Letrozole with or without Ribociclib before Surgery in Treating Women with Stage II-III Estrogen Receptor-Positive, HER2-Negative Breast Cancer

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent
• Pathologically confirmed invasive breast cancer by core needle biopsy
• Female subjects, age ≥ 18 years
• Only postmenopausal women will be eligible; subjects will be classified as being postmenopausal if they have had: * Bilateral surgical oophorectomy, or * No spontaneous menses > 1 year or * No menses for < 1 year with follicle stimulating hormone (FSH) and estradiol levels in postmenopausal range, according to institutional standards
• Performance Status of Eastern Cooperative Oncology Group (ECOG) 0-2
• Invasive breast cancer must be estrogen receptor-positive (ER+) in > 66 % of the cells or ER allred score 6-8; if ER is positive in >= 66%, the staining intensity (weak, intermediate, strong) is needed to calculate the allred score to determine eligibility; in institutions where ER expression is classified only by < 1%, 1-10%, and > 10% cut-offs, > 10% expression is required for inclusion
• Invasive breast cancer must be HER2 negative; HER2 negative is defined as a single test or both tests used to determine HER2 status (in situ hybridization [ISH] and immunohistochemistry [IHC]) show: * IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of the invasive tumor cells * IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within =< 10% of the invasive tumor cells * ISH single-probe average HER2 copy number < 4.0 signals/cell * ISH dual-probe HER2/chromosome 17 centromere probe (CEP17) ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell
• Documentation of mammogram, ultrasound and magnetic resonance imaging (MRI) of the ipsilateral breast all performed within 42 days prior to registration
• Clinical T2-T4c, any N, M0 invasive breast cancer, by American Joint Committee on Cancer (AJCC) 7th edition clinical staging, with the goal being surgery to complete excision of the tumor in the breast and the lymph node; * The extent of disease is a solitary lesion where the lesion: ** is palpable ** size can be measured bi-dimensionally by tape, ruler or caliper technique, and ** largest tumor diameter is at least 2.0 cm (that is considered measurable by the World Health Organization[WHO] criteria) * Note: ** Patients with contralateral invasive breast cancer are not eligible ** Patients with contralateral ductal carcinoma in situ (DCIS) are eligible ** Patients with multifocal/multi-centric invasive breast cancer are not eligible; additional foci of DCIS in the same breast are acceptable
• Tissue acquisition: subject must agree to provide the required research biopsies at baseline, at day 14 (+7 days [d]) and at surgery for biomarker and correlative studies
• Absolute neutrophil count >= 1500 /uL
• Platelets >= 100,000 /uL
• Hemoglobin >= 9.0 g/dL
• Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within institutional upper limit of normal (IULN) or corrected to within normal limits with supplements before first dose of study medication; (supplements used for this purpose to be approved by primary investigator [PI])
• International normalized ratio (INR) =< 1.5
• Serum creatinine =< 1.5 mg/dL or creatinine clearance >= 50mL/min
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN)
• Total bilirubin =< IULN; or total bilirubin =< 3.0 x IULN or direct bilirubin =< 1.5 ULN in patients with well documented Gilbert’s syndrome
• Subject has cholesterol panel and triglyceride done before first treatment
• Must be able to swallow ribociclib / placebo capsules/tablets

Exclusion Criteria

• Current use of other investigational agents
• Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau d’orange without erythema)
• An excisional biopsy of this breast cancer
• Surgical axillary staging procedure prior to study entry * Note: fine-needle aspiration (FNA) or core needle biopsy of axillary node is permitted
• Hormone replacement therapy of any type, megestrol acetate, or raloxifene within four weeks prior to first study treatment
• Clinical or radiographic evidence of metastatic disease; metastatic workup is not required * Note: isolated ipsilateral supraclavicular node involvement is permitted
• Treatment for this cancer including surgery, radiation therapy, chemotherapy, biotherapy, hormonal therapy or investigational agent prior to study entry
• History of invasive breast cancer prior to the current diagnosis
• Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole
• Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Patient has a known history of human immunodeficiency virus (HIV) infection (testing is not mandatory)
• Patient has any other concurrent severe and/or uncontrolled medical conditions that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.); hepatitis testing at screening is not mandatory, but may be done per investigator discretion
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered a major surgery)
• Patient with Child-Pugh score B or C
• Patient has a history of non-compliance to medical regimen or inability to grant consent
• Patient is currently receiving or has received systemic corticosteroids =< 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment
• Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed
• Clinically significant, uncontrolled heart disease and/or recent events including any of the following: * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening * History of documented congestive heart failure (New York Heart Association functional classification III-IV) * Documented cardiomyopathy * Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening * History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening * Congenital long QT syndrome or family history of long QT syndrome * Bradycardia (heart rate <50 at rest), by electrocardiography (ECG) or pulse, at screening * Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening
• On screening, inability to determine the Fridericia's corrected QT (QTcF) interval on the ECG (i.e.: unreadable or not interpretable) or QTcF> 450 msec (using Fridericia’s correction); all as determined by screening ECG
• Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug: * Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges * Those having a narrow therapeutic window and are predominantly metabolized through CYP3A4/5 * Those having a known risk to prolong the QT interval or induce Torsades de Pointes * Herbal preparations/medications