PFS is defined as time from randomization to progression of disease or death of any cause, whichever comes first. It will be assessed by imaging until progressive disease or start of next-line therapy.

The percentage of patients with ctDNA alterations (i.e. such as but not limited to Rb, ESR1, cyclin D1, CDKN2A, PIK3CA, p53 and PTEN) will be provided over time to characterize the biological evolution of the disease in each patient. The association of these alterations with clinical outcomes will also be provided.

AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. A SAE which caused death of the participant was considered as fatal SAE. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.

ORR defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by local investigators according to RECIST 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Progression-free survival was defined as the time from the date of randomization to the date of the first documented progression as per local review and according to RECIST 1.1 or death due to any cause. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed at the time of last patient, last visit (LPLV).

Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, PFS is censored at the date of last adequate tumor assessment.

These are the number of participants who had adverse events or serious adverse events regardless of whether is was suspected to be drug-related or not

These are the percentage of participants that had adverse events or serious adverse events regardless of whether is was suspected to be drug-related or not

Standard 3+3 phase-I design will be utilized in this trial. Briefly, a minimum of 3 evaluable patients will be entered at first dose level (=300 mg ribociclib) and T-DM1 (3.6 mg/kg IV). If 1 out of the first 3 patients enrolled experiences a dose-limiting toxicity (DLT), 3 additional patients will be enrolled to that dose level. If no more than 1 patient in 6 experiences a DLT, dose escalation of ribociclib will continue to next dose-level. If 2 or more patients at any given dose level experience a DLT, dose escalation will stop and the Recommended Phase2 Dose (RP2D) will be defined. Maximum dose-escalation of Ribociclib (LEE011) will be up to 600 mg.

CBR is defined as the proportion of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) at week 24 by RECIST 1.1 criteria. CBR will be reported with 90% confidence interval, adjusting for two-stage design using the method from Atkinson and Brown.

CBR is defined as the proportion of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) at week 24 by RECIST 1.1 criteria. CBR will be reported with 90% confidence interval, adjusting for two-stage design using the method from Atkinson and Brown.

400-600 mg of Ribociclib, when taken with Tamoxifen 20 mg. The Phase I portion of the study is a dose escalation to confirm the dose limiting toxicity (DLT) and the RP2D for ribociclib with Tamoxifen. DLT is defined as an adverse event or abnormal laboratory value assessed as having a reasonable possibility related to the study medication, unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1) with LEE011 and Tamoxifen. National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading. In this study, a DLT will occur if CTCAE grade 4 neutropenia lasts more than 4 consecutive days, if CTCAE grade 3 thrombocytopenia is associated with clinically significant bleeding or if there is grade 4 thrombocytopenia.

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a reasonably possible relationship to the study medication(s) and is unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1) and meets any of the criteria defined in the protocol. National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading.

Clinical Benefit Rate (CBR) is defined as the percentage of participants with a complete response (CR) or partial response (PR) or with stable disease (SD) as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response or Non-Progressive Disease (NCRNPD) during first 24 weeks of first dose. CR=disappearance of all non-nodal target lesions, PR=at least a 30% decrease in the sum of diameter of all target lesions, SD=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD), PD=at least a 20% increase in the sum of diameter of all target lesions. The hypothesis was to be rejected if the lower limit of the 95% Confidence Interval for Clinical Benefit Rate (CBR) was greater than 10%.

Complete response (CR) or partial response (PR), or stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD) at Week 24.

Dose limiting toxicities

Progression Free Survival per RECIST v 1.1 by local investigator assessment

Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.

To characterize PK profiles of LEE011 and Letrozole.

DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria.

Adverse events were collected for approximately 4.5 years for dose expansion including the 30 days safety follow-up period.