Study of Physiological and High Dose Estradiol in the Treatment of Hormone Receptor Positive Metastatic Breast Cancer

Inclusion Criteria

• Postmenopausal women with advanced hormone receptor positive (ER and or PgR) breast cancer, has received prior treatment with an aromatase inhibitor in the advanced disease setting, and experienced at least 24 weeks of progression free survival. As long as the patient experienced an aromatase inhibitor response as defined this way, she is still eligible even if she has received further lines of endocrine therapy, which may include other aromatase inhibitors or tamoxifen, even if these subsequent lines of treatment were unsuccessful (see below for permitted chemotherapy and trastuzumab therapy).

OR

• Postmenopausal women with systemic or unresectable local relapse after taking at least two years of adjuvant aromatase inhibitor therapy.
• Clinical diagnosis of postmenopausal status is defined as either:
• Age greater than 50 years and amenorrhea for 1 year
• Bilateral Surgical ovariectomy
• Serum FSH and estradiol level in the postmenopausal range before the initiation of AI therapy.
• If the patient was receiving an LHRH agonist to maintain a postmenopausal state during AI therapy this should be continued since recovery of menses would lead to uncontrolled estrogen exposure and pregnancy during estrogen therapy is contraindicated.
• Tumor cell expression of ER and/or PgR can be ascertained on either the primary or the metastatic site. However when both types of tissue are available, the metastatic site should be used to determine eligibility. ER and/or PgR positive are defined as at least 10% of malignant cells with positive nuclear staining.
• The patients may have received adjuvant and/or neoadjuvant chemotherapy.
• Prior radiotherapy is permitted as long as it was planned before the start of the study medication and is completed within 3 weeks of trial medication starting.
• Prior tamoxifen therapy is also permitted as adjuvant or advanced disease therapy.
• Patients with ER+ HER2+ disease are eligible even of they have received trastuzumab in the past (and even if it was administered in combination with endocrine treatment) as long as they meet all other eligibility criteria. Trastuzumab therapy must be held during estradiol treatment.
• Use of prior experimental agents alone or in combination with endocrine therapy is also permissible, but a wash out of one month is required if the immediate prior therapy involved a study medication that had not been subject to regulatory approval.
• Prior adjuvant chemotherapy is permitted as well as one line of chemotherapy for advanced disease.
• Patient must have at least one measurable lesion defined by RECIST criteria. To be considered measurable, a baseline lesion must have a minimum diameter to compensate for measurement error: 1 cm for soft tissue lesions, 1 cm for lung lesions including pleural lesions measured by CT scan, 1 cm for liver lesions measured by CT scan.
• Patients with bone only disease can also be enrolled if they meet the following criteria:
• Four or more lesions more than one cm, measurable on CT scan bone windows.
• At least one tumor marker that is elevated to at least two times the upper limit of normal.
• All patients should have a baseline bone scan with X-ray evaluation of all hot spots, CT chest abdomen and pelvis (with bone windows), and tumor marker assessment. Also CT scan of the extremities should be done on suspicious areas seen on X-ray evaluation of all hot spots if these extremity lesions are to be followed for response.
• The patient must have an ECOG performance status of 0-2
• The patient should have a life expectancy of > 6 months.
• The patient must have adequate hematologic function, defined as ANC >1000/mm3 and platelets > 75,000/mm3.
• The patient must have adequate renal function, defined as serum creatinine less than or equal to 1.5 times the upper limit of normal.
• The patient must have adequate liver function defined as serum bilirubin less than or equal to 1.5 times the upper limit of normal (three ti