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

Phase 2

Completed

Conditions: Breast Cancer
Invasive Breast Cancer

Interventions: Drug: Anastrozole
Drug: Letrozole
Drug: Exemestane
Drug: Tamoxifen

Registration Number: NCT03219476

Lead Sponsor: Medical College of Wisconsin

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

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 37

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Neoadjuvant endocrine therapy treatment (physician's choice)	Anastrozole	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.
Neoadjuvant endocrine therapy treatment (physician's choice)	Letrozole	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.
Neoadjuvant endocrine therapy treatment (physician's choice)	Exemestane	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.
Neoadjuvant endocrine therapy treatment (physician's choice)	Tamoxifen	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.

Primary Outcome Measures

Name	Time	Method
Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy.	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

Name	Time	Method
Number of Subjects Who Achieve Complete Radiographic Response.	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).
Number of Subjects Who Achieve a Partial Radiographic Response.	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).