Clinical significance of locoregional and systemic treatment in operable high-risk breast cancer patients with more than four positive axillary lymph nodes

Purpose: Breast cancer cases with four or more involved axillary lymph nodes (ALNs) feature an aggressive clinical history despite intensive treatment. However, therapies for improving the prognosis for these high-risk patients and the prognostic role of clinical characteristics have been little investigated. Therefore, we sought to assess potential prognostic factors for these patients in female Chinese patients and identify the treatment modalities they might benefit from, which offers implications for clinical practice. Patients and methods: A total of 518 patients with four or more involved ALNs were retrospectively analyzed. Survival-curve analysis was performed with the Kaplan-Meier method, and Cox proportional hazard regression was applied to identify independent variables for disease-free survival (DFS) and overall survival (OS). Results: The patients were divided into groups depending on the number of ALNs, with 38.22% having four to six positive ALNs and 61.78% having seven or more ALNs. Compared with the seven or more-positive ALN subgroup, patients with four to six positive ALNs tended to have smaller tumors and were more likely to undergo modified radical mastectomy rather than radical mastectomy (both P<0.001). Univariate analysis revealed that a fluorouracil/doxorubicin (epirubicin)/cyclophosphamide (CA[E]F) regimen or a CA(E) F followed by docetaxel (CA[E]F > T) regimen conferred significantly better DFS (P=0.0075) and OS (P<0.0001) than those achieved from a cyclophosphamide/methotrexate/fluorouracil regimen, which was almost completely generated by the seven or more ALN subgroup (P=0.0088 and P=0.0001, respectively). Postoperative radiotherapy was associated with better DFS (P=0.0360), which was also generated by the seven or more ALN subgroup (P=0.0107). Subgroup analysis also clarified that the type of surgery conferred a modest effect on DFS in the seven or more ALN subgroup (P=0.0305). Multivariate survival analysis revealed that ALN status (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.31-3.05; P=0.001), tumor size (HR 1.48, 95% CI 1.06-2.08; P=0.022), and type of surgery (HR 0.47, 95% CI 0.30-0.74; P=0.001) were independent prognostic factors for DFS. Meanwhile, ALN status (HR 2.96, 95% CI 1.51-5.77; P=0.002), tumor size (HR 2.32, 95% CI 1.38-3.89; P=0.001), type of surgery (HR=0.39, 95% CI 0.20-0.76; P=0.006), and regimen of chemotherapy (HR=0.64, 95% CI 0.50-0.85; P=0.002) were identified as independent prognostic factors for OS. Conclusion: Besides the classical prognostic factors and the improvement of prognosis achieved from the anthracycline-based or anthracycline-taxane combination chemotherapy compared to cyclophosphamide/methotrexate/fluorouracil chemotherapy, our findings showed benefits on DFS and OS for appropriate local treatments, including radiotherapy and sufficient ALN dissection for high-risk breast cancer patients with four or more ALNs involved, which suggests that much importance should also be attached to local treatment besides adjuvant systemic therapy.