Statement: patients with a perfectly normal ejection fraction are the primary candidates for primary clinical trial and those above 55 years are excluded from secondary clinical trial
Primary_evidence: Inclusion criteria: Inclusion Criteria:   Female patients age 18 years or older   Histologically proven breast cancer after failure or relapse of no more than three lines of chemotherapy including adjuvant, irrespective of prior hormone therapy metastatic disease (stage IV);   HER2-negative patients (HER2 1+ or negative, or HER2 2+ and FISH negative)   At least one measurable tumour lesion (RECIST);   Availability of tumour samples   Written informed consent that is consistent with ICH-GCP guidelines and local law   Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 - 2. Exclusion criteria: Exclusion Criteria:   Active infectious disease   Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhoea   Serious illness, concomitant non-oncological disease or mental problems considered by the investigator to be incompatible with the protocol   Active/symptomatic brain metastases   Cardiac left ventricular function with resting ejection fraction < 50% (below upper limit of normal)   ANC less than 1500/mm3 platelet count less than 100 000/mm3   Bilirubin greater than 1.5 mg /dl (>26 and#61549 mol /L, SI unit equivalent)   AST and ALT greater than 2.5 times the upper limit of normal or greater 5 times the upper limit of normal in case of known liver metastases   Serum creatinine greater than 1.5 mg/dl (>132 and#61549 mol/L, SI unit equivalent)   Patients who are sexually active and unwilling to use a medically acceptable method of contraception   Pregnancy or breast-feeding   Concomitant treatment with other investigational drugs or other anti-cancer-therapy during this study and/or during the past two/four weeks, prior to the first treatment with the trial drug. Concurrent treatment with biphosphonates is allowed   Previous treatment with trastuzumab, EGFR-, or EGFR/HER2-inhibitors patients unable to comply with the protocol   Active alcohol or drug abuse   Other malignancy within the past 5 years
Secondary_evidence: Premenopausal women 55 years of age or younger with regular menstrual cycles (at least four cycles in the last six months). Women with fewer than 4 menses in the last 6 months or who have had a hysterectomy with ovaries intact will be considered premenopausal if FSH level < 20.   Women with breast density  25% (scattered fibroglandular densities or greater) are eligible.   Prior Treatment   Patients who are currently receiving hormone replacement therapy (estrogen or progesterone); or are taking tamoxifen or raloxifene are not eligible. Women who have taken these medications must have stopped for at least 4 months prior to study entry.   Topical estrogen (eg, transdermal patches and vaginal estrogens) is allowed.   Patients who are currently using hormonal contraception, should be taking it for at least 4 months prior to study entry.   Vitamin D Use   Patients who are taking regular vitamin D supplementation (above 400 IUs daily) and refuse or are unable to stop use are not eligible. Women who agree to stop will need to do so for at least 6 months prior to registration.   Patients may not start vitamin D supplementation after registration (regardless of results of vitamin D testing) but they may continue vitamin D if they are already taking 400 IUs daily or less and have been taking vitamin D for at least 6 months prior to baseline mammogram.   Patients with a history of breast cancer (including DCIS) or ovarian cancer are not eligible.   Patients with a history of breast implants or breast reduction are not eligible.   Patients with two or more bone fractures in the past five years are not eligible.   Patients with a diagnosis of osteoporosis with physician recommendation for treatment of low bone mass are not eligible.   Patients known to have hyperparathyroid disease or other serious disturbances of calcium metabolism requiring intervention in the past 5 years are not eligible.   Patients with a history of kidney stones (unless documented not to have been a calcium stone) are not eligible.   Patients participating in a concurrent breast cancer chemoprevention trial are not eligible.   Required initial laboratory values - Calcium < 10.5 mg/dL