Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Node-Negative Breast Cancer

Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive HER2-Negative Node-Negative Breast Cancer Patients to Assess Responses and Mechanisms of Endocrine Resistance

This is an exploratory interventional study that initiates standard-of-care anti-estrogen treatment preoperatively for four weeks.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Invasive Breast Cancer
• Intervention / Treatment: Drug: Anastrozole; Drug: Letrozole; Drug: Exemestane; Drug: Tamoxifen

Detailed Description

STUDY RATIONALE: Patients with hormone receptor (HR)+, HER2- node-negative breast cancers generally undergo surgical resection upfront, followed by adjuvant chemotherapy, if needed, in addition to adjuvant endocrine therapy. Because endocrine therapy is primarily delivered in the postoperative setting, the ability to assess the tumor response to this treatment modality is lost and very difficult to assess. This study offers the unique opportunity to assess the responsiveness of breast tumors to endocrine therapy while the tumors are still in vivo by treating patients with endocrine therapy before surgery and assessing molecular changes with treatment. By comparing pre- and post-treatment levels of molecular markers in individual tumors, the team expects to identify predictors of responsiveness to existing agents and identify new candidate therapeutic targets.

PRIMARY OBJECTIVE: The primary objective is to determine the frequency of increased HER family of receptor tyrosine kinases protein expression in tumors, following treatment with neoadjuvant endocrine therapy and their correlation with Ki-67 tumor responses. The team will measure cancer cell protein levels of growth factor receptors of the human epidermal growth factor receptor (HER) family before and after neoadjuvant endocrine therapy. The data will be used to inform a future randomized trial of combined endocrine and the most promising anti-HER targeted therapy.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female; age ≥18 years.
• Pathologically proven diagnosis of invasive breast cancer, clinically stage I-II.
• Clinically lymph node negative, confirmed by clinical exam and/or ultrasound imaging.
• Estrogen- and/or progesterone-receptor-positive tumor, defined ≥1% positively staining cells by immunohistochemistry, according to the current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.
• HER2/neu must be negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Pretreatment evaluations (minimum diagnostic workup) within 28 days prior to study
• Qualify for anti-endocrine treatment (per medical oncologist).
• Informed consent provided.
• If history of contralateral breast cancer, patient completed all treatment two years prior
• No treatment for this breast cancer or any malignancy within two years (except non-melanomatous skin cancer, carcinoma in situ of the cervix and contralateral breast cancer)
• Using adequate methods of contraception; negative pregnancy test.
• No strong CYP2D6 inhibitors.

• Adequate organ function with baseline lab values.

  • Absolute neutrophil count (ANC) ≥ 1500/µL.
  • Hemoglobin (Hb) ≥ 9g/dL.
  • Platelet count ≥ 100,000/µL.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x upper limit of normal (ULN).
  • Serum bilirubin within ≤ 1.5 x ULN.

Exclusion Criteria:

• American Joint Committee on Cancer (AJCC) clinical T4, N1-3 or M1, breast cancer.
• Synchronous non-breast malignancy (exceptions include non-melanomatous skin cancer, carcinoma in situ of the cervix).
• Purely noninvasive breast cancer (i.e., ductal carcinoma in situ, lobular carcinoma in situ).
• Men with breast cancer.
• Medical, psychiatric or other condition that would prevent the patient from receiving the protocol therapy or providing informed consent.
• Pregnant or lactating women.

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: Neoadjuvant endocrine therapy treatment (physician's choice); Once enrolled, patients would be treated with the current standard-of-care endocrine therapy. Choice of endocrine therapy (aromatase inhibitors or tamoxifen) would be decided by medical oncologist, following a review of the patient's medical history and menstrual status. The patient would be treated with endocrine therapy in a neoadjuvant setting for four weeks, with dosing continuing until surgery.

Drug: Anastrozole; 1 mg once daily.; Other Names: Arimidex; Drug: Letrozole; 2.5mg once daily.; Other Names: Femara; Drug: Exemestane; 25 mg once daily.; Other Names: Aromasin; Drug: Tamoxifen; 20 mg once daily.; Other Names: Soltamox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy.	ImmunoHistoChemistry (IHC) will be used. The IHC test gives a score of 0 to 3+ that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample. If the score is 0 to 1+ (up to 25% of cells stained), it's called "HER2 negative." If the score is 2+ (approximately 50% of cells stained), it's called "borderline." A score of 3+ (approximately 75% or more of cells stained) is called "HER2 positive." Upregulation means increased staining from a prior observation; Downregulation means decreased staining from a prior observation; and No Change means similar staining from a prior observation.	At four weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Who Achieve Complete Radiographic Response.	This will be assessed by World Health Organization (WHO) criteria: Complete Response (CR): The disappearance of all known disease, based on a comparison between the measurements at baseline and after four weeks of treatment with neoadjuvant therapy.; Partial Response (PR): A 50% or greater decrease in the product of the bi-dimensional measurements of the lesion (total tumor size), based on a comparison between the measurements at baseline and after four weeks of treatment with neoadjuvant therapy.; No Change (NC): A 50% decrease in total tumor size cannot be established nor has a 25% increase in the size of the lesion been demonstrated.; Progressive Disease (PD): A 25% or greater increase in the total tumor size of the measurable lesions (calculated on the smallest diameter recorded over time).	At four weeks.
Number of Subjects Who Achieve a Partial Radiographic Response.	This will be assessed by World Health Organization (WHO) criteria: Complete Response (CR): The disappearance of all known disease, based on a comparison between the measurements at baseline and after four weeks of treatment with neoadjuvant therapy.; Partial Response (PR): A 50% or greater decrease in the product of the bi-dimensional measurements of the lesion (total tumor size), based on a comparison between the measurements at baseline and after four weeks of treatment with neoadjuvant therapy.; No Change (NC): A 50% decrease in total tumor size cannot be established nor has a 25% increase in the size of the lesion been demonstrated.; Progressive Disease (PD): A 25% or greater increase in the total tumor size of the measurable lesions (calculated on the smallest diameter recorded over time).	At four weeks.

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Investigators: Principal Investigator: Lubna Chaudhary, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2017
• Primary Completion (Actual): February 4, 2020
• Study Completion (Actual): March 20, 2025

Study Registration Dates

• First Submitted: July 12, 2017
• First Submitted That Met QC Criteria: July 14, 2017
• First Posted (Actual): July 17, 2017

Study Record Updates

• Last Update Posted (Actual): April 29, 2025
• Last Update Submitted That Met QC Criteria: April 23, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: breast cancer; HR+; aromatase inhibitor; HER2-negative; estrogen receptor; Neoadjuvant Treatment; progesterone receptor; Anti-estrogen therapy; endocrine-targeted therapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Bone Density Conservation Agents; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Letrozole; Anastrozole; Tamoxifen; Exemestane
• Other Study ID Numbers: PRO30178

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: No