Brest Cancer ER+ and HER2 NegativePhase 2DELTANCT07866430
De-EscaLaTion of Aromatase Inhibitor Therapy: A Randomized Phase II Study of De-escalated Letrozole in Hormone Receptor-Positive Early Breast Cancer
A Phase 2 study testing Letrozole in people with Brest Cancer ER+ and HER2 Negative, run by Montefiore Medical Center at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 59 years, women only
- Conditions the study is for
- Brest Cancer ER+ and HER2 Negative
- What is being tested?
- Letrozole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 144 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2026to Dec 2032
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 59 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Participants must have histologically confirmed breast cancer, clinical stage I-III as per the AJCC 8th edition (Anatomic Prognostic Staging).
- 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).
Show all 16Show fewer
- 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:
- Age ≥60 years
- Age <60 years with ≥12 months of spontaneous amenorrhea without chemotherapy, endocrine therapy, ovarian suppression, pregnancy, or lactation
- Prior bilateral oophorectomy
- Age <60 years with hysterectomy and laboratory values in the postmenopausal range (elevated FSH and low estradiol)
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Montefiore Medical Center
The Bronx, New York, 10461-1975
Jesus R Anampa, MD, 7184058505, janampa@montefiore.org
Akash Shah, 7184058505, ashah1@montefiore.org
About this study
Official title: De-EscaLaTion of Aromatase Inhibitor Therapy: A Randomized Phase II Study of De-escalated Letrozole in Hormone Receptor-Positive Early Breast Cancer (DELTA Trial)
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.
Read the detailed description
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.
- Conditions
- Brest Cancer ER+ and HER2 Negative
- Being tested
- Letrozole
- Keywords
- Biomarkers, Patient Reported Outcomes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LetrozoleDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm A (letrozole standard dosing) | Active comparator | letrozole 2.5 mg orally once daily Receives: Drug: Letrozole |
| Arm B (letrozole de-escalated dosing) | Experimental | letrozole 2.5 mg orally every other day Receives: Drug: Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: from baseline and up to 6 weeks of study treatment
Secondary outcomes (20)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: from baseline and after up to 6 weeks of therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Oct 2026
- Study startSep 2026 (estimated)
- Primary completionOct 2032 (estimated)
- Study completionDec 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (76)Papers the sponsor has linked to this study.
- Other trials for Brest Cancer ER+ and HER2 NegativeStudies of the same condition, open and under way.
- More trials run by Montefiore Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 144 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Montefiore Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jesus R Anampa, MD, Principal investigator, Montefiore Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07866430
- Sponsor's protocol ID
- 2026-482
- Acronym
- DELTA
- Status last verified
- Aug 2026
- First submitted
- 14 Sep 2026
- Last updated
- 8 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001 Sep 15;19(18):3808-16. doi: 10.1200/JCO.2001.19.18.3808.
PubMed 11559718Serrano D, Gandini S, Thomas P, Crew KD, Kumar NB, Vornik LA, Lee JJ, Veronesi P, Viale G, Guerrieri-Gonzaga A, Lazzeroni M, Johansson H, D'Amico M, Guasone F, Spinaci S, Bertelsen BE, Mellgren G, Bedrosian I, Weber D, Castile T, Dimond E, Heckman-Stoddard BM, Szabo E, Brown PH, DeCensi A, Bonanni B. Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2023 May 1;9(5):664-672. doi: 10.1001/jamaoncol.2023.0089.
PubMed 36951827Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, Xue EA, Cheng E, D'Alfonso TM, Jones JG, Anampa J, Rohan TE, Sparano JA, Condeelis JS, Oktay MH. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med. 2017 Jul 5;9(397):eaan0026. doi: 10.1126/scitranslmed.aan0026.
