RADIANT: Pre-op Radiation With Abemaciclib and Letrozole

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