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).
- To evaluate ER protein expression in ILC tissues at baseline and following neoadjuvant
- To evaluate PR protein expression in ILC tissues at baseline and following neo-adjuvant
- 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.
- To evaluate DNA methylation in ILC tissues at baseline and following neo-adjuvant
- 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.
- 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
- 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
- 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
- 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.