The primary objective of this study is to determine if estrogen receptor-targeted therapy with fulvestrant used in combination with Everolimus is an effective and safe therapy for women with hormone receptor positive metastatic breast cancer after failure of aromatase inhibitor therapy.

Fulvestrant, which degrades ER, is used after aromatase inhibitor (AI) failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mammalian target of rapamycin (mTOR), a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis.

Inclusion Criteria:

• Postmenopausal status, defined as any one of the following criteria: Documented history of bilateral oophorectomy, Age 60 years or more, OR Age 45 to 59 and satisfying one or more of the following criteria: Amenorrhea for at least 12 months and intact uterus OR Amenorrhea for less than 12 months and a follicle stimulating hormone (FSH) concentration - within postmenopausal range including: Patients who have had a hysterectomy or Patients who have received hormone replacement
• Patients must have histologically confirmed invasive breast cancer
• Metastatic or locally advanced disease
• Patients must have estrogen receptor and/or progesterone receptor positive disease
• Measurable or evaluable disease
• Failure of aromatase inhibitor therapy within the previous 6 months. Patients who received prior tamoxifen are eligible to enroll
• Prior aromatase inhibitor therapy or other endocrine therapy must be discontinued at least 1 week prior to enrollment and any toxicity from such therapy must have reverted to grade I or less at the time of enrollment
• Patients must not have received chemotherapy, radiation therapy, or had surgery within 4 weeks prior to enrollment and any toxicity from such therapy must have recovered to grade 1 or less prior to enrollment
• Patients must not have received either of the study medications previously
• WHO performance status of 0, 1, or 2
• Adequate organ function defined as follows: Adequate renal function, defined by a serum creatinine within the upper limits of normal, Adequate liver function, defined by a bilirubin of < 1.5 the upper limit of normal (ULN) and aspartate aminotransferase (AST), alanine aminotransferase (ALT) of ≤ 2.5 times the ULN, Adequate bone marrow function, defined as an absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count (PLT) >100,000/ul, Hb >9 gm/dl, international normalized ratio (INR) <1.3, and because fulvestrant is administered intramuscularly, it should not be used in patients with bleeding diatheses, thrombocytopenia or in patients on anticoagulants
• Patients will be asked to provide a tumor paraffin block if available
• Ability to understand and sign a written informed consent for participation in the trial

Exclusion Criteria:

• Known severe hypersensitivity to everolimus (or similar drugs) or any of the excipients of this product
• Premenopausal status
• Other coexisting malignancies with the exception of basal cell carcinoma or cervical cancer in situ
• Patients with brain metastasis or leptomeningeal involvement
• Patients with malignant pleural effusion or ascites only disease
• Rapidly progressive visceral disease
• WHO performance status of 3 or 4
• As judged by the investigator, uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection, Symptomatic congestive heart failure, Unstable angina pectoris or significant cardiac arrhythmia, Psychiatric illness/social situations that would limit compliance with study requirements, Severely impaired lung function such as severe chronic obstructive pulmonary disease (COPD) or interstitial lung disease, a known forced expiratory volume at one second (FEV1) of < 1.5 liters, or dyspnea of grade III or greater, Uncontrolled diabetes as defined by a fasting blood sugar (FBS) of > 1.5 ULM, Known liver disease such as cirrhosis or chronic hepatitis, Known HIV positivity, OR known condition causing malabsorption
• Chronic treatment with systemic steroids or other immunosuppressive agents
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
• Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the clinical trial
• Prior treatment with an mTOR inhibitor
• Treatment with a non-approved or investigational drug within 30 days or 5 half-lives of the drug, whichever is greater, before Day 1 of study treatment
• In the opinion of the investigator, bleeding diathesis or anticoagulation therapy that would preclude intramuscular injections
• History of hypersensitivity to castor oil

2 were not evaluable as described in participant flow and not included in demographic table.

Potential toxicities of mammalian target of rapamycin (mTOR) inhibitors and our observation that a third of patients had no benefit from this strategy, we need to identify biomarkers that correlate with treatment benefit for better patient selection.