Neoadjuvant Phase II Trial in Patients With T1c Operable, HER2-positive Breast Cancer According to TOP2A Status (NeoTOP)

Inclusion Criteria:

• Women aged ≥ 18;
• Patient has histologically confirmed breast cancer, with a clinical tumour diameter of > 1 cm (cT1c, cT2-3 or T4a)-
• Any N status
• No clinically or radiologically detectable metastases (M0);
• HR negative (both ER and PR < 10% by IHC); for T1c status, otherwise HR negative or positive
• Her-2 positive (i.e. IHC score 3+ or FISH/SISH/CISH positive);
• Performance status ≤ 1 (according to WHO criteria);
• Patients not previously treated by surgery, radiotherapy, hormone therapy or chemotherapy;
• Hæmatology: Absolute neutrophil count (ANC) ≥1,500/mm3; Platelets ≥100,000/mm3; Total white blood cell count (WBC) ≥3.000/mm3 ; Hb> 9g/dl;
• Hepatic Function: Total bilirubin ≤1.5 time the upper normal limit (UNL); ASAT ≤ 1.5xUNL; ALAT ≤ 1.5xUNL; Alkaline phosphatase ≤ 2.5xUNL;
• Renal Function: Serum creatinine ≤1.5xUNL (and if Serum creatinine >1.5xUNL, Creatinine clearance ≥50 mL/min (MDRD formula);
• Metabolic Function: Magnesium ≥ lower limit of normal; Calcium ≥ lower limit of normal;
• Patient with not controlled heart disease and for whom anthracyclines are not contraindicated. Cardiac ejection fraction ≥50% measured by MUGA or ECHO done within 4 weeks before inclusion;
• Patient agreeing to use effective contraception during and for ≥ 7 months after completion of study treatment;
• Patient able to comply with the protocol;
• Patient must have signed a written informed consent form prior to any study specific procedures;
• Patient must be affiliated to a Social Health Insurance.

Exclusion Criteria:

• Bilateral or multifocal breast cancer;
• Non-measurable tumour;
• Any form of breast cancer other than those described in the inclusion criteria, particularly inflammatory and/or overlooked forms (T4b or T4d);
• HER2 negative status (i.e. IHC score 0 or 1+, or IHC score 2+ and FISH/SISH/CISH negative);
• RH positive (ER or PR ≥ 10% by IHC) ;
• Patient has a history of second cancer, with exception of in situ cervical cancer or basocellular skin cancer which is regarded as cured;
• Patient has already been treated for new breast cancer;
• Patients have already undergone surgery for their disease or have had primary axillary dissection;
• Prior docetaxel administration or anti-HER2 antibody therapy (e.g.: trastuzumab or pertuzumab);

• Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as, but not limited to:

  • Heart or kidney failure, medullary, respiratory or liver failure, dyspnea
  • Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, poorly controlled hypertension) ≤ 1 year before enrollment
  • Uncontrolled diabetes
  • Significant neurological or psychiatric abnormalities
  • Symptomatic or progressive disorder of the central nervous system (CNS) or metastasis at the initial check-up.
  • Peripheral neuropathy > grade 2
  • Acute urinary infection, ongoing hemorrhagic cystitis;
• Patients with a known history of HIV seropositivity;
• Sensitivity to any of the study medications or any of the ingredients or excipients of these medications;
• Patients receiving of the concomitant medications with phenytoin;
• Patients who received any other investigational drugs within 30 days of initiation of treatment and/or during the study;
• Must not have had a major surgical procedure within 30 days of initiation of treatment;
• Pregnant women, women who are likely to become pregnant or are breast-feeding;
• Patients with 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;
• Patients with history of non compliance to medical regimens or unwilling or unable to comply with the protocol;
• Individual deprived of liberty or placed under the authority of a tutor.