Protocol B (Version 7, 12-Jun-2014) Editorial Amendment to update the protocol version B, with the administrative letters 1-4 (DIL) into the protocol, update of Appendix 10 (Declaration of Helsinki).

Protocol C (Version 8, 06-Aug-2014) Prognostic Marker Inclusion Criterion #12 with score CPS-EG, allowed now the use of surgical biopsy: … using local estrogen receptor status and grade assessed on core biopsies taken before start of neoadjuvant treatment either / or surgical biopsy. Predictive Marker Inclusion Criterion #5, had to be PR positive in residual tissue or with the core biopsy: … (>=1% ER and/or PR positive stained cells). Retreatment and dose reduction section: Increased clarifications to guidance was provided based on gained experience in the palbociclib program. Exclusion criterion #14 now allowed prior neoadjuvant treatment to allow the entry of patients from ADAPT and similar trials: Prior neoadjuvant treatment was acceptable. Section 6.3.3 “Human Pharmacokinetik Data”, Section 6.3.4 “QTc Evaluation Data, Chapter 6.3.7 “Combination with other endocrine agents”, and Section 6.3.8 “Long Term Toxicity Data” were updated with the most recent nonclinical and clinical information. The blood sample for ctDNA was increased from 10 ml to 20 ml. Editorial amendment to update protocol version C with administrative letter 5 (DIL), FDA-IND number amended.

Protocol D (Version 9, 09-Feb-2015) Inclusion criterion #5: Clarification for testing in case of bilateral breast cancer; inclusion criterion #6: Centrally testing possibility was extended to core biopsy; inclusion criterion #12: Now allowed patients with a CPS-EG Score of 2, if ypN+, to participate; exclusion criterion #15: Proton Pump Inhibitors were no longer unallowed. Addition of additional stratification criteria: CPS EG score 3 vs. 2 and ypN+. Update of Section 6.3.3 “Human Pharmacokinetic (PK) Data; update of Section 12.5.1 “Prohibited Medication”, proton pump inhibitors removed; update of section 15.5 ff: Statistical Analysis due to change of inclusion criterion.

Protocol E (Version 10, 12-Apr-2016) Inclusion criterion #2: Specification for bilaterial breast cancer was added; inclusion criterion #5: Specification which tissue could be used for central testing was added; inclusion criterion #6: Specification for bilaterial breast cancer was added; inclusion criterion #10: Radiotherapy requirements were adjusted to standard guidelines; exclusion criterion #5: Specified to electrolyte disorders in general, exclusion criterion #13: Removal of endocrine treatment timing which was a description but not an exclusion criterion (was replaced with definition of radiotherapy window); exclusion criterion #16: Study entry time was specified as date of randomization. Endocrine treatment options were updated. Patients could now receive either tamoxifen or AI (letrozole, anastrozole, or exemestane). For premenopausal patients, concurrent LHRH agonist use was allowed. Patients could now concurrently receive bisphosphonates or rank ligand inhibitors, if necessary for treatment or prevention of osteopenia or osteoporosis. Safety monitoring frequency was adjusted to IDMC recommendation. Ophthamologic assessment was removed due to new information in palbociclib IB versions. Optional samples for circulating tumor cells (CTC), RNAlater and fresh frozen tissue was removed. An optional ctDNA sample collection time-point at detection of progressive disease was added. Specification of relevant overdose definition and removal of notification requirement for non-relevant overdose.

Protocol G (Version 11, 04-May-2017) Specification of potential outcomes of the EIA (futility, sample size re-estimation up to a new total number of 1250 patients, efficacy) were added to the statistical sections. Rationale: The adaptive design of the study allowed adjustment of the patient number based on outcome of the 1st EIA. New information on human PK data based on the IB (2017) was added.

Administrative Amendment Protocol G (Version 11 –- 9th April 2019) Summary of changes Update of GBG Subboard Neoadjuvant, and International Steering Committee members, resp. (chapter 1). Change of International Principal Investigator / Coordinating Investigator (chapter 1). Adding of new position “Unblinded independent statistician” (chapter 1).