PubMed 28679654Verma C, Eremin JM, Robins A, Bennett AJ, Cowley GP, El-Sheemy MA, Jibril JA, Eremin O. Abnormal T regulatory cells (Tregs: FOXP3+, CTLA-4+), myeloid-derived suppressor cells (MDSCs: monocytic, granulocytic) and polarised T helper cell profiles (Th1, Th2, Th17) in women with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC) and surgery: failure of abolition of abnormal treg profile with treatment and correlation of treg levels with pathological response to NAC. J Transl Med. 2013 Jan 15;11:16. doi: 10.1186/1479-5876-11-16.
PubMed 23320561Lopes AD, Galdino NAL, Figueiredo AB, Brianese RC, Morais KLP, De Brot M, Osorio CABT, Teixeira-Carvalho A, Calsavara VF, Evangelista GFB, Alves NS, Makdissi FB, Sanches SM, Cordeiro de Lima VC, Carraro DM, Gollob KJ. Systemic immune mediators reflect tumour-infiltrating lymphocyte intensity and predict therapeutic response in triple-negative breast cancer. Immunology. 2023 Jun;169(2):229-241. doi: 10.1111/imm.13627. Epub 2023 Feb 20.
PubMed 36703241Miceli R, Cao C, Maolanon NN, Jacobs R, Wu J, Orlandi R. Plasma Profile of Immune Determinants Predicts Pathological Complete Response in Locally Advanced Breast Cancer Patients: A Pilot Study. Clin Breast Cancer. 2022 Oct;22(7):705-714. doi: 10.1016/j.clbc.2022.05.007. Epub 2022 May 23.
PubMed 35725806Bidard FC, Proudhon C, Pierga JY. Circulating tumor cells in breast cancer. Mol Oncol. 2016 Mar;10(3):418-30. doi: 10.1016/j.molonc.2016.01.001. Epub 2016 Jan 12.
PubMed 26809472Massague J, Obenauf AC. Metastatic colonization by circulating tumour cells. Nature. 2016 Jan 21;529(7586):298-306. doi: 10.1038/nature17038.
PubMed 26791720Dasgupta A, Lim AR, Ghajar CM. Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol. 2017 Jan;11(1):40-61. doi: 10.1002/1878-0261.12022.
PubMed 28085223Carter L, Rothwell DG, Mesquita B, Smowton C, Leong HS, Fernandez-Gutierrez F, Li Y, Burt DJ, Antonello J, Morrow CJ, Hodgkinson CL, Morris K, Priest L, Carter M, Miller C, Hughes A, Blackhall F, Dive C, Brady G. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat Med. 2017 Jan;23(1):114-119. doi: 10.1038/nm.4239. Epub 2016 Nov 21.
PubMed 27869802Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, Tejwani S, Schott AF, O'Rourke MA, Lew DL, Doyle GV, Gralow JR, Livingston RB, Hayes DF. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014 Nov 1;32(31):3483-9. doi: 10.1200/JCO.2014.56.2561. Epub 2014 Jun 2.
PubMed 24888818Kalinich M, Bhan I, Kwan TT, Miyamoto DT, Javaid S, LiCausi JA, Milner JD, Hong X, Goyal L, Sil S, Choz M, Ho U, Kapur R, Muzikansky A, Zhang H, Weitz DA, Sequist LV, Ryan DP, Chung RT, Zhu AX, Isselbacher KJ, Ting DT, Toner M, Maheswaran S, Haber DA. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1123-1128. doi: 10.1073/pnas.1617032114. Epub 2017 Jan 17.
PubMed 28096363Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA, Fehm T, Schneeweiss A, Lichtenegger W, Beckmann MW, Friese K, Pantel K, Janni W; SUCCESS Study Group. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014 May 15;106(5):dju066. doi: 10.1093/jnci/dju066.
PubMed 24832787Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010 Jun;17(6):1471-4. doi: 10.1245/s10434-010-0985-4.
PubMed 20180029Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4218-24. doi: 10.1158/1078-0432.CCR-05-2821.
