Using the lymph nodal ratio to predict the risk of locoregional recurrence in lymph node-positive breast cancer patients treated with mastectomy without radiation therapy

Background To evaluate the prognostic value of axillary lymph node ratio (LNR) as compared to the number of involved nodes (pN stage) in patients with axillary lymph node-positive breast cancer treated with mastectomy without radiation. Methods We performed a retrospective analysis of the clinical data of patients with stage II-III node-positive breast cancer (N=1068) between 1998 and 2007. Locoregional recurrence-free survival (LRFS) and overall survival (OS) were compared based on the LNR and pN staging. Results A total of 780 cases were classified as pN1, 183 as pN2, and 105 as pN3. With respect to LNR, 690 cases had a LNR from 0.01-0.20, 269 cases a LNR from 0.21-0.65, and 109 cases a LNR > 0.65. The median follow-up time was 62 months. Univariate analysis showed that both LNR and pN stage were prognostic factors of LRFS and OS (p<0.05). Multivariate analysis indicated that LNR was an