FMD and Neoadjuvant Chemo-immunotherapy in TNBC

Despite the significantly superior efficacy of neoadjuvant chemoimmunotherapy, a considerable proportion of early-stage treated triple-negative breast cancer (TNBC) patients ultimately experience recurrence, particularly those who do not achieve pathological complete response (pCR) after surgery. Therefore, there is an urgent need to develop new and effective treatment strategies to improve outcomes for TNBC patients. Additionally, selecting patients who are more likely to benefit from neoadjuvant chemotherapy combined with immunotherapy remains a clinical challenge. The fasting-mimicking diet (FMD) is a strictly calorie-restricted, low-sugar, low-protein, and high-fat dietary regimen that shares metabolic and anti-tumor effects with water-only fasting while reducing the risk of severe adverse reactions, leading to extensive exploration in both preclinical and clinical settings. Numerous clinical trials in breast cancer and various other cancers have investigated FMD, consistently demonstrating that FMD enhances the efficacy of standard anti-tumor therapies with a favorable safety profile. Furthermore, FMD has shown potent immunomodulatory effects in both in vivo studies and cancer patients, with the activation of anti-tumor immunity being a key mechanism underlying the anti-cancer effects of FMD alone or in combination with chemotherapy. Based on the above research background, this study focuses on operable early-stage or locally advanced triple-negative or near-triple-negative breast cancer. Patients will receive neoadjuvant standard chemotherapy combined with immunotherapy alongside FMD dietary intervention, aiming to explore the efficacy and safety of FMD dietary intervention in combination with standard neoadjuvant therapy for breast cancer patients.

Inclusion criteria

• Written informed consent obtained from the patient or their legal representative.
• Good patient compliance, willing and able to adhere to the prescribed dietary intervention plan, visits, treatment schedule, laboratory tests, and other study procedures.
• Female, aged 18 to 70 years.
• ECOG performance status score of 0 to 1, with an expected survival of >12 weeks.
• Female patients of childbearing potential must agree to use reliable methods of contraception from before trial entry, throughout the study, and for 8 weeks after the completion of the study.
• Patients with pathologically confirmed primary breast cancer, with a primary tumor ≥2 cm and regional lymph node status N0-N3 (AJCC Version 8); patients with positive lymph nodes may have a primary tumor of any size; no distant metastases (M0).
• Triple-negative or near-triple-negative subtype, defined as HR-negative or low expression (ER and/or PR positivity rate 1%-10%) and HER2-negative (IHC 0, 1+, or 2+ with FISH-negative).
• No prior history of any anti-tumor therapy, including chemotherapy, radiotherapy, and biological therapy.
• Hemoglobin ≥90 g/L (can be maintained or exceed this level via transfusion).
• Absolute neutrophil count ≥1.5 × 10E9/L.
• Platelet count ≥100 × 10E9/L.
• Total bilirubin ≤1.5 × upper limit of normal (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
• Creatinine ≤1.5 × ULN.
• Fasting blood glucose <250 mg/dL (13.89 mmol/L).
• Pregnancy must be ruled out for women of childbearing potential (aged 15-49).

Exclusion criteria

• Previous administration of any systemic anti-cancer therapy, including cytotoxic chemotherapy, targeted therapy, immunotherapy, or investigational treatment.
• Prior radiotherapy for breast cancer.
• Documented evidence (pathological or radiological) of distant metastasis prior to treatment initiation.
• History of another malignancy within the five years preceding treatment initiation in this study, except for carcinoma in situ of the cervix, cured basal cell carcinoma, or urothelial tumors of the bladder (including Ta and Tis).
• Known allergy or hypersensitivity to any component of the investigational drugs or products.
• Active autoimmune disease requiring systemic treatment (e.g., systemic lupus erythematosus, psoriasis, etc.).
• Body Mass Index (BMI) < 19 kg/m².
• Unintentional weight loss ≥5% within the past 3 months, unless the patient's BMI >22 kg/m² and weight loss at study entry is <10%; or unintentional weight loss ≥10% within the past 3 months, unless the patient's BMI >25 kg/m² and weight loss at study entry is <15%. In either case, weight must have been stable for at least one month prior to enrollment.
• Eating disorders, including anorexia nervosa, bulimia nervosa, etc.
• Baseline fasting blood glucose ≤60 mg/dL (3.33 mmol/L).
• Severe infection within 4 weeks prior to enrollment, including but not limited to hospitalization for infectious complications, bacteremia, or severe pneumonia.
• Type 1 or Type 2 diabetes mellitus requiring medication (including but not limited to insulin or insulin secretagogues), with the exception of metformin.
• Any unstable systemic disease, including: uncontrolled hypertension, unstable angina, angina pectoris with onset within the last 3 months, congestive heart failure, myocardial infarction (within 6 months prior to enrollment).
• Severe arrhythmia requiring medication, or significant hepatic, renal, or metabolic disease.
• Known infection with Human Immunodeficiency Virus (HIV).
• Active, uncontrolled hepatitis B or hepatitis C.
• Pregnant or lactating women.
• History of diagnosed neurological or psychiatric disorders, including epilepsy or dementia.
• Any other condition deemed by the investigator as unsuitable for participation.