Axillary Lymph Node Metastasis, Breast Cancer
Conditions
Keywords
breast cancer, cfDNA, TuFEst model, Fragmentomics, Axillary lymph node, Sentinel lymph node biopsy, Neoadjuvant therapy, Magnetic resonance imaging, Diagnostic accuracy, Machine learning
Brief summary
Through the research of this project, we expect to validate the clinical utility of the TuFEst-LN model in assessing axillary lymph node status in breast cancer patients. Specifically, we aim to prospectively validate its ability to identify pathologically node-negative patients among clinically and radiologically assessed cN0 patients undergoing upfront surgery ，and explore the predictive value of the TuFEst-LN model combined with preoperative MRI for ypN status assessment in initially node-positive patients following neoadjuvant therapy.
Detailed description
Through the research of this project, we aim to prospectively validate the locked TuFEst-LN model, a cfDNA fragmentomics-based liquid biopsy model, for axillary lymph node status assessment in patients with breast cancer. This study will evaluate the ability of the TuFEst-LN model to identify pathologically node-negative patients among clinically and radiologically assessed cN0 patients with cT1-3 invasive breast cancer undergoing upfront surgery without neoadjuvant therapy. In addition, this study will explore the predictive value of the TuFEst-LN model combined with preoperative magnetic resonance imaging (MRI) for post-neoadjuvant pathological axillary lymph node status (ypN) in initially node-positive breast cancer patients. Peripheral blood samples and clinical data will be prospectively collected from multiple centers, and model predictions will be compared with final surgical pathology as the reference standard. This study aims to validate the clinical utility of cfDNA fragmentomics-based liquid biopsy for noninvasive axillary lymph node assessment and provide evidence for individualized axillary management in breast cancer.
Interventions
OTHERNo Intervention: Observational Cohort
No Intervention: Observational Cohort
Sponsors
Second Affiliated Hospital, Zhejiang University, School of Medicine
Shandong Cancer Hospital and Institute
Suzhou Municipal Hospital
Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University
First People's Hospital of Hangzhou
Ningbo Medical Center Lihuili Hospital
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cohort 1-Specific Inclusion Criteria Participants in Cohort 1 must meet all of the following criteria: 1. Histologically confirmed invasive breast cancer. 2. Clinical stage cT1-3, cN0, M0 disease at enrollment. 3. No clinically palpable suspicious metastatic axillary lymph nodes identified by physical examination. 4. No radiologically suspicious metastatic axillary lymph nodes identified by preoperative axillary imaging (at least ultrasound examination). Patients with suspicious lymph nodes must have negative cytological or histological findings confirmed by fine-needle aspiration or core needle biopsy. 5. No prior neoadjuvant therapy, including chemotherapy, targeted therapy, immunotherapy, endocrine therapy, or breast/axillary radiotherapy before enrollment. 6. Planned to undergo definitive breast surgery with sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND). 7. Ability to provide qualified preoperative plasma samples for cfDNA analysis. Cohort 2-Specific Inclusion Criteria Participants in Cohort 2 must meet all of the following criteria: 1. Histologically confirmed invasive breast cancer. 2. Ipsilateral axillary lymph node metastasis confirmed by fine-needle aspiration or core needle biopsy at initial diagnosis. 3. No evidence of distant metastasis (M0), and planned to receive standard neoadjuvant systemic therapy followed by definitive breast and axillary surgery. 4. Completion of the planned neoadjuvant therapy, or premature discontinuation due to clinical reasons while remaining eligible for subsequent surgery. 5. Ability to provide a baseline plasma sample (T0) within 24-72 hours before initiation of the first systemic treatment (including chemotherapy, immunotherapy, or targeted therapy). 6. Availability of preoperative breast and axillary magnetic resonance imaging (MRI) after completion of neoadjuvant therapy. Patients unable to undergo MRI due to contraindications or other reasons may be included in the cfDNA-only analysis set but will not be included in the complete-case analysis of the combined cfDNA-MRI model. 7. Ability to provide a second plasma sample (T1) within 24-72 hours before surgery after completion of neoadjuvant therapy. Patients without T0 samples may still be included in the exploratory analysis of T1 cfDNA combined with MRI for ypN prediction. 8. Availability of complete postoperative breast and axillary pathological evaluation results.
Exclusion criteria
Participants meeting any of the following criteria will be excluded: 1. Pregnancy or breastfeeding. 2. Prior surgical removal of the primary breast lesion before enrollment, resulting in inability to obtain the required preoperative blood samples. 3. Presence of confirmed distant metastasis. 4. Presence of supraclavicular, internal mammary, or other lymph node lesions that cannot be adequately assessed by planned surgery and pathological evaluation. 5. History of another active malignancy within the previous 5 years, except for cured non-melanoma skin cancer, cervical carcinoma in situ, or other malignancies considered by investigators unlikely to affect study outcomes. 6. Receipt of whole blood, plasma, or other blood product transfusion within 30 days prior to enrollment. 7. Insufficient plasma sample volume, severe hemolysis, or failure to meet cfDNA sequencing quality control requirements determined by the central laboratory. 8. Absence of evaluable axillary surgical pathological results. 9. Any other condition considered by the investigator to make the patient unsuitable for participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological axillary lymph node positivity rate among TuFEst-LN-negative patients | up to 2 weeks | Defined as the proportion of patients with pathological axillary lymph node positivity (pN1mi or higher) among patients predicted as negative by the locked TuFEst-LN model in Cohort 1. FOR = FN/(TN+FN) = 1-NPV. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Negative Predictive Value (NPV) of the TuFEst-LN Model | 2 weeks | The proportion of patients with negative pathological axillary lymph node status (pN0 or pN0(i+)) among patients classified as negative by the locked TuFEst-LN model. |
| Sensitivity and False Negative Rate (FNR) for Detecting Pathological Axillary Lymph Node Positivity | 2 weeks | The ability of the locked TuFEst-LN model to identify patients with pathological axillary lymph node metastasis (pN1mi or higher). FNR is defined as 1-sensitivity. |
| Specificity of the TuFEst-LN Model | 2 weeks | The proportion of patients with true pathological node-negative status (pN0 or pN0(i+)) who are correctly classified as negative by the locked TuFEst-LN model. |
| Positive Predictive Value (PPV), Overall Accuracy, and Discrimination Performance | 2 weeks | Evaluation of the predictive performance of the locked TuFEst-LN model, including PPV, overall accuracy, area under the receiver operating characteristic curve (ROC-AUC), area under the precision-recall curve (PR-AUC), and likelihood ratios. |
| Proportion of Patients Classified as Negative by the TuFEst-LN Model | 2 weeks | The proportion of evaluable patients in Cohort 1 who are classified as negative by the locked TuFEst-LN model, used to estimate the potential rate of sentinel lymph node biopsy (SLNB) omission. |
| Calibration and Net Clinical Benefit of the TuFEst-LN Model | 2 weeks | Assessment of model calibration and clinical utility using Brier score, calibration intercept, calibration slope, calibration curve, and decision curve analysis. |
| Pathological Burden of Missed Positive Cases | 2 weeks | Evaluation of pathological characteristics among false-negative patients, including the number of micrometastatic and macrometastatic lymph node cases, extranodal extension, and other adverse pathological features. |
Countries
China
Contacts
CONTACTChao Ni
Outcome results
None listed