This phase 1b study investigates the safety and feasibility of combining pre-operative radiation therapy with Cyclin-Dependent Kinase 4 (CDK4/6) inhibitors in participants with hormone receptor positive/HER2 negative (HR+/HER2-) breast cancer. The study aims to assess the benefits of concurrent use of these treatments in a specific participant population, focusing on their safety and tolerability. The hypothesis is that the combination therapy will be well-tolerated, providing valuable insights into its effectiveness for future clinical applications.

In this phase 1b study, researchers will conduct a comprehensive investigation into the concurrent administration of pre-operative radiation therapy and CDK4/6 inhibitors in a carefully selected participant population diagnosed with hormone receptor positive/HER2 negative (HR+/HER2-) breast cancer. The study aims to elucidate the safety and feasibility of this combination therapy. Participants will undergo rigorous evaluation and monitoring to assess the potential synergistic effects and adverse reactions resulting from the simultaneous use of radiation and CDK4/6 inhibitors. Detailed clinical assessments, imaging studies, and laboratory analyses will be performed to monitor treatment response and any associated side effects.

The study hypothesizes that this combination therapy will be well-tolerated, paving the way for further investigations into its efficacy. By closely examining the outcomes and tolerability of this treatment approach, researchers aim to contribute valuable data to the understanding of novel therapeutic strategies for HR+/HER2- breast cancer. The detailed analysis of participant responses and safety profiles in this study will provide crucial insights for optimizing future clinical interventions and improving outcomes for individuals diagnosed with this specific breast cancer subtype.

Inclusion Criteria:

• Histologically and/or cytologically confirmed diagnosis of invasive (ductal, lobular or mixed histology), Clinically inapparent tumor that is not palpable. (cT1-T2N0)disease. Minimum tumor size of 1.5 cm
• Expression of ER or progesterone receptors (PR)and negative expression of HER2 per American Society of Clinical Oncology, (ASCO) Common Alerting Protocol (CAP) guidelines
• Oncotype diagnosis (DX) Breast Recurrence score of less than 25 on core biopsy specimen
• Post-menopausal status defined:
• age <60 with amenorrhea for at least 12 months in the absence of prior chemotherapy, tamoxifen, toremifene, or ovarian suppression and estradiol and FSH (follicle stimulating hormone) in postmenopausal range.
• No clinical suspicion of metastasis disease
• Eastern Cooperative Oncology Group (ECOG) performance status of follicle stimulating hormone (PFS) ≤2
• Eligible to undergo surgery, either lumpectomy or mastectomy for local treatment of the breast cancer
• Able to swallow oral medications
• Adequate organ function for all of the following:

Absolute Neutrophil (ANC) >1.5 x 10/L Platelets >100 x 10/L Hemoglobin >8 g/dL - May receive erythrocyte transfusions to achieve this level Total Bilirubin <1.5 x Upper Limit of Normal (ULN) Alanine Aminotransferase (ATL) and Aspartate Aminotransferase (AST) <3 x ULN

• HR positive/HER2 -negative breast cancers are allowed as long as no other exclusions exist

Exclusion Criteria:

• History of ipsilateral breast cancer
• Prior treatment with CDK4/6 inhibitors or aromatase inhibitors
• History of chest wall or ipsilateral breast radiation
• Inflammatory breast cancer
• Needs neoadjuvant chemotherapy
• Presence of distant metastatic disease
• Contraindication for surgery
• Uncontrolled hypertension (systolic blood pressure >190 mm Hg or diastolic blood pressure >100 mm Hg)
• Any condition including the presence of laboratory abnormalities, which, in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study
• Life expectancy < 12 weeks
• History of allergy or hypersensitivity to any of the study drugs
• Any significant medical condition, laboratory abnormality, or psychiatric illness
• Serious and/or uncontrolled preexisting medical condition
• Has had major surgery within 14 days prior to enrollment
• Has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to enrollment, or is currently enrolled in any other type of medical research
• Has active systemic bacterial infection
• Personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest

Female