Studieoverzicht - 2012-03 TRAIN-2

R: chemotherapy randomization for all eligble patients

FEC-T cycle of 3 weeks
F = 5-fluorouracil 500 mg/m²; E = epirubicin 90 mg/m²; C = cyclophosphamide 500 mg/m²; T = trastuzumab 6 mg/kg (loading dose 8 mg/kg)

PTC cycle of 3 weeks, day 1 PTC, day 8 only P
P = paclitaxel 80 mg/m²; T = trastuzumab 6 mg/kg (loading dose 8 mg/kg); C = carboplatin AUC = 6 mg.min/ml
Pertuzumab (Ptz) cycle of 3 weeks, 420 mg (loading dose 840 mg)

* Local treatment of breast (and axilla if necessary) with evaluation of pathologic response

Post-surgery all patients will receive trastuzumab as per local standard of care, as well as endocrine treatment (only for ER positive patients), additional surgery, and/or radiotherapy as required. Post-surgery, different forms of trastuzumab, including subcutaneous trastuzumab are allowed.

Primary objectives 

1. To compare the efficacy of six cycles neoadjuvant PTC plus pertuzumab preceded by either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus pertuzumab in HER2 positive breast cancer

Secondary objectives

1. To describe the safety of the various regimens

2. To identify prognostic and predictive biomarkers for pCR after neoadjuvant treatment

Primary endpoint

The primary endpoint is pathologic complete response (pCR) rate at surgery.

Secondary endpoints

- Recurrence-free, distant metastasis-free, breast cancer specific, and overall survival (time from randomization to event)

- Percentage of conservative surgeries carried out

- Percentage of patients with grade >2 toxicity (CTCAE v4.03)

1.    Histologically confirmed infiltrating breast cancer
2.    Stage II or stage III disease. Nodal status must be examined by ultrasound, fine needle
       aspiration, sentinel node biopsy, or FDG-PET scan.
3.    Overexpression and/or amplification of HER2 in an invasive component of the core biopsy, according
       to one of the following definitions:

• >30%
  of invasive tumor cells showing strong complete circumferential membrane
  staining (score 3+)

• HER2 gene
  amplification defined as >6 HER2 gene copies per nucleus by in situ
  hybridization.

4.    Age ≥18
5.    Eastern Cooperative Oncology Group performance status ≤1
6.    No previous radiation therapy or chemotherapy
7.    No other malignancy except carcinoma in situ, unless the other malignancy was treated ≥5 years ago
       with curative intent without the use of chemotherapy or radiation therapy.
8.    Adequate bone marrow function (ANC >1.5 x 10⁹/l, platelets >100 x 10⁹/l)
9.    Adequate hepatic function (ALAT, ASAT and bilirubin <2.5 times upper limit of normal)
10.  Adequate renal function (creatinine clearance >50 ml/min)
11.  LVEF ≥50% measured by echocardiography or MUGA
12.  No current pregnancy or breastfeeding. Women of childbearing potential must use adequate
       contraceptive protection
13.  No evidence of distant metastases. Evaluation of the presence of distant metastases may include
       chest X-ray, liver ultrasound, isotope bone-scan, CT-scan of chest and abdomen and/or FDG-PET
       scan, according to local procedures.
14.  No evidence of bilateral infiltrating breast cancer. Evaluation of the presence of bilateral infiltrating
       breast cancer may include mammography, breast ultrasound and/or MRI breast.
15.  No concurrent anti-cancer treatment or another investigational drug.
16.  Absence of any psychological, familial, sociological, or geographical condition potentially hampering
       compliance with the study protocol and follow-up schedule
17.  Absence of any medical condition that would place the patient at unusual risk
18.  Signed written informed consent