Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer

Inclusion Criteria:

1. Adult women (≥ 18 years of age) with LABC or MBC not amenable to curative treatment bysurgery or radiotherapy, refractory to NSAI

2. Histological or cytological confirmation of ER+ BC and/or PgR+.

3. Postmenopausal women.

4. Radiological or objective evidence of recurrence or progression on or after the lastsystemic therapy prior to randomization

5. Patients must have:

• At least one lesion that can be accurately measured in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI

• Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurabledisease as defined above.

6. Adequate bone marrow and coagulation according RCP

7. Adequate liver function, according RCP

8. Adequate renal function, according RCP

9. ECOG Performance Status ≤ 2

10. Written informed consent

Exclusion Criteria:

1. HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situhybridization positive).

2. Patients who received chemotherapy for MBC

3. Patients who received more than one NSAI treatment for LABC or MBC

4. Pre-menopausal, pregnant, lactating women.

5. Known hypersensitivity to mTOR inhibitors

6. Patients with rare hereditary problems of galactose intolerance, Lapp lactasedeficiency or glucose galactose malabsorption.

7. Radiotherapy within four weeks prior to enrollment

8. Currently receiving hormone replacement therapy, unless discontinued prior toenrollment.

9. Patients receiving concomitant immunosuppressive agents or chronic corticosteroidsuse, at the time of study entry except in some cases

10. Patients with symptomatic visceral disease in need of urgent disease control

11. Symptomatic brain or other CNS metastases.

12. Patients with a known history of HIV seropositivity.

13. Active, bleeding diathesis, or on oral anti-vitamin K medication (except cases).

14. Any severe and / or uncontrolled medical conditions such as:

• Unstable angina pectoris, symptomatic congestive heart failure, myocardialinfarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia

• Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN

• Acute and chronic, active infectious disorders

• Impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter the absorption of the study treatments (e.g., ulcerativedisease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)

• Inability to swallow oral medications

• Significant symptomatic deterioration of lung function.

15. Hepatic-related exclusion criteria:

• History of liver disease, such as cirrhosis or chronic active hepatitis B and C.

• Presence of Hepatitis B surface antigen (HbsAg) and/or of Hepatitis B Virus -Deoxyribonucleic acid (HBV-DNA)

• Presence of anti-HCV and/or HCV-RNA-PCR

• History of, or current alcohol misuse/abuse within the past 12 months

• Patients being treated with drugs recognized as being strong inhibitors orinducers of the isoenzyme CYP3A within the last 5 days prior to enrollment.

• History of non-compliance to medical regimens.

• Patients unwilling to or unable to comply with the protocol

16. Patients being treated with drugs recognized as being strong inhibitors or inducers ofthe isoenzyme CYP3A

17. History of non-compliance to medical regimens.

18. Patients unwilling to or unable to comply with the protocol. Screening for hepatitis B Prior to enrollment, peculiar patients should be tested for hepatitis B viral load andserologic markers, that is, HBV-DNA, HBsAg, HBsAb, and HBcAb: Screening for hepatitis C Patients with any of the following risk factors for hepatitis Cshould be tested