Assessment of Safety and Efficacy of Estetrol in Postmenopausal Women With Advanced Estrogen Receptor Positive (ER+) Breast Cancer

Inclusion Criteria:

* Postmenopausal women with ER-positive and HER2-negative locally advanced and/or metastatic breast cancer, who progressed on standard therapies or for whom standard therapies are intolerant;
* Patients should have experienced a natural or surgical menopause at least 5 years ago;
* Failure of anti-estrogen treatment with tamoxifen and aromatase inhibitor(s) due to the development of resistance or unacceptable side effects with this treatment;
* No undiagnosed vaginal bleeding;
* No treatment with fulvestrant within 6 months of start of treatment;
* Life expectancy at least 6 months;
* Tumour assessment (CT scan) before the start of the E4 treatment;
* Body mass index (BMI) between (≥) 18 and (≤) 35 kg/m2;
* Able to swallow an oral medication;
* Acceptable values of hematological parameters, liver and kidney function and calcium levels;
* Acceptable values of hemostasis parameters (as of second cohort);
* Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-2 (as of second cohort);
* Reasonable physical and mental health as judged by the investigator and determined by physical examination, clinical laboratory assessments and vital signs;
* Willing to give informed consent in writing.

Exclusion Criteria:

* Uncontrolled nausea, vomiting, or diarrhea;
* History of venous or arterial thromboembolic disease or a known defect in the blood coagulation system;
* History of severe cardiac events or life threatening cardiac dysrhythmia (as of second cohort);
* Patients who have unstable angina or clinical congestive heart failure (as of second cohort);
* Uncontrolled hypertension, i.e. systolic blood pressure 160 mmHg and/or diastolic blood pressure 100 mmHg in the last 6 months with or without medication;
* Diabetes mellitus with poor glycaemic control in the last 6 months (HbA1c above 7.5%);
* Any other serious disease including systemic lupus erythematosus and untreated cholelithiasis;
* Smoking \>10 cigarettes/day;
* Use of any other cancer therapy including radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy, or use of other investigational agents at the start of treatment.