Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.

The aim of this prospective, randomized, multicenter, open-label, phase II study is to test if chemotherapy can be replaced by the combination of ribociclib plus letrozole as a neo-adjuvant therapy for patients with non-metastatic primary luminal breast cancer.

Based on Ki67 levels after two weeks of initial letrozole treatment in postmenopausal patients with hormone receptor positive, HER2 negative, stage II/III breast cancer, patients are either advised to continue letrozole treatment (if Ki67 \<1%) or will be randomized between standard chemotherapy (AC-T) or ribociclib in combination with letrozole (if Ki67 ≥1%).

Eligibility Criteria:
Inclusion Criteria:

* Postmenopausal women presenting with histological proven (core biopsy material) hormone receptor positive (ER≥50%, PR any), HER2 negative, stage II/ III breast cancer.
* Measurable disease (breast and/or lymph nodes)
* WHO 0-2
* Adequate bone marrow function (within 4 weeks prior to registration): WBC≥3.0x109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l
* Adequate liver function (within 4 weeks prior to registration): bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL
* Adequate renal function (within 4 weeks prior to registration): the calculated creatinine clearance should be ≥50 ml/min
* Accessible for treatment and follow-up
* Written informed consent

Inclusion criteria randomization specific:

In order to be eligible to be randomized in this study, a subject must meet all of the following criteria:

* Registration in the NEOLBC trial before 2 weeks biopsy
* Use of letrozole
* Outcome central Ki67 determination in two weeks biopsy available.

Exclusion Criteria:

* Evidence of distant metastases (M1)
* Previous invasive breast cancer
* Prior chemotherapy, radiation therapy or hormonal therapy with the exception of patients who received letrozole ≤ 14 days (+ max. 4 days) prior to registration and who are still on letrozole.
* Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
* Peripheral neuropathy \> grade 2, whatever the cause
* Serious other diseases as infections (hepatitis B, C and HIV), recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias or on screening, any of the following cardiac parameters: bradycardia (heart rate \<50 at rest) or QTcF ≥450 msec.
* Known hypersensitivity reaction to any of the components of the treatment (peanuts, soy)
* Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
* Currently receiving any of the following substances and cannot be discontinued 7 days prior to randomisation:

  * Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelo's, star-fruit, pomegranate and Seville oranges.
  * That have a known risk to prolong the QT interval or induce Torsades de Pointes.
  * That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
  * Herbal preparations/medications, dietary supplements.
* Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.