PubMed 16857794
Study at a glance
From the registry record, last updated by the sponsor on 8 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- De-EscaLaTion of Aromatase Inhibitor Therapy: A Randomized Phase II Study of De-escalated Letrozole in Hormone Receptor-Positive Early Breast Cancer (DELTA Trial)
- ClinicalTrials.gov ID
- NCT07866430
- Acronym / sponsor ID
- DELTA / 2026-482
- Conditions
- Brest Cancer ER+ and HER2 Negative
- Keywords
- Biomarkers, Patient Reported Outcomes
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 144 participants (estimated)
- Lead sponsor
- Montefiore Medical CenterUniversity, hospital or other
- Study start
- Sep 2026 (estimated)
- Primary completion
- Oct 2032 (estimated)
- Study completion
- Dec 2032 (estimated)
- First posted
- 8 Oct 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A (letrozole standard dosing) | Active comparator | Drug: Letrozoleletrozole 2.5 mg orally once daily |
| Arm B (letrozole de-escalated dosing) | Experimental | Drug: Letrozoleletrozole 2.5 mg orally every other day |
Who may qualify
- Ages
- 18 to 59 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (16 listed)
- Participants must have histologically confirmed breast cancer, clinical stage I-III as per the AJCC 8th edition (Anatomic Prognostic Staging).
- 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.
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LetrozoleThis 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. | Drug | Arm A (letrozole standard dosing), Arm B (letrozole de-escalated dosing) |
Primary outcome
Tumor proliferation measured by ki67
Time frame: from baseline and up to 6 weeks of study treatment
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.
20 secondary outcomes
Proportion of tumors achieving ≥50% reduction in Ki-67
Time frame: from baseline and after up to 6 weeks of therapy
Proportion of tumors with post-treatment Ki-67 ≤10%
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in circulating hormone levels- estradiol
Time frame: from baseline and up to 6 weeks of therapy
Change from baseline in circulating hormone levels- estrone
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in circulating hormone levels- estrone sulfate
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- total cholesterol
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- LDL cholesterol
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- HDL cholesterol
Time frame: from baseline and after up to 6 weeks of therapy
Change from baseline in lipid profile parameters- triglycerides
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
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
Time frame: from baseline and after up to 6 weeks of therapy
Change From baseline in TMEM doorway score
Time frame: from baseline and after up to 6 weeks of therapy
Change in proportion of Mena isoform (MenaINV) between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Change in proportion of cancer stem cells between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Change in dormant cancer cells between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Change in number of Circulating Tumor Cells (CTCs) between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Change in expression of MenaINV between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Change in stem markers between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Change in pro-inflammatory cytokines between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Change in Peripheral Blood Mononuclear Cell (PMBC) profile between study arms
Time frame: from baseline and after up to 6 weeks of therapy
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Oct 2026.
- Background: PubMed 11559718Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001 Sep 15;19(18):3808-16. doi: 10.1200/JCO.2001.19.18.3808.
- Background: PubMed 36951827Serrano D, Gandini S, Thomas P, Crew KD, Kumar NB, Vornik LA, Lee JJ, Veronesi P, Viale G, Guerrieri-Gonzaga A, Lazzeroni M, Johansson H, D'Amico M, Guasone F, Spinaci S, Bertelsen BE, Mellgren G, Bedrosian I, Weber D, Castile T, Dimond E, Heckman-Stoddard BM, Szabo E, Brown PH, DeCensi A, Bonanni B. Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2023 May 1;9(5):664-672. doi: 10.1001/jamaoncol.2023.0089.
- Background: PubMed 28679654Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, Xue EA, Cheng E, D'Alfonso TM, Jones JG, Anampa J, Rohan TE, Sparano JA, Condeelis JS, Oktay MH. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med. 2017 Jul 5;9(397):eaan0026. doi: 10.1126/scitranslmed.aan0026.
