Breast Cancer, HER2-positive Breast Cancer, Early Breast Cancer
Conditions
Keywords
Neoadjuvant Therapy, De-escalation, Paclitaxel, Trastuzumab, Pertuzumab, Pathological Complete Response, THP Regimen
Brief summary
This phase II study evaluates the efficacy and safety of a de-escalated neoadjuvant chemotherapy regimen in patients with early-stage HER2-positive breast cancer. The experimental regimen consists of 12 weekly cycles of paclitaxel combined with trastuzumab and pertuzumab (THP), without anthracyclines. The study aims to determine if this less toxic regimen can achieve high rates of pathological complete response (pCR) comparable to standard anthracycline-containing regimens. The results are compared with a historical control group of patients who received the standard TCHP regimen (docetaxel, carboplatin, trastuzumab, pertuzumab). A total of 186 participants are included in the analysis: 93 patients prospectively treated with the de-escalated THP regimen and 93 patients in the retrospective historical control group (TCHP). The primary endpoint is the pCR rate at the time of surgery. Secondary endpoints include toxicity, rate of breast-conserving surgery, and 3-year event-free survival.
Detailed description
Background: Standard neoadjuvant therapy for HER2-positive breast cancer often includes anthracyclines (AC-THP) or platinum-based regimens (TCHP), which are associated with significant toxicity. De-escalation strategies aim to reduce toxicity without compromising efficacy, particularly in patients with early-stage disease. Study Design: This is an investigator-initiated, single-center, open-label, non-randomized phase II study. * Prospective Cohort (n=93): Patients with Stage IIA-IIB (cT1-2 N0-1, cT3 N0) HER2+ breast cancer receive Paclitaxel (80 mg/m2 weekly for 12 weeks) + Trastuzumab (loading 8 mg/kg, then 6 mg/kg q3w) + Pertuzumab (loading 840 mg, then 420 mg q3w). * Historical Control Cohort (n=93): Patients with similar baseline characteristics (Stage IIA-IIB) treated with standard TCHP regimen (Docetaxel 75 mg/m2 + Carboplatin AUC6 + Trastuzumab + Pertuzumab q3w for 6 cycles). Primary Objective: To evaluate the pathological complete response (pCR, ypT0/is ypN0) rate in the de-escalated arm. Secondary Objectives: 1. To compare the safety profile (incidence of Grade 3-4 adverse events) between THP and TCHP regimens. 2. To assess the rate of breast-conserving surgery. 3. To evaluate long-term oncological outcomes (3-year Event-Free Survival). The study hypothesis is that the de-escalated THP regimen provides a favorable toxicity profile while maintaining high efficacy in a selected population of early HER2+ breast cancer patients.
Interventions
DRUGPaclitaxel
80 mg/m2 IV weekly for 12 weeks
DRUGtrastuzumab
Loading dose 8 mg/kg, then 6 mg/kg IV every 3 weeks
DRUGPertuzumab
Loading dose 840 mg, then 420 mg IV every 3 weeks
DRUGDocetaxel
75 mg/m2 IV every 3 weeks for 6 cycles
DRUGcarboplatin
AUC 6 IV every 3 weeks for 6 cycles
PROCEDURERadical Surgery
Standard radical resection (mastectomy or breast-conserving surgery) with axillary staging (sentinel lymph node biopsy and/or axillary lymph node dissection \[Levels I-II\], according to current clinical guidelines).
Risk-adapted post-neoadjuvant treatment based on pathological response: * Patients with pCR (ypT≤1a, ypN0, RCB 0-I) receive Trastuzumab to complete 1 year of anti-HER2 therapy (combined with endocrine therapy for luminal subtypes). * Patients with residual disease (ypT≥1b and/or ypN+ and/or RCB II-III) receive Trastuzumab emtansine (T-DM1) 3.6 mg/kg every 3 weeks for up to 14 cycles (combined with endocrine therapy for luminal subtypes). Adjuvant radiotherapy is administered if clinically indicated.
Sponsors
National Medical Research Radiological Centre of the Ministry of Health of Russia
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective single-arm de-escalation cohort compared with a retrospective historical control cohort.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed invasive breast carcinoma. * HER2-positive status defined as IHC 3+ or FISH amplification (ratio \>= 2.0). * Clinical Stage IIA-IIB (cT1-T2 N0-N1, cT3 N0, M0). * Operable disease planned for surgical resection. * ECOG performance status 0-1. * Left Ventricular Ejection Fraction (LVEF) \>= 50% by Echocardiography. * Adequate bone marrow, hepatic, and renal function. * Signed informed consent form.
Exclusion criteria
* Metastatic disease (Stage IV). * Prior systemic therapy for breast cancer (chemotherapy, immunotherapy, or anti-HER2 therapy). * Serious cardiac history (congestive heart failure, unstable angina, myocardial infarction within 6 months). * Other synchronous or metachronous malignancies within 5 years (except non-melanoma skin cancer or carcinoma in situ of the cervix). * Pregnancy or breastfeeding. * Known hypersensitivity to study drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate | At the time of surgery (approximately 12-18 weeks after treatment initiation) | Defined as the absence of invasive cancer in the breast and axillary lymph nodes (ypT0/is ypN0) at the time of surgery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Grade 3-4 Adverse Events | From first dose until 30 days after last dose | Assessment of treatment-related toxicity (neutropenia, diarrhea, etc.) according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0, where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death. |
| Rate of Breast-Conserving Surgery | At the time of surgery | Proportion of patients eligible for and undergoing breast-conserving surgery |
| 3-Year Event-Free Survival (EFS) | 3 years from enrollment | Time from enrollment to disease progression, local recurrence, distant metastasis, or death from any cause |
Countries
Russia
Contacts
PRINCIPAL_INVESTIGATORLarisa Bolotina, MD, PhD
P.A. Hertsen Moscow Oncology Research Institute
Outcome results
None listed