Elderly Metastatic Breast Cancer: Pertuzumab-Herceptin vs Pertuzumab-Herceptin-Metronomic Chemotherapy, Followed by T-DM1

• Overall survival [ Designated as safety issue: No ]
• Breast cancer specific survival [ Designated as safety issue: No ]
• Tumor response rate as measured by RECIST v1.1 [ Designated as safety issue: No ]
• Evolution of HRQoL as assessed by EORTC QLQ-C30 and ELD 15 [ Time Frame: Up to 1 year after treatment start ] [ Designated as safety issue: No ]
• Evolution of geriatric assessment [ Time Frame: Up to 1 year after treatment start ] [ Designated as safety issue: No ]
• if T-DM1: progression free survival rate [ Time Frame: 6 months after start of T-DM1 treatment ] [ Designated as safety issue: No ]

Chemotherapy and HER2 targeted agents can improve survival significantly in metastatic breast cancer. Chemotherapy however is associated with significant side-effects and can impact on Quality of Life and functionality in older patients.

The investigators aim to establish HER2 targeted regimens with minimal toxicity in order to delay or even avoid the use of classical chemotherapy because of competing risks of death in this frail/elderly patient group.

• Drug: Pertuzumab + trastuzumab

  Trastuzumab: loading dose of 8 mg/kg of body weight on cycle 1, followed by a maintenance dose of 6 mg/kg every 3 weeks.

  Pertuzumab: loading dose of 840 mg on cycle 1, followed by 420 mg for subsequent cycles, every 3 weeks.

  if T-DM1: 3.6 mg/kg IV, every 3 weeks.

• Drug: Pertuzumab + trastuzumab + metronomic chemotherapy
  Pertuzumab and trastuzumab will be administered as in arm A. Cyclophosphamide: daily dose of 50 mg/day. if T-DM1: as in arm A

• Active Comparator: Pertuzumab + trastuzumab (PH)
  Pertuzumab + trastuzumab. After progression,patients will be given the option of receiving T-DM1
  Intervention: Drug: Pertuzumab + trastuzumab
• Experimental: PH + metronomic chemotherapy (PHM)
  Pertuzumab + trastuzumab + metronomic chemotherapy. After progression,patients will be given the option of receiving T-DM1
  Intervention: Drug: Pertuzumab + trastuzumab + metronomic chemotherapy

Inclusion Criteria:

• Female patients with histologically proven HER-2 positive
• Newly diagnosed or recurrent (after surgery) stage IV disease (TNM/AJCC v.7).
• Patients must have measurable (RECIST v. 1.1) or evaluable disease
• Performance status (PS) 0-3 (WHO)
• Age ≥ 70 years of age, or ≥ 60 years old with required number of dependencies
• Life expectancy of more than 12 weeks
• Previous adjuvant chemotherapy/anti HER-2 therapy after surgery is allowed, given that the time interval from end of previous treatment to initiation of treatment for metastatic disease is ≥ 6 months.
• Up to one line of anti-HER therapy (trastuzumab or lapatinib) is allowed in combination with hormone therapy for hormone sensitive metastatic breast cancer.
• Adequate organ function
• Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

• No brain metastases that are untreated, symptomatic, or require steroids to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastases within 2 months prior to the first study treatment.
• No prior chemotherapy for metastatic disease is allowed
• No prior treatment with pertuzumab is allowed
• No history of exposure to the following cumulative doses of anthracyclines:
• Doxorubicin or liposomal doxorubicin > 360 mg/m2
• Epirubicin > 720 mg/m2
• Mitoxantrone > 120 mg/m2
• Idarubicin > 90 mg/m2
• If another anthracycline or more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
• No history of palliative radiotherapy within 14 days of randomization
• No history of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin
• No current uncontrolled hypertension (persistent systolic > 180 mmHg and/or diastolic > 100 mmHg)
• No LVEF below 50%
• No history of significant cardiac disease defined as:
• Symptomatic CHF (NYHA classes II-IV)
• High-risk uncontrolled arrhythmias
• History of myocardial infarction within 6 months prior to randomization
• Clinically significant valvular heart disease
• No angina pectoris requiring anti-angina treatment
• No peripheral neuropathy of Grade ≥ 3 per NCI CTCAE version 4.0.
• No current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures, known infection with HIV, active hepatitis B and/or hepatitis C virus)
• No major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
• No history of receiving any investigational treatment within 28 days of randomization
• No history of intolerance (including Grade 3-4 infusion reaction) to trastuzumab
• No unwillingness or inability to comply with the requirements of the protocol as assessed by the investigator
• 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