Breast Cancer
Conditions
Brief summary
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).
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.
Interventions
DRUGTamoxifen
DRUGAnastrozole
DRUGFulvestrant
Sponsors
Priscilla McAuliffe
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Log-transformed Ki67 Proliferative Index | Baseline, Day 21-27 | Ki67 expression is a routine pathologic marker that is strongly associated with cell proliferation. It is extensively used as a prognostic and predictive marker in cancer. Ki67 was calculated as a percentage of 1000 tumor cells counted in both the pre- and post-treatment specimens. The primary endpoint was change in log-transformed Ki67 at post-treatment compared to baseline. We used fixed paired differences with mean (SD) log (post/pre). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pre-treatment Ki67 Proliferative Index | Baseline | Ki67 expression is a routine pathologic marker that is strongly associated with cell proliferation. It is extensively used as a prognostic and predictive marker in cancer. Ki67 was calculated as a percentage of 1000 tumor cells counted in both the pre- and post-treatment specimens. |
| Post-treatment Ki67 Proliferative Index | Day 21-27 | Ki67 expression is a routine pathologic marker that is strongly associated with cell proliferation. It is extensively used as a prognostic and predictive marker in cancer. Ki67 was calculated as a percentage of 1000 tumor cells counted in both the pre- and post-treatment specimens. |
| Pre-treatment Estrogen Receptor H Score | Baseline | Estrogen receptor (ER) Histologic (H) Score is calculated as the sum of intensity of staining (0 to 3+) multiplied by the proportion (%) of cells staining positive and has a dynamic range of 0 to 300. ER H score pre-treatment was determined for each of the three treatment groups. |
| Post-treatment Estrogen Receptor (ER) H Score | Day 21-27 | Estrogen receptor (ER) Histologic (H) Score is calculated as the sum of intensity of staining (0 to 3+) multiplied by the proportion (%) of cells staining positive and has a dynamic range of 0 to 300. ER H score was determined in each of the three post treatment groups. |
| Pre-treatment Progesterone Receptor (PR) H Score | Baseline | Progesterone receptor (PR) Histologic (H) Score is calculated as the sum of intensity of staining (0 to 3+) multiplied by the proportion (%) of cells staining positive and has a dynamic range of 0 to 300. PR H Score was determined at baseline. |
| Post-treatment Progesterone Receptor (PR) H Score | Day 21-27 | Progesterone receptor (PR) Histologic (H) Score is calculated as the sum of intensity of staining (0 to 3+) multiplied by the proportion (%) of cells staining positive and has a dynamic range of 0 to 300. PR H score was determined post treatment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORPriscilla McAuliffe, MD
UPMC Magee Womens Hopspital
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 66.82 years STANDARD_DEVIATION 8.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 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 | 2 Participants |
| Race (NIH/OMB) White | 169 Participants |
| Sex: Female, Male Female | 201 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 66 | 0 / 73 |
| other Total, other adverse events | 2 / 62 | 3 / 66 | 5 / 73 |
| serious Total, serious adverse events | 0 / 62 | 1 / 66 | 0 / 73 |
Outcome results
None listed