Neoadjuvant Imlunestrant Plus Abemaciclib Treatment Guided by Ki67 Index After 2 Weeks for ER-Positive HER2-Negative Breast Cancer

This is a prospective, open-label, single-center, randomized controlled Phase II clinical study aimed at evaluating the efficacy and safety of neoadjuvant imlunestrant combined with abemaciclib guided by the Ki67 index after 2 weeks in patients with ER+/HER2- breast cancer. Eligible subjects who provide informed consent will first receive a 2-week window-of-opportunity treatment with imlunestrant combined with abemaciclib, followed by a biopsy of the primary lesion to assess Ki67 at 2 weeks. If the Ki67 of the primary lesion after 2 weeks is <7.4%, they will be randomized in a 1:1 ratio to either Imlunestrant plus abemaciclib or neoadjuvant chemotherapy. If the Ki67 of the primary lesion after 2 weeks is ≥7.4%, patients will be assigned to neoadjuvant chemotherapy.

Inclusion criteria

• Female patients aged 18 to 75 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Primary breast tumor diameter > 1 cm.
• Histologically confirmed invasive ER+/HER2- breast cancer, meeting ER≥50% and Ki67≥10%. HER2 negativity is defined as HER2 immunohistochemistry (IHC) 0-1+, or IHC 2+ with fluorescence in situ hybridization (FISH) confirming no amplification.
• Clinical tumor stage: cT1c-T4, cN0-cN2, cM0.
• Willing to undergo breast cancer surgery once surgical criteria are met after neoadjuvant therapy.
• Adequate organ function, meeting all of the following:

• Hemoglobin (Hb)≥90 g/L and patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion;
• Absolute neutrophil count (ANC)≥1.5×10^9/L;
• Platelet count (PLT)≥100×10^9/L;
• Total bilirubin (TBIL)≤1.5×the upper limit of normal (ULN) and patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted;
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×ULN;
• Alkaline phosphatase (ALP)≤2.5×ULN;
• Serum creatinine (Cr)≤1.5×ULN;
• Prothrombin time (PT) and activated partial thromboplastin time (APTT)≤1.5×ULN, and international normalized ratio (INR)≤1.5×ULN (in patients not receiving anticoagulation).
• Left ventricular ejection fraction (LVEF)≥55% at baseline as measured by echocardiography or multi-gated acquisition (MUGA) scan.
• Women with premenopausal status should receive ovarian suppression with a gonadotropin-releasing hormone agonist such as goserelin or leuprolide before initiation of treatment to become postmenopausal status. Postmenopausal due to surgical/natural menopause requires at least 1 of the following:

• prior bilateral oophorectomy;
• age≥60 years;
• age<60 years, amenorrheic for at least 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression), and FSH and estradiol levels in the postmenopausal range.
• Women of childbearing potential must have a negative serum pregnancy test. Such patients must use a medically acceptable method of contraception during study treatment and for at least 6 months after the last dose of the study drug(s).
• The subject voluntarily agrees to participate, signs the informed consent form, has good compliance, and is willing to adhere to follow-up.

Exclusion criteria

• Stage IV (metastatic) breast cancer or bilateral breast cancer.
• Prior history of invasive breast cancer.
• Prior history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS).
• Any prior chemotherapy, endocrine therapy, or anti-HER2 therapy for breast cancer; or prior excisional biopsy of the primary breast tumor and/or axillary lymph nodes, or prior local radiotherapy (excluding diagnostic biopsy for primary breast cancer or surgery for benign breast tumors).
• Any other malignancy within the past 5 years, except cured cervical carcinoma in situ and non-melanoma skin cancer.
• Peripheral neuropathy≥Grade 2 per NCI-CTCAE v6.0.
• Serious cardiovascular or cerebrovascular disease within 6 months prior to randomization, including but not limited to congestive heart failure, unstable angina, severe arrhythmias uncontrolled by medication, severe conduction abnormalities or clinically significant valvular disease, uncontrolled severe hypertension, myocardial infarction, or cerebrovascular accident.
• Any serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Major surgery within 4 weeks prior to randomization without full recovery, or an anticipated need for major surgery during study treatment.
• Known active liver disease, including but not limited to active hepatitis B (defined as HBsAg positive with HBV-DNA≥1000 IU/mL), hepatitis C (defined as HCV-Ab positive with HCV-RNA above the assay's lower limit of quantification), or autoimmune liver disease.
• Severe and uncontrolled infection or known HIV infection.
• Active systemic bacterial infection (requiring intravenous antibiotics at time of initiating study treatment) or fungal infection.
• Pregnant or breastfeeding.
• Known allergy to the study drug or any of its excipients, or a history of severe hypersensitivity reactions to other monoclonal antibodies.
• Known abuse of psychotropic substances, alcoholism, or drug abuse.
• Known, definite neurological or psychiatric disorders associated with poor compliance, including but not limited to epilepsy or dementia.
• Any other serious physical or mental illness or laboratory abnormality that may increase the risk of study participation or interfere with study treatment and outcomes, or any other condition that, in the investigator's judgment, makes the patient unsuitable for this study.
• The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to randomization, or is currently enrolled in any other type of medical research (for example: medical device) judged by the sponsor not to be scientifically or medically compatible with this study.