Endocrine Response in Women With Invasive Lobular Breast Cancer
Endocrine Response in Women With Invasive Lobular Breast Cancer
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).
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.
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 will be highly encouraged to
 undergo a baseline research core biopsy of their breast tumor. If this is not possible
 or the patient refuses, the pre-treatment tumor sample must be obtained from their
 archival diagnostic core biopsy. If definitive surgery is not performed at day 21-27
 after study treatment, a second post-treatment research core biopsy will need to be
 obtained from their breast tumor. For patients undergoing surgery, the second biopsy
 will be removed from the breast tumor tissue excised during their operation. Note: In
 the event that the baseline breast tumor biopsy performed for research purposes does
 not yield adequate tumor tissue for analysis of the primary and secondary endpoints,
 tissue will be requested from the patient's archival clinical diagnostic core biopsy
 if it is available.The patient will still remain on study and complete protocol
 therapy as planned in this unlikely event.

 -  Hormone receptor (HR) status of the invasive component must be documented before trial
 enrollment. The tumor must be HR-positive. HR will be considered positive if staining
 is 1% or greater for ER and/or PR. 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. HER2 status will
 be determined locally only, based upon current ASCO/CAP guidelines.

 -  Patients must be female.

 -  Participants must be fully postmenopausal.

 -  ECOG performance status of 0, 1 or 2.

 -  Adequate organ and marrow function as defined by a history and physical exam that
 rules out comorbidities that would be exclusions to participation in the study (see
 exclusion criteria) and clinical laboratory parameters as deemed clinically
 appropriate by the treating physician.

 -  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 study
 enrollment. Vaginal preparations (e.g., Vagifem® or Estring®)

 -  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 or a known history of liver disease, especially
 moderate (Child-Pugh Class B) to severe (Child-Pugh Class C) hepatic impairment.

 -  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.

 -  Increased Risk of bleeding: including a history of a bleeding diathesis and/or known
 history of severe thrombocytopenia. NOTE: Anticoagulant use is not a contraindication
 to fulvestrant, but caution is advised in administration in patients on
 anticoagulation. Patients on anticoagulation who will receive fulvestrant will have PT
 and aPTT/INR assessed at baseline.