Purpose

RATIONALE: Currently, adjuvant endocrine therapy often follows a "one-size-fits- all" approach, with most premenopausal women receiving tamoxifen, and most postmenopausal receiving aromatase inhibitor therapy. In current clinical practice, patients with invasive lobular carcinoma are treated no differently than patients with invasive ductal carcinoma based on the void of information specific to patients with this tumor type. Identification of a biological signal of tamoxifen and/or AI-resistance and/or fulvestrant-sensitivity in ILC patients would have dramatic implications for the future management of this breast cancer subtype. PURPOSE: To study whether fulvestrant is more effective than anastrozole or tamoxifen in reducing Ki67 in ILC and whether that Ki67 reduction will correlate with alterations in expression of ER and ER-regulated genes. Differential Ki67 effect in this study will serve as a surrogate for outcome of ILC patients on endocrine therapy. Primary Objective: To determine the change from baseline to post-treatment Ki67 values in ER-positive, HER2-negative ILC tissue derived from postmenopausal women awaiting definitive surgery or further neoadjuvant treatment who are randomized to 21-24 days of neoadjuvant endocrine treatments with fulvestrant (two 250 mg IM injections given on day 1), anastrozole (1mg given orally daily), or tamoxifen (20mg given orally daily).

Condition

Eligibility

Eligible Ages
All ages
Eligible Genders
Female
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Histologically confirmed invasive lobular breast cancer that is hormone receptor-positive and HER2-negative, measuring at least 1 centimeter (cm) radiographically or clinically, clinical stages I-III. Invasive lobular histology will be diagnosed at the enrolling institution for purposes of study participation. Subsequently, invasive lobular histology will be confirmed by central pathology review, but this central review will not be required prior to patient enrollment.
  • Prior to initiation of study agents, study participants must agree to both a baseline research core biopsy, and if definitive surgery is not performed at day 21-24 after treatment, a second post-treatment research core biopsy. For patients undergoing surgery, the second biopsy will be removed from tissue excised during their operation.
  • Hormone receptor (HR) status of the invasive component must be documented on the diagnostic core biopsy before trial enrollment. The tumor must be ER-positive. ER will be considered positive if staining is 1% or greater. This will be determined at the enrolling institution for purposes of study participation and enrollment onto the trial. Subsequently, HR status will be confirmed by central pathology review, but this central review will not be required prior to enrolling the patient.
  • Patients must be female
  • Participants must be fully postmenopausal
  • ECOG performance status of 0, 1 or 2
  • Adequate organ and marrow function as defined below:
  • leukocytes >3,000/mm3
  • absolute neutrophil count >1,500/mm3
  • platelets >100,000/mm3
  • total bilirubin within normal laboratory limits
  • AST(SGOT)/ALT(SGPT) ≤2.5 times the laboratory upper limit of normal
  • Creatinine ≤1.5 times the upper limit of normal
  • Prior use of hormone contraceptives and replacement therapy is allowed (e.g., estrogen and/or progestin), but must have been discontinued at least 30 days prior to the diagnostic biopsy. Vaginal preparations (e.g., Vagifem® or Estring®) are allowed.
  • Participant must be aware of the nature of her malignancy, understand the study requirements and risks and be able and willing to sign a written informed consent document.

Exclusion Criteria

  • Prior or concurrent use of hormonal therapy, chemotherapy, radiation therapy, or novel therapy to treat the current breast cancer, including any history of prior irradiation to the ipsilateral breast. Additionally, the patient must not have had hormonal therapy for breast cancer treatment or for breast cancer prevention within 2 years prior to study enrollment. (Note: Synchronous breast, cancer (including bilateral breast cancer) at separate sites is permissible, provided the patient does not receive medical treatments for breast cancer or radiation therapy to the ipsilateral breast during the 21 day study intervention period.
  • Concurrent use of any other investigational agents.
  • History of allergic reactions/hypersensitivity attributed to compounds of similar chemical or biologic composition to tamoxifen, anastrozole, or fulvestrant or any of their ingredients.
  • History of thromboembolic disease or uterine cancer that is considered a contraindication to tamoxifen.
  • Active hepatitis viral infections.
  • Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • HER-2 positivity.

Study Design

Phase
N/A
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
tamoxifen
Tamoxifen is administered orally, at a dose of 20 mg,daily, for 21 days
  • Drug: Tamoxifen
Active Comparator
Anastrozole
1mg given orally daily for 21 days
  • Drug: Anastrozole
Active Comparator
fulvestrant
500 mg, administered as two 250 mg IM injections, given on days 1 and 14
  • Drug: Fulvestrant

Recruiting Locations

ALBERT EINSTEIN COLLEGE OF MEDICINE Montefiore Medical Center
Bronx, New York 10467
Contact:
Joseph Sparano, MD
718-405-8404
JSPARANO@montefiore.org

More Details

NCT ID
NCT02206984
Status
Recruiting
Sponsor
Rachel Jankowitz

Study Contact

Brenda L Steele, BSN, RN
412-641-3418
Steebx@upmc.edu

Detailed Description

OBJECTIVES

Primary

To determine the change from baseline to post-treatment Ki67 values in ER-positive, HER2-negative ILC tissue derived from postmenopausal women awaiting definitive surgery or further neoadjuvant treatment who are randomized to 21-24 days of neoadjuvant endocrine treatments with fulvestrant (two 250 mg IM injections given on day 1), anastrozole (1mg given orally daily), or tamoxifen (20mg given orally daily).

Secondary

- To evaluate ER protein expression in ILC tissues at baseline and following neoadjuvant endocrine therapy.

- To evaluate PR protein expression in ILC tissues at baseline and following neo-adjuvant endocrine therapy.

- To evaluate ER-related and ILC-specific candidate gene mRNA expression in ILC tissues at baseline and following neoadjuvant endocrine therapy in an effort to identify biomarkers of endocrine response and putative drivers of endocrine resistance in ILC.

- To evaluate associations between changes in Ki67 in ILC tissues following neoadjuvant endocrine therapy with ER and PR protein expression, or ER and candidate gene mRNA expression at baseline and post-treatment.

Exploratory

- To evaluate DNA methylation in ILC tissues at baseline and following neo-adjuvant endocrine therapy.

- To evaluate associations between germline and somatic DNA sequence variants with changes in Ki67 in ILC tissues following neo-adjuvant endocrine therapy.

- To evaluate the activity of signaling pathways in ILC tissues by immunohistochemical or other protein analyses, such as histone modifications, at baseline and following neo-adjuvant endocrine therapy.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.