Study to Compare Neoadjuvant Combination of Trastuzumab and Pertuzumab With Concurrent Taxane Chemotherapy or Endocrine Therapy and Quality of Life Assessment Under Adjuvant Therapy in Operable HER2+/HR+ Breast Cancer Patients

This is a prospective, phase IIa, multicenter, randomized, open-label study comparing a pre-surgical combination of trastuzumab and pertuzumab with concurrent weekly paclitaxel chemotherapy or endocrine therapy given for 12 weeks with a quality of life assessment for 40 additional weeks in patients with operable HER2+/HR+ breast cancer.


Eligibility Criteria:
Inclusion Criteria:

* Female patients, age at diagnosis 18 years and older
* Histologically confirmed unilateral primary invasive carcinoma of the breast
* Patients must qualify for neoadjuvant treatment as follows:

  * No clinical evidence for distant metastasis (M0)
  * Clinical cT1c-T4a-c (participation of patients with tumors \> cT2 is strongly recommended) and no evidence for distant metastases (M0)
  * All clinical N (participation of patients with cN+, also in case of cT1c, is strongly recommended)
  * Known positive HR-status and centrally confirmed HER2+-status by IHC/FISH
  * Patients need to fulfill adequate blood count and organ function to receive chemotherapy (see exclusion criteria).
* Tumor block available for central pathology review
* Performance Status ECOG ≤ 1 or KI ≥ 80%
* Negative pregnancy test (urine or serum) within 7 days prior to registration in premenopausal patients
* Patients of childbearing potential must accept to implement a highly effective (less than 1% failure rate according to Pearl index) non-hormonal contraceptive measures during the study treatment and for 6 months following the last dose of study treatment (trastuzumab and pertuzumab) such as:

  * Intrauterine device (IUD)
  * bilateral tubal occlusion
  * vasectomised partner
  * sexual abstinence
* Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
* The patient must be accessible for treatment and follow-up
* LVEF \> 55%; LVEF within normal limits of each institution measured by echocardiography (within 42 days prior to randomization)
* Normal ECG (within 42 days prior to randomization)

Exclusion Criteria:

* Known hypersensitivity reaction to the compounds or incorporated substances
* Prior malignancy with a disease-free survival of \< 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri
* Non-operable breast cancer including inflammatory breast cancer
* Previous or concurrent treatment with cytotoxic agents for any reason
* Concurrent treatment with other experimental drugs and participation in another clinical trial or clinical research project within 30 days prior to study entry is excluded
* Male breast cancer
* Concurrent pregnancy
* Breastfeeding
* Sequential breast cancer
* Reasons indicating risk of poor compliance
* Known polyneuropathy ≥ grade 2
* Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study including but not confined to:

  * Uncompensated chronic heart failure or systolic dysfunction (LVEF \< 55%, CHF NYHA classes II-IV),
  * unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block,
  * Angina pectoris within the last 6 months requiring anti-anginal medication,
  * Clinically significant valvular heart disease,
  * Evidence of myocardial infarction on electrocardiogram (ECG),
  * Poorly controlled hypertension (e.g., systolic \> 180 mm Hg or diastolic \> 100 mm Hg).
* Inadequate organ function including but not confined to:

  * hepatic impairment (Child Pugh Class C)
  * pulmonary disease (severe dyspnea at rest requiring oxygen therapy)
* Abnormal blood values:

  * Thrombocytopenia \> CTCAE grade 1
  * Increases in ALT/AST \> CTCAE grade 1
  * Hypokalaemia \> CTCAE grade 1
  * Neutropenia \> CTCAE grade 1
  * Anaemia \> CTCAE grade 1