Primary objective:
To explore after 6 months of treatment the ability of palbociclib in combination with letrozole to induce global molecular changes measured by either the Oncotype DX Breast Recurrence Score® (the "Assay") test result at surgery (post-treatment Recurrence Score® (RS) result), or pathological Complete Response (pCR) in patients with aggressive luminal tumors (pre-treatment RS result 18-25 or 26-100, and Ki67≥ 20).
Secondary objectives:
BIOLOGY
* To explore the ability of palbociclib in combination with letrozole to induce global molecular changes measured by post-treatment RS result, in patients with aggressive luminal tumors (pre-treatment RS result 18-25 and Ki67≥ 20) after 6 months of treatment.
* To explore the ability of palbociclib in combination with letrozole to induce global molecular reduction measured by either the post-treatment RS result, and/or Residual Cancer Burden (RCB), and/or Ki67 in patients with aggressive luminal tumors (pre-treatment RS result 18-25 or 26-100 and Ki67 ≥ 20) after 6 months of treatment.
* To verify the ability of palbociclib in combination with letrozole to induce global molecular reduction (measured as either post-treatment RS≤25 or RCB score of 0-I) in \>35% of patients in cohort B with pre-treatment RS 26-100;
* To verify the ability of palbociclib in combination with letrozole to induce increase in RS result (measured as post-treatment RS 26-100) in \<3% of patients in cohort A with pre-treatment RS 18-25;
* To evaluate the concordance rate between the RCB score (0- I vs. II-III) and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in combination with letrozole;
* To evaluate the concordance rate between the preoperative endocrine prognostic index (PEPI) score and post-treatment RS result in both cohorts of patients after treatment with palbociclib in combination with letrozole;
* To evaluate the concordance rate between the pCR and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in combination with letrozole;
* To determine the change in RS result as measured by median absolute value or median percentage after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS 0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS≤25 for patients in cohort B.
EFFICACY
* To determine the Overall Response Rate (ORR) of patients treated with palbociclib in combination with letrozole.
* To evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole.
* To determine the rate of breast conserving surgery.
SAFETY
• To assess the safety and tolerability of palbociclib in combination with letrozole.
A two-stage Simon's statistical design will be used for both cohorts (minimax design in co-hort B and optimal design in cohort A). A total of 66 patients will be enrolled into this trial, N=33 patients in cohort with high-risk tumors (Cohort B: pre-treatment RS\>25) and N=33 patients in cohort with intermediate-risk tumors (Cohort A: pre-treatment RS18-25).
The accrual goal will be of 26 patients (N=13 patients in each cohort) during the first stage. The interim analysis has been planned after 15 patients (cohort B) and 9 patients (cohort A) will be available for biological response evaluation, and in case of positive findings, the trial will recruit additional 40 patients (N=20 patients in each cohort).
* The study would be defined as positive at final analysis in the cohort B (pre-treatment RS\>25), if 8 or more than 8 patients with biological signal (post-treatment RS≤25) are observed (≥28.6%) among 28 evaluable patients.
* The study would be defined as positive at final analysis in the cohort A (pre-treatment RS18-25), if 25 or more than 25 patients with biological stabilization (post-treatment RS≤25) are observed (≥89.3%) among 28 evaluable patients.
Study treatment management
After signing the informed consent form (ICF) and confirmed pre- eligibility, patients will be pre-registered in the study. A tissue biopsy from the primary breast cancer has to be provided at screening and will be used to perform central confirmation of Ki67 levels and HR status, as well as central assessment of RS. Pre-registered patients can receive up to 4 weeks of letrozole before inclusion; pre-menopausal patients will require to combine it with a Luteinizing Hormone-Releasing Hormone (LHRH) analogue. Patients are eligible to enter one of the two cohorts according to RS assessment as follow:
* Cohort A: patients with pre-treatment RS 18-25;
* Cohort B: patients with pre-treatment RS 26-100. Patients with pre-treatment RS 0-17 will be considered not eligible. Patients allocated to the cohort A or B will receive 24 weeks of palbociclib (for 21 days every 4 weeks) in combination with letrozole (once daily, beginning on day 1 and continuing through day 28 of every 28-day cycle). Premenopausal women must also be treated with an LHRH analogue during the treatment phase.
