A Phase 2 interventional study of Letrozole in Brest Cancer ER+ and HER2 Negative, sponsored by Montefiore Medical Center. Not yet recruiting at 1 site in United States. Open to female participants aged 18 Years to 59 Years. Per ClinicalTrials.gov, last updated 2026-10-08.
Sponsored by Montefiore Medical Center · Phase 2, Interventional, and Treatment
This study is a randomized, open-label, phase II trial designed to evaluate whether alternate-day dosing of letrozole preserves antiproliferative activity compared with standard daily dosing in postmenopausal women with estrogen receptor-positive, HER2-negative breast cancer.
The objective of the study is to determine whether alternate-day dosing maintains suppression of tumor proliferation comparable to standard daily dosing. This study is designed to evaluate a dose de-escalation strategy using alternate-day letrozole dosing in patients with hormone receptor-positive breast cancer. By assessing short-term changes in Ki-67 following treatment, this study will determine whether reduced dosing maintains antiproliferative activity comparable to standard daily therapy. Demonstrating similar suppression of tumor proliferation with alternate-day dosing would provide important biological evidence that reduced-dose endocrine therapy may maintain therapeutic activity while potentially improving tolerability. Such findings could support the development of future strategies aimed at optimizing endocrine therapy dosing, improving patient adherence, and ultimately enhancing long-term outcomes for patients with hormone receptor-positive breast cancer.
In addition, this study will generate important translational data regarding the relationship between endocrine therapy dosing, systemic estrogen suppression, lipid profile panel, and tumor proliferation. By integrating tumor-based biomarkers with pharmacodynamic measurements, the study seeks to better understand whether reduced-dose aromatase inhibition can achieve similar biological effects as standard dosing. If successful, this approach could inform future clinical trials evaluating endocrine therapy optimization and may contribute to more individualized endocrine treatment strategies for patients with hormone receptor-positive breast cancer.
Montefiore Medical Center is the lead sponsor of 403 studies on the registry; 71 are open to participants now.
Of its 81 completed or terminated interventional studies of FDA-regulated products, 73 (90%) have results posted.
Counted across the registry records on this site, refreshed daily.
Tumors must be estrogen receptor-positive (ER expression ≥ 10%) and HER2 negative (IHC 0-1+, or IHC 2+ with negative FISH). Tumors can be progesterone receptor positive or negative.
Participants must be planned to undergo surgery upfront.
Age ≥18 years.
Participants must be postmenopausal female.
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
Participants must have an adequate organ and marrow function as defined below:
absolute neutrophil count ≥1,000/mcL platelets ≥100,000/mcL total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN creatinine ≤ institutional ULN
Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Participants must not have received prior therapy for current breast cancer.
Participants must be postmenopausal defined as any of the following:
Exclusion Criteria:
Participants who are candidates for neoadjuvant therapy.
Participants who are receiving any other investigation agents.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to letrozole.
Participants with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous.
Male participants at birth
History of severe osteoporosis (T score \< -4 either spine or hip), or presence of vertebral fracture.
letrozole 2.5 mg orally once daily
Drug: Letrozole
letrozole 2.5 mg orally every other day
Drug: Letrozole
This study is designed as a non-inferiority trial. Prior neoadjuvant endocrine therapy studies have demonstrated that short-term aromatase inhibitor therapy typically produces substantial reductions in tumor proliferation, with Ki-67 reductions of approximately 70-80% after several weeks of treatment.
Tumor proliferation measured by ki67
The primary endpoint is tumor proliferation measured by ki67 and will assess the log-transformed relative change in Ki-67 The mean log relative change will be compared between treatment arms using a linear regression model including treatment arm and the stratification factors.
Time frame: from baseline and up to 6 weeks of study treatment
Proportion of tumors achieving ≥50% reduction in Ki-67
The proportion of patients achieving at least a 50% reduction in Ki-67 will be summarized within each treatment group. Comparisons between groups will be performed using logistic regression models adjusting for stratification factors, and results will be reported as odds ratios with 95% confidence intervals.
Time frame: from baseline and after up to 6 weeks of therapy
Proportion of tumors with post-treatment Ki-67 ≤10%
The proportion of tumors with post-treatment Ki-67 ≤10% will be summarized within each treatment arm. Differences between groups will be evaluated using logistic regression models adjusting for stratification factors.
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in circulating hormone levels- estradiol
Serum concentrations of estradiol will be measured using ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Hormone levels will be analyzed on the logarithmic scale. The log relative change in hormone levels between baseline and on-treatment measurements will be calculated and compared between treatment arms using linear regression models adjusting for stratification factors. Results will be presented as geometric mean ratios with 95% confidence intervals.
Time frame: from baseline and up to 6 weeks of therapy
Change from baseline in circulating hormone levels- estrone
Serum concentrations of estrone will be measured using ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Hormone levels will be analyzed on the logarithmic scale. The log relative change in hormone levels between baseline and on-treatment measurements will be calculated and compared between treatment arms using linear regression models adjusting for stratification factors. Results will be presented as geometric mean ratios with 95% confidence intervals.
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in circulating hormone levels- estrone sulfate
Serum concentrations of estrone sulfate will be measured using ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Hormone levels will be analyzed on the logarithmic scale. The log relative change in hormone levels between baseline and on-treatment measurements will be calculated and compared between treatment arms using linear regression models adjusting for stratification factors. Results will be presented as geometric mean ratios with 95% confidence intervals.
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- total cholesterol
Total cholesterol will be measured using standard clinical laboratory assays. Changes in lipid parameters will be summarized descriptively and compared between treatment arms using linear regression models adjusting for baseline lipid levels and stratification factors.