- Background: PubMed 23320561Verma C, Eremin JM, Robins A, Bennett AJ, Cowley GP, El-Sheemy MA, Jibril JA, Eremin O. Abnormal T regulatory cells (Tregs: FOXP3+, CTLA-4+), myeloid-derived suppressor cells (MDSCs: monocytic, granulocytic) and polarised T helper cell profiles (Th1, Th2, Th17) in women with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC) and surgery: failure of abolition of abnormal treg profile with treatment and correlation of treg levels with pathological response to NAC. J Transl Med. 2013 Jan 15;11:16. doi: 10.1186/1479-5876-11-16.
- Background: PubMed 36703241Lopes AD, Galdino NAL, Figueiredo AB, Brianese RC, Morais KLP, De Brot M, Osorio CABT, Teixeira-Carvalho A, Calsavara VF, Evangelista GFB, Alves NS, Makdissi FB, Sanches SM, Cordeiro de Lima VC, Carraro DM, Gollob KJ. Systemic immune mediators reflect tumour-infiltrating lymphocyte intensity and predict therapeutic response in triple-negative breast cancer. Immunology. 2023 Jun;169(2):229-241. doi: 10.1111/imm.13627. Epub 2023 Feb 20.
- Background: PubMed 35725806Miceli R, Cao C, Maolanon NN, Jacobs R, Wu J, Orlandi R. Plasma Profile of Immune Determinants Predicts Pathological Complete Response in Locally Advanced Breast Cancer Patients: A Pilot Study. Clin Breast Cancer. 2022 Oct;22(7):705-714. doi: 10.1016/j.clbc.2022.05.007. Epub 2022 May 23.
- Background: PubMed 26809472Bidard FC, Proudhon C, Pierga JY. Circulating tumor cells in breast cancer. Mol Oncol. 2016 Mar;10(3):418-30. doi: 10.1016/j.molonc.2016.01.001. Epub 2016 Jan 12.
- Background: PubMed 26791720Massague J, Obenauf AC. Metastatic colonization by circulating tumour cells. Nature. 2016 Jan 21;529(7586):298-306. doi: 10.1038/nature17038.
- Background: PubMed 28085223Dasgupta A, Lim AR, Ghajar CM. Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol. 2017 Jan;11(1):40-61. doi: 10.1002/1878-0261.12022.
- Background: PubMed 27869802Carter L, Rothwell DG, Mesquita B, Smowton C, Leong HS, Fernandez-Gutierrez F, Li Y, Burt DJ, Antonello J, Morrow CJ, Hodgkinson CL, Morris K, Priest L, Carter M, Miller C, Hughes A, Blackhall F, Dive C, Brady G. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat Med. 2017 Jan;23(1):114-119. doi: 10.1038/nm.4239. Epub 2016 Nov 21.
- Background: PubMed 24888818Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, Tejwani S, Schott AF, O'Rourke MA, Lew DL, Doyle GV, Gralow JR, Livingston RB, Hayes DF. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014 Nov 1;32(31):3483-9. doi: 10.1200/JCO.2014.56.2561. Epub 2014 Jun 2.
- Background: PubMed 28096363Kalinich M, Bhan I, Kwan TT, Miyamoto DT, Javaid S, LiCausi JA, Milner JD, Hong X, Goyal L, Sil S, Choz M, Ho U, Kapur R, Muzikansky A, Zhang H, Weitz DA, Sequist LV, Ryan DP, Chung RT, Zhu AX, Isselbacher KJ, Ting DT, Toner M, Maheswaran S, Haber DA. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1123-1128. doi: 10.1073/pnas.1617032114. Epub 2017 Jan 17.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Jesus R Anampa, MD principal investigator
Montefiore Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Letrozole in people with Brest Cancer ER+ and HER2 Negative, run by Montefiore Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 8 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jesus Anampa, MD (7184058505, janampa@montefiore.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tumor proliferation measured by ki67 (time frame: from baseline and up to 6 weeks of study treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07866430, which also lists 76 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Oct 2026.