both arms of the trial, assess HMG-CoA Reductase immunohistochemistry (IHC) expression in pre- and post-treatment tumor tissue to determine if there is a correlation with changes in antiproliferative response, based on Ki67 (from pre- to post-treatment). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive letrozole orally (PO) once daily (QD) and simvastatin PO QD for 14 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive letrozole PO QD for 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 30 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
40
Given PO
Given PO
Grady Healthcare System
Atlanta, Georgia, United States
RECRUITINGEmory University Hospital Midtown
Atlanta, Georgia, United States
RECRUITINGEmory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
RECRUITINGEmory Saint Joseph's Hospital
Atlanta, Georgia, United States
RECRUITINGMean percentage change in Ki-67
Negative change denotes reduction. Ki-67 is a validated surrogate marker for disease-free survival in patients with hormone receptor positive (HR+), HER2- breast cancer. Ki-67 values at 14 days are expressed as geometric mean proportions of the baseline and transformed into percentage change. Geometric mean percentage change of Ki-67 from pre- to post-treatment is calculated and compared between the two treatment arms. A two-sided Mann-Whitney U or Wilcoxon Rank-Sum test is used.
Time frame: From pre-surgical baseline to 14 days following preoperative therapy
Response per Ki-67
Responders are defined as those with \>= 40% pre- to post-treatment decrease in Ki-67, and non-responders are those with \< 40% decrease in Ki-67. Descriptive statistics (mean, standard deviation, median, min, max) are applied to biomarkers of interest at 2 designated time points, prior to preoperative therapy (utilizing archival tissue from baseline biopsy) and following completion of 14 days of preoperative therapy. Absolute change or percentage change of biomarkers is calculated and compared between the two treatment arms using the nonparametric Mann-Whitney U test. Correlation among biomarkers is described by Pearson correlation coefficient with 95% confidence interval. The p-value is adjusted by Benjamini-Hochberg procedure to control the false discovery rate.
Time frame: Through study completion, an average of 1 year
Change in the level of the following immune biomarkers: Percentage of CD8+ T cells, percentage of FOXp3 Treg cells, ratio of CD8+/Treg ratio
Based on multiplex immunofluorescence. Descriptive statistics (mean, standard deviation, median, min, max) are applied to biomarkers of interest at 2 designated time points, prior to preoperative therapy (utilizing archival tissue from baseline biopsy) and following completion of 14 days of preoperative therapy. Absolute change or percentage change of biomarkers is calculated and compared between the two treatment arms using the nonparametric Mann-Whitney U test. Correlation among biomarkers is described by Pearson correlation coefficient with 95% confidence interval. The p-value is adjusted by Benjamini-Hochberg procedure to control the false discovery rate.
Time frame: Through study completion, an average of 1 year
Patient-Reported Outcomes Measurement Information System (PROMIS) for pain
Time frame: Up to 30 days after surgery
Incidence of adverse events
Evaluated per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 criteria. Adverse events are summarized descriptively using frequencies and percentages of all captured toxicities and grades using CTCAE v.5 criteria.
Time frame: Up to 30 days after surgery
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.