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Hormone Antagonists

All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of \<1% in the biopsy taken after those two weeks of treatment are advised to stay on letrozole treatment until surgery. However, treatment choice is free.

All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of ≥1% in the biopsy taken after those two weeks of treatment are randomized between chemotherapy (standard AC-T chemotherapy) or ribociclib plus letrozole (ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks)).

Dose dense AC-T chemotherapy: consisting of 4 cycles of AC (doxorubicin and cyclophosphamide at a dose of 60 and 600 mg/m² as an i.v. bolus, respectively) 2-weekly, plus G-CSF (6 mg once per cycle) 24-48 hr after chemotherapy, followed by cycles of T (4 cycles docetaxel 100 mg/m² 3-weekly or 12 cycles paclitaxel 80 mg/m2 weekly).

Chemotherapy

Ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks).

Ribociclib plus letrozole

Judith R Kroep, MD PhD

Sabine C Linn, Prof. MD

Gerrit-Jan Liefers, MD PhD

A. E van Leeuwen-Stok, PhD

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%).

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

ERα DNA binding will be determined in the primary core biopsy and two weeks biopsy, where after the change in these measurements over time can be determined.

Gene expression profiling will be determined in the primary core biopsy and two weeks biopsy, where after the change in these measurements over time can be determined.

Determine if ribociclib plus letrozole gives a ≥100% improvement in CCCA as compared to chemotherapy in the surgical specimen.

The correlation between the different Ki67 measurements will be determined in the primary core biopsy, two weeks biopsy and surgical specimen.

The ER pathway activity will be determined in the primary core biopsy, two weeks biopsy and surgical specimen and then correlated with clinical outcome.

Activity will be determined using a Bayesian network model of the ER transcriptional program, which interprets the pathway target genes' mRNA levels (from Affymetrix HG-U133Plus2.0 arrays) and infers a probability that the ER pathway is active in a certain sample.

The pathologic response will be determined in the surgical specimen of the patients in the randomized study arms where after the difference between the two groups can be determined.

Tumor biology and biomarkers will be determined in the primary core biopsy, two weeks biopsy and surgical specimen, where after the change in tumor biology and biomarkers over time can be determined.

Toxicities are graded according to NCI CTCAE v4.03.

The correlation of tumor measurements between MRI and palpation will be determined at three different time points.

EFS is defined as the time from randomization to the first date of local, regional, or distant relapse, second primary invasive breast cancer including contralateral breast cancer, progression according to RECIST 1.1 or death due to any cause which ever occurred first.

OS is defined as the time from randomization to date of death.

Spots Global Cancer Trial Database for ribociclib plus letrozole