The prognostic value of NR is supported by several studies [4
]. Vinh-Hung et al. reported the superiority of NR over pN stage in predicting disease-specific survival, and Danko et al. revealed that the prognostic value of NR for disease-free survival remained significant even when stratified by pN stage [8
]. Recently, Ahn et al. showed that NR is a better predictor of disease-free survival than pN stage, especially in patients with high-risk features such as young age, HER2-enriched or triple-negative tumor, and recommended that NR should be preferentially considered in decision making for adjuvant treatment [13
Although most studies used a value between 0.20 and 0.25 as a minimal cut-off threshold to distinguish risk groups, there is no consensus on which value is the most reliable [5
]. We used 0.15 as a cut-off value, which may be considered somewhat low. Because the number of positive nodes is inevitably limited in the N1 category, however, the distribution of the NR is strongly affected by the number of nodes sampled. While other studies have focused on patients with between 10 and 16 excised nodes, the present study investigated patients with a median of 18 excised nodes.
Extensive data suggest that other clinico-pathologic findings also can predict an increased risk of locoregional recurrence and even distant metastasis, such as young age, higher histologic grade, negative hormone receptors, presence of ECE, presence of LVI, and inadequate resection margins [15
]. Recently, Truong et al. reported that T1-T2 breast cancer patients with one to three positive nodes, young age (< 50 years), histologic grade 3, or ER-negative disease had high 10-year locoregional recurrence risks (up to 20%), even after breast-conserving surgery was followed by whole breast radiotherapy [15
]. In the current study, those findings were not significant factors for locoregional recurrence or distant metastasis independently but showed selective significance in adjusted analysis combined with the NR.
Regardless of the extent of surgery, substantially high locoregional recurrence rates have been reported in patients with 1-3 positive nodes [15
]. Locoregional recurrence also has been linked to distant metastasis and long-term breast cancer mortality [25
]. In a meta-analysis of five National Surgical Adjuvant Breast and Bowel Project (NSABP) trials, patients who experienced locoregional recurrence had a considerably lower 5-year DMFS: 51.4% after ipsilateral breast tumor recurrence, 31.5% after axillary recurrence, and 12.1% after supraclavicular metastasis, respectively [27
]. Data from the Breast Cancer Trialists' Collaborative Group (BCTCG) showed the overall absolute reduction of 5-year locoregional recurrence by 19%, resulting in a 5% overall absolute reduction of 15-year breast cancer mortality risk in patients who underwent either breast-conserving surgery or mastectomy [28
]. In the current study, the HNR group showed lower LRRFS, DMFS, and DFS. However, it is inconclusive whether decreased risk of distant metastasis resulted from decreased locoregional recurrence because only a small number of patients experienced locoregional recurrence.
The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) has suggested that adding regional RT may improve survival compared with whole breast RT only when administered after breast-conserving surgery in patients who have T1-T2 breast cancer with N1 or moderate to high risk N0 [29
]. The current study revealed that regional RT reduced the risk of distant metastasis in the HNR group only; however, this finding could also support the interpretation that regional RT is unnecessary for LNR patients who have undergone adequate axillary dissection and had no poor prognostic factors. For optimization of the locoregional modality, it is necessary to better define the selection criteria for adjuvant RT. The NR may be a useful indicator for deciding whether to use adjuvant regional RT to treat patients with N1 disease.
Inadequate nodal sampling (less than 10), histology grade 3, estrogen receptor-negative breast carcinomas, or presence of LVI are all considered to be related to the risk of regional recurrence. Previous studies have shown that sampling fewer than 10 axillary nodes is associated with an increased risk of subsequent locoregional recurrence [15
]. Tai et al. included in their study only patients with 10 or more excised nodes in order to avoid the possibility of an increased regional relapse rate resulting from understaging or undertreatment [6
]. The adjuvant regional RT could compensate for the compromised regional control resulting from inadequate axillary dissection; however, this result does not directly apply to patients in the HNR group who have undergone adequate axillary dissection and remain at substantial risk for locoregional recurrence [31