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- LDL cholesterol
LDL cholesterol will be measured using standard clinical laboratory assays. Changes in lipid parameters will be summarized descriptively and compared between treatment arms using linear regression models adjusting for baseline lipid levels and stratification factors.
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- HDL cholesterol
HDL cholesterol will be measured using standard clinical laboratory assays. Changes in lipid parameters will be summarized descriptively and compared between treatment arms using linear regression models adjusting for baseline lipid levels and stratification factors.
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- triglycerides
Triglycerides will be measured using standard clinical laboratory assays. Changes in lipid parameters will be summarized descriptively and compared between treatment arms using linear regression models adjusting for baseline lipid levels and stratification factors.
Time frame: from baseline and after up to 6 weeks of therapy
Toxicity profile measured using Common Terminology Criteria for Adverse Events (CTCAE) version 6.0
Adverse events will be graded according to CTCAE v6.0. The incidence of treatment-emergent adverse events will be summarized by treatment arm and grade. Comparisons between treatment groups will be conducted using chi-square or Fisher's exact tests, as appropriate.
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline of quality of life assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) 29 survey
The PROMIS-29 assesses 7 domains with 4 questions each. There is an additional question that assesses pain intensity 0-10 on numeric rating scale. The researchers will use the two-sample t-test to compare T score in each of the 7 domains between standard dose letrozole and alternate dose letrozole groups. The researchers will also calculate change in each T score in each domain and will compare the change between standard dose letrozole and alternate dose letrozole groups using the two-sample t-test.
Time frame: from baseline and after up to 6 weeks of therapy
Change From baseline in TMEM doorway score
TMEM doorway score will be obtained before letrozole (from diagnostic core biopsy) and after 4-6 week letrozole therapy (from surgical specimen). First, the researchers will use paired t test (Wilcoxon signed rank test if normality violated) to compare the change in TMEM doorway score in the overall population and then will conduct stratified analysis by letrozole dose. We will further use the two-sample t-test (or Mann-Whitney U test if normality violated) to compare change in TMEM doorway score between standard dose letrozole and de-escalated dose letrozole.
Time frame: from baseline and after up to 6 weeks of therapy
Change in proportion of Mena isoform (MenaINV) between study arms
MenaINV will be measured in formalin-fixed paraffin embedded tissue samples using immunofluorescence. Upon completion of staining, the slides will be evaluated by pathologists to confirm the quality of the stain; and if deemed acceptable, imaged on an automated digital whole slide scanner. The average intensity of MenaINV will be then quantified across all regions of interest in each slide and defined as the MenaINV score. Change in proportion would be analyzed using chi-square test.
Time frame: from baseline and after up to 6 weeks of therapy
Change in proportion of cancer stem cells between study arms
Stem cells will be identified based on expression of SOX9, a transcription factor associated with pluripotency programs. For detecting SOX9 we will use rabbit anti-SOX9 and DAPI. Alexa Fluor-546 goat anti-rabbit will be used as a secondary antibody. Otherwise, we will use the IF staining, scanning and analysis protocol. Change in proportion would be analyzed using chi-square test
Time frame: from baseline and after up to 6 weeks of therapy
Change in dormant cancer cells between study arms
Dormant cells will be identified based on expression of NR2F1, a transcription factor associated with cell cycle arrest programs. Change in proportion would be analyzed using chi-square test.
Time frame: from baseline and after up to 6 weeks of therapy
Change in number of Circulating Tumor Cells (CTCs) between study arms
CTCs will be enumerated using the RareCyte platform a selection-free, density-based liquid biopsy system that does not rely on EpCAM capture and therefore avoids the biomarker-expression bias inherent to affinity-based methods. Change in proportion would be analyzed using chi-square test.
Time frame: from baseline and after up to 6 weeks of therapy
Change in expression of MenaINV between study arms
Slides will be stained with the RarePlex immunofluorescence panel in addition to nuclear dye, anti-CD45 and a pan-cytokeratin/EpCAM cocktail and be also stained with our custom-made chicken anti-MenaINV antibody and processed with inclusion of an additional channel in the machine-learning algorithm and then scanned on the CyteFinder automated fluorescence microscope. Change in proportion would be analyzed using chi-square test.
Time frame: from baseline and after up to 6 weeks of therapy
Change in stem markers between study arms
Slides will be stained with the RarePlex immunofluorescence panel in addition to nuclear dye, anti-CD45 and a pan-cytokeratin/EpCAM cocktail and be also stained with anti-SOX9 antibody (Millipore 3205915) and processed with inclusion of an additional channel in the machine-learning algorithm. , then scanned on the CyteFinder automated fluorescence microscope. Change in proportion would be analyzed using chi-square test.
Time frame: from baseline and after up to 6 weeks of therapy
Change in pro-inflammatory cytokines between study arms
The researchers will measure pro-inflammatory cytokines using a soluble factor multiplex bead assay. Given that the researchers are interested in the pro-dormancy response to therapy, and TGF-β2 has been implemented in induction of dormancy we will also measure the levels of TGFβ growth factors using Bio-Plex Pro TGF-β 3-plex Assay. Change in proportion would be analyzed using chi-square test.
Time frame: from baseline and after up to 6 weeks of therapy
Change in Peripheral Blood Mononuclear Cell (PMBC) profile between study arms
Using flow cytometry we will determine the changes in the PMBC levels before and after neoadjuvant treatment. Change in proportion would be analyzed using chi-square test.
Time frame: from baseline and after up to 6 weeks of therapy
Plan to share: No
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