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

• ClinicalTrials.gov Identifier: NCT03219476
• Recruitment Status: Active, not recruiting
• First Posted: July 17, 2017
• Results First Posted: October 18, 2022
• Last Update Posted: November 15, 2022
• Sponsor: Medical College of Wisconsin
• Information provided by (Responsible Party): Lubna Chaudhary, Medical College of Wisconsin

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Invasive Breast Cancer	Drug: Anastrozole; Drug: Letrozole; Drug: Exemestane; Drug: Tamoxifen	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive HER2-Negative Node-Negative Breast Cancer Patients to Assess Responses and Mechanisms of Endocrine Resistance
• Actual Study Start Date: February 5, 2017
• Actual Primary Completion Date: February 4, 2020
• Estimated Study Completion Date: July 1, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. [ Time Frame: At four weeks. ]
   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.

Secondary Outcome Measures :

1. Number of Subjects Who Achieve Complete Radiographic Response. [ Time Frame: At four weeks. ]

   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).
2. Number of Subjects Who Achieve a Partial Radiographic Response. [ Time Frame: At four weeks. ]

   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Cis females.
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Wisconsin

Froedtert Hospital

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Medical College of Wisconsin

Investigators

• Principal Investigator: Lubna Chaudhary; Medical College of Wisconsin

  Study Documents (Full-Text)

Documents provided by Lubna Chaudhary, Medical College of Wisconsin:

Study Protocol and Statistical Analysis Plan  [PDF] November 27, 2018

Informed Consent Form  [PDF] January 9, 2019

More Information

• Responsible Party: Lubna Chaudhary, Associate Professor, Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT03219476
• Other Study ID Numbers: PRO30178
• First Posted: July 17, 2017
• Results First Posted: October 18, 2022
• Last Update Posted: November 15, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Lubna Chaudhary, Medical College of Wisconsin:

aromatase inhibitor; breast cancer; estrogen receptor; progesterone receptor; endocrine-targeted therapy; Anti-estrogen therapy; HR+; HER2-negative; Neoadjuvant Treatment

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Tamoxifen; Letrozole; Anastrozole; Exemestane; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Bone Density Conservation Agents