Imlunestrant and Abemaciclib for the Treatment of Estrogen Receptor Positive Breast Cancer in Patients With Minimal Residual Disease, MIRI Trial

Inclusion Criteria: * Participants must have localized ER+ (≥ 10% on surgical pathology), HER2 negative, any grade, invasive breast cancer. Pathological stage (from time of surgery, including patients who received neoadjuvant therapy) I - III by American Joint Committee on Cancer (AJCC) 8th edition staging * Note: Invasive breast cancer must be ER+ in ≥ 10% of the cells and HER2 negative (immunohistochemistry \[IHC\] 0 or 1+ and/or fluorescence in situ hybridization \[FISH\] negative with a ratio \< 2) by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. For Immunohistochemistry (IHC) 2+, the tumor must be FISH negative with a ratio \< 2. ER, progesterone receptor (PR) and HER2 measurements should be performed according to institutional (local) guidelines, in a Clinical Laboratory Improvement Act (CLIA)-approved setting * Detectable ctDNA in a CLIA-certified lab (separate pre-screening consent available) within the past six months. Participants must have no clinical or radiographic evidence of recurrence as determined by the treating investigator * Confirmation of adequate archival tissue (either initial biopsy or surgical specimen) (15-20 unstained slides cut at 5 µm or 1 block) required before study entry. If adequate surgical tissue is available, this is preferred. Otherwise tissue from diagnostic biopsy is acceptable. If adequate tissue not available, principal investigator (PI) approval is required prior to study entry * No prior history of other malignancies within past 5 years (besides breast cancer as per inclusion #1). Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin. No concurrent malignancy or other serious medical condition as deemed by the investigator * Participants may or may not have received (neo)adjuvant chemotherapy and/or biological therapy at the time of screening, with no more than grade 1 residual toxicity (except ≤ grade 2 neuropathy or ≤ grade 2 alopecia) * Participants may or may not have received adjuvant radiotherapy, with no more than grade 1 residual toxicity * Pre- and postmenopausal women and men are eligible. Premenopausal women must have a negative serum pregnancy test at time of screening * Pregnancy testing does not need to be pursued in female patients who are: * Age ≥ 60 years; OR * Age \< 60 with intact uterus AND amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range * OR status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation * Must be ≥ 18 years of age * History of CDK 4/6 inhibitor is permitted provided the last dose was more than 6 months ago (from consent date) * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky ≥ 70%) * Patients must currently be on endocrine therapy in the adjuvant setting and must have received (neo) adjuvant endocrine therapy for at least 24 months (cumulative duration) * Ability to understand and the willingness to sign a written informed consent document. Patient must sign the informed consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements * Participants must currently be receiving adjuvant endocrine therapy and have been on adjuvant endocrine therapy for at least 2 years. Adjuvant endocrine therapy can be either tamoxifen or aromatase inhibitor (AI), i.e prior use of any AI, including letrozole, anastrozole or exemestane, or tamoxifen is allowed. Concurrent gonadotrophin releasing hormone (GNRH) agonist is required with AI in pre - and/or peri-menopausal patients and men * Absolute neutrophil count ≥ 1.5 × 10\^9/L * Platelets ≥ 100 × 10\^9/L * Hemoglobin ≥ 9.0 g/dL * Serum creatinine \< 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 x institutional upper limit of normal (ULN) * Total bilirubin \< institutional 1.5 times ULN; or total bilirubin ≤ 3.0 x institutional ULN. Patients with Gilbert's Syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted * The patient is able to swallow oral medications Exclusion Criteria: * Participants with metastatic disease (including contralateral axillary lymph nodes) or inflammatory breast cancer. Of note, if a patient had locally advanced breast cancer leading to inflammation, this would not exclude the patient on the grounds of inflammatory carcinoma * Participants who have had CDK 4/6 inhibitor therapy within the past 6 months. Use of prior CDK 4/6 inhibitor with last dose more than 6 months ago is permitted * Participants who are receiving any other anti-cancer investigational agents. Participation in other observational studies is permitted * History of other malignancies within past 5 years, except ductal carcinoma in situ of the breast, cervical cancer in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin. No concurrent malignancy or other serious medical condition as deemed by the investigator * Herbal products and supplements will generally not be allowed, but specific supplements (such as cannabidiol \[CBD\] oil) can be considered on a case-by-case basis by Overall PI * Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (e.g. estimated creatinine clearance \< 30ml/min), unstable angina pectoris, cardiac arrhythmia, a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with impairment of gastrointestinal (G