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Inclusion Criteria:

1. The patient must have histologically confirmed HER2 positive invasive carcinoma of the breast in the reference laboratory of the participating center. HER2 positive criteria to be applied are those used in the participating countries:

   * Belgium: FISH amplification ratio ≥ 2 in the reference laboratory of the participating center
   * The Netherlands: IHC 3+ or FISH ratio ≥ 2 in the reference laboratory of the participating center
2. The patient must have documented progressive disease and present with at least 2 non-bone "target" metastatic lesions, unequivocally of neoplastic origin with

   * a transaxial diameter greater than 2 cm on the screening diagnostic CT/MRI for all non-bone lesions except lymphnodes
   * a short axis greater than 1,5 cm for lymphnodes on the screening diagnostic CT/MRI These two lesions should not be confluent with adjacent lesions and not have been irradiated previously.
3. A concurrent biopsy of a metastatic site is mandatory (with two formalin fixed paraffin embedded (FFPE) core sample and two snap frozen tumor sample) after progression has been documented and before inclusion and the patient agrees with the procedure.
4. Primary tumor blocks (or 11 unstained slides) available for confirmatory central laboratory HER2 testing in Institut Jules Bordet. If available, a snap frozen sample of the primary tumor will also be centralized in Institut Jules Bordet.
5. Age ≥ 18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1
7. No significant cardiac history and current LVEF ≥ 50%
8. Adequate organ function, evidenced by the following laboratory results:

   * Absolute neutrophil count \> 1,500 cells/mm3
   * Platelet count \> 100,000 cells/mm3
   * Hemoglobin \> 9 g/dL
   * AST(SGOT) and ALT (SGPT) \< 2.5 x ULN
   * Total Bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert's syndrome. Patients with known Gilbert's Syndrome should have direct bilirubin within normal limits.
   * Serum alkaline phosphatase ≤ 2.5 x ULN. Patients with bone metastases: alkaline phosphatase ≤ 5 x ULN
   * Serum creatinine \< 2.0 mg/dL or 177 μmol/L
   * International normalized ratio (INR) and activated partial thromboplastin time or partial thromboplastin time (aPTT or PTT) \< 1.5 x ULN (unless on therapeutic anti-coagulation except vitamin K antagonists which are prohibited in this study)
9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
10. For women of childbearing potential a serum pregnancy test will be done (and it must be negative) and an agreement to use a highly-effective form of contraception during all the study and at least the following 7 months will be obtained.
11. Signed written informed consent obtained prior to any study specific procedure.
12. Completion of all necessary baseline surgical, laboratory and imaging investigations prior to patient inclusion.

Exclusion Criteria:

1. Patients with bone only metastases are not eligible.
2. Diffuse liver (≥50%) involvement on imaging.
3. Patients with brain metastasis as the sole site of metastatic disease and/or are symptomatic or require therapy to control symptoms NB: Brain metastasis are allowed provided they are asymptomatic and/or controlled by previous radiotherapy. In case of recent prior brain radiotherapy, there must be evidence on MRI imaging of brain metastatic control for at least 6 weeks since the end of radiotherapy. Moreover, the patient should be at the end of corticosteroid therapy and be clinically asymptomatic.
4. Current uncontrolled hypertension despite medication intake (systolic \> 150 mmHg and/or diastolic \> 100 mmHg)
5. Current unstable angina
6. History of symptomatic CHF of any New York Heart Association (NYHA) criteria or ventricular arrhythmia that requires treatment
7. History of myocardial infarction within the last 6 months
8. History of a decrease in LVEF to \< 40% or symptomatic CHF with previous trastuzumab treatment
9. Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy
10. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures)
11. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those previously mentioned
12. Pregnant or lactating women
13. Concurrent, serious, uncontrolled infections or current known infection with HIV, active hepatitis B and/or hepatitis C.
14. Known prior severe hypersensitivity to trastuzumab
15. Patient who received lapatinib within the 15 days prior to 89Zr-Trastuzumab injection
16. Patient under a prohibited concomitant therapy, including vitamine K antagonist
17. Patients with a peripheral neuropathy Grade 3 or higher

• Antwerp, Edegem, Belgium
• Brussels, Belgium
• Amsterdam, Netherlands
• Groningen, Netherlands
• Nijmegen, Netherlands