The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study

Inclusion Criteria:

1. Hormone receptor positive (HR+) HER2 negative metastatic breast cancer. Cut-offvalues for positive/negative staining should be as per standard practice inaccordance with ASCO/CAP (American Society of Clinical Oncology/College of AmericanPathologists) guidelines. Verification of histology is preferred at the time ofrecurrence and where not possible or necessary in the judgment of the treatingphysician, the study will accept histology from the initial diagnosis.

2. Candidate for planned endocrine therapy in combination with 1st use of palbociclibor ribociclib, in the metastatic setting. The planned endocrine partner can be anaromatase inhibitor (letrozole, anastrozole, exemestane) or fulvestrant, selectedthrough patient/provider choice.

3. Aged 65 years or older

4. Adequate bone marrow and organ function. Laboratory values must be within normalinstitutional limits, or within ranges as indicated below, or demonstrate minorabnormalities that are deemed clinically non-significant by the investigator.

• Absolute neutrophil count ≥ 1,000/µL

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (participantswith documented Gilbert's disease are allowed total bilirubin up to 5X ULN)

• AST (SGOT)/ALT (SGPT) <3 x institutional ULN, or ≤ 5 x ULN for subjects withdocumented metastatic disease to the liver.

5. Baseline QTc ≤ 480 ms (only for ribociclib patients)

6. Ability to understand and the willingness to provide informed consent. Note: Remoteconsent is allowed per institutional guidelines.

Exclusion Criteria:

1. Previous treatment with a CDK4/6 inhibitor for metastatic breast cancer, or previoustreatment within the past 12 months with a CDK4/6 inhibitor in the neo/adjuvantbreast cancer setting.

2. Received greater than 30 days (in the metastatic setting) of the specific endocrinetherapy agent planned as partner to the CDK4/6 inhibitor in the study at the time ofrandomization.

3. Known history of intolerance or allergy to the planned agents used in this trial.

4. Uncontrolled intercurrent illness that, as evaluated by the treating clinician,would hinder compliance with study requirements.

5. Concurrent therapy with other investigational agents.

6. Rapidly progressive brain metastases.

7. Active or chronic Hepatitis B or C are eligible provided they meet liver functionlaboratory criteria and are not on medication with a known interaction with thestudy agents.

8. Current use of drugs that have known potential to prolong the QT interval (e.g.,antiarrhythmic drugs), for patients on ribociclib. Note: If concomitant use cannotbe avoided, monitor ECG when initiating, during concomitant use, and as clinicallyindicated. Refer to crediblemeds.org as a resource.

9. Prior or concurrent malignancies that are undergoing active treatment.