The goal of this observational study is to validate the predictive ability of a six-gene risk score model for lung metastasis in patients with early-stage breast cancer.
The main questions it aims to answer are:
Does the gene risk score accurately identify patients at high risk of developing lung metastases? Does it predict lung metastasis-free survival and overall survival in these patients? How does its performance compare with traditional clinical indicators (such as TNM stage, molecular subtype, and Ki-67) across different breast cancer subtypes? Participants will be women aged 70 years or younger with newly diagnosed, non-metastatic early-stage breast cancer. They will receive standard treatment according to routine clinical practice. A single tumor tissue sample (from biopsy or surgery) will be collected for testing the expression of six specific genes, and a risk score will be calculated to classify patients into high-risk or low-risk groups. All participants will be followed for up to 120 months to monitor lung metastasis occurrence and survival outcomes. In addition, the study will explore differences in immune microenvironment characteristics between the two risk groups using a subset of tumor samples.
Female, age 18 to 70 ;
Histopathologically confirmed previously untreated primary early-stage breast cancer, excluding occult breast cancer, inflammatory breast cancer, and Paget's disease of the breast;
Histopathologically confirmed primary early-stage breast cancer with no evidence of distant metastasis;
At least one measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1;
History of any other malignancy within the past 5 years, except for breast cancer;
Evidence of metastatic breast cancer by imaging or pathology;
Uncontrolled pleural effusion, pericardial effusion, or ascites;
Life-threatening arrhythmias or higher-grade atrioventricular block.
Newly diagnosed, previously untreated early-stage breast cancer patients without distant metastasis, treated at Sun Yat-sen Memorial Hospital. Female, aged ≤70, ECOG ≤2. Approximately 330 participants will be enrolled consecutively.
Cohort
Prospective
Standard management
Other interventionStandard Management
Lung Metastasis Incidence
Cumulative incidence of lung metastasis from the date of diagnosis to first radiographic or pathological confirmation. Lung metastasis is diagnosed by contrast-enhanced chest computed tomography (CT), positron emission tomography-computed tomography (PET-CT), or lung biopsy.
Area Under the Receiver Operating Characteristic (ROC) Curve of the Gene Risk Score for Predicting Lung Metastasis
The area under the ROC curve (AUC) of the six-gene risk score in predicting lung metastasis, using the occurrence of lung metastasis during follow-up as the gold-standard outcome. Sensitivity, specificity, positive predictive value, and negative predictive value will also be calculated.
Lung Metastasis-Free Survival and Overall Survival
Lung metastasis-free survival is defined as the time from study enrollment to first imaging or pathological confirmation of lung metastasis. Overall survival is defined as the time from study enrollment to death from any cause.
Predictive Performance of the Gene Risk Score Across Molecular Subtypes
Evaluation of the six-gene risk score's predictive accuracy for lung metastasis in each molecular subtype (Luminal A, Luminal B, HER2-positive, and triple-negative breast cancer), as classified by ASCO/CAP guidelines. The area under the ROC curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value will be calculated for each subtype. The log-rank test will be used to compare lung metastasis incidence between high-risk and low-risk groups within each subtype.
Comparison of Predictive Performance Between the Gene Risk Score, Clinicopathological Factors, and Their Combination
Head-to-head comparison of three models in predicting lung metastasis: (1) a clinicopathological model incorporating TNM stage, molecular subtype, and Ki-67 index; (2) the six-gene risk score model; and (3) a combined model integrating both. Time-dependent ROC curves will be used to compare the AUCs at 3, 5, and 10 years, with differences assessed by the DeLong test. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) will quantify the added value of the gene risk score beyond conventional factors.
Immunosuppressive Microenvironment Characteristics in High- versus Low-Risk Groups
Multiplex immunofluorescence staining will be performed on tumor tissue sections from 40 randomly selected patients per group to detect CD8 (cytotoxic T lymphocytes), PD-1 (exhausted T cells), PD-L1 (M2 macrophages and tumor cells), and CD68 (macrophages). Quantitative analysis will compare positive cell density per mm², the proportion of PD-1⁺CD8⁺ double-positive cells among CD8⁺ T cells, and the proportion of PD-L1⁺CD68⁺ double-positive cells among CD68⁺ macrophages between high-risk and low-risk groups using the Mann-Whitney U test. Spearman correlation will assess the relationship between continuous risk scores and immune cell densities.
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