Breast Cancer, Invasive Breast Cancer
Conditions
Keywords
aromatase inhibitor, breast cancer, estrogen receptor, progesterone receptor, endocrine-targeted therapy, Anti-estrogen therapy, HR+, HER2-negative, Neoadjuvant Treatment
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.
Interventions
DRUGAnastrozole
1 mg once daily.
DRUGLetrozole
2.5mg once daily.
DRUGExemestane
25 mg once daily.
DRUGTamoxifen
20 mg once daily.
Sponsors
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Anastrozole: 1 mg once daily.
Letrozole: 2.5mg once daily.
Exemestane: 25 mg once daily.
Tamoxifen: 20 mg once daily. | 37 |
| Total | 37 |
Baseline characteristics
| Characteristic | Neoadjuvant Endocrine Therapy Treatment (Physician's Choice) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Region of Enrollment United States | 37 participants |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 37 |
| other Total, other adverse events | 2 / 37 |
| serious Total, serious adverse events | 1 / 37 |
Outcome results
Primary
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.
Time frame: At four weeks.
Population: All 37 subjects were analyzed for each of the protein markers.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Change From Baseline in Human Epidermal Growth Factor Receptor 1 (HER1) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Upregulation | 1 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 1 (HER1) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | No Change | 36 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 1 (HER1) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Downregulation | 0 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 2 (HER2) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Upregulation | 17 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 2 (HER2) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | No Change | 18 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 2 (HER2) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Downregulation | 2 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 3 (HER3) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Downregulation | 18 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 3 (HER3) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Upregulation | 1 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 3 (HER3) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | No Change | 18 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 4 (HER4) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Upregulation | 1 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 4 (HER4) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | No Change | 18 Participants |
| Change From Baseline in Human Epidermal Growth Factor Receptor 4 (HER4) Cell Protein Levels. | Change in Baseline of Cancer Cell Protein Levels of Human Epidermal Growth Factor Receptor (HER) Family Members (HER1-4) Following Neoadjuvant Endocrine Therapy. | Downregulation | 18 Participants |
Secondary
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).
Time frame: At four weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Change From Baseline in Human Epidermal Growth Factor Receptor 1 (HER1) Cell Protein Levels. | Number of Subjects Who Achieve a Partial Radiographic Response. | 1 Participants |
Secondary
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).
Time frame: At four weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Change From Baseline in Human Epidermal Growth Factor Receptor 1 (HER1) Cell Protein Levels. | Number of Subjects Who Achieve Complete Radiographic Response. | 0 Participants |