Culmerciclib Combined With Letrozole and Dual HER2 Blockade as Neoadjuvant Therapy for HR+/HER2+ Breast Cancer

HR-positive/HER2-positive breast cancer accounts for approximately 10% of all breast cancers and shows lower pathological complete response rates to neoadjuvant therapy compared with the HR-negative/HER2-positive subtype. Crosstalk between HER2 and ER signaling pathways contributes to resistance to endocrine and anti-HER2 therapy. Preclinical evidence suggests that CDK4/6 inhibitors synergize with anti-HER2 therapy and may restore tumor sensitivity to HER2 blockade.

Eligible patients receive:

* culmerciclib 180 mg orally once daily, in 28-day cycles, for 5 cycles;
* Letrozole 2.5 mg orally once daily, in 28-day cycles, for 5 cycles;
* Trastuzumab (TQB211) 8 mg/kg loading dose followed by 6 mg/kg intravenously every 3 weeks, for 6 doses;
* Pertuzumab (TQB2440) 840 mg loading dose followed by 420 mg intravenously every 3 weeks, for 6 doses.

Tumor response is assessed by imaging (ultrasound, mammography, and MRI) according to RECIST 1.1. After completion of 5 cycles of neoadjuvant treatment, patients undergo definitive breast cancer surgery, and postoperative pathology is evaluated for bpCR and RCB. Adverse events are assessed per CTCAE v5.0. Exploratory analyses will investigate correlations between biomarkers and treatment response.

• Culmerciclib (Drug): 180 mg orally once daily, in 28-day cycles, for a total of 5 cycles.
• Letrozole (Drug): 2.5 mg orally once daily, in 28-day cycles, for a total of 5 cycles.
• Trastuzumab (TQB211) (Drug): 8 mg/kg intravenous loading dose, followed by 6 mg/kg intravenously every 3 weeks, for a total of 6 doses.
• Pertuzumab (TQB2440) (Drug): 840 mg intravenous loading dose, followed by 420 mg intravenously every 3 weeks, for a total of 6 doses

Primary outcomes

• Breast Pathological Complete Response Rate (bpCR) [At time of surgery, after completion of 5 cycles of neoadjuvant therapy (approximately 5 months from treatment start)]: Proportion of patients achieving ypT0/is ypN0 (no invasive cancer in the breast and no involved axillary lymph nodes), assessed by postoperative pathology.

Secondary outcomes

• Objective Response Rate (ORR) [At end of neoadjuvant treatment (approximately 5 months from treatment start)]: Proportion of patients achieving complete response (CR) or partial response (PR) assessed by imaging according to RECIST 1.1.
• Residual Cancer Burden (RCB) [At time of surgery (approximately 5 months from treatment start)]: Residual cancer burden index and class (RCB-0, I, II, III) assessed by postoperative pathology.
• Ki67 Change Rate [From baseline to surgery (approximately 5 months)]: Change in Ki67 proliferation index from baseline (pre-treatment biopsy) to surgery.
• Patient-Reported Outcomes (PRO) [From baseline through end of treatment (approximately 5 months)]: Patient-reported quality of life and symptom measures collected during treatment.
• Incidence and Severity of Adverse Events [From first dose through 30 days after surgery (approximately 6 months)]: Number and severity of adverse events graded according to CTCAE v5.0.

Sex: Female, ages: 18 Years to 70 Years

Inclusion Criteria:

* Histologically confirmed HR-positive (ER >=50%, PR >=10%) and HER2-positive (IHC 3+ or ISH+) breast cancer;
* Clinical stage II-III (AJCC 8th edition);
* Treatment-naive: no prior systemic anti-tumor therapy for breast cancer;
* ECOG performance status 0-1;
* Adequate organ function;
* Signed informed consent.

Exclusion Criteria:

* Distant metastasis (stage IV disease);
* Prior chemotherapy, endocrine therapy, or anti-HER2 therapy for the current breast cancer;
* Severe cardiac dysfunction or left ventricular ejection fraction (LVEF) below the institutional lower limit of normal;
* Pregnancy or lactation;
* Any other condition that, in the investigator's opinion, makes the patient unsuitable for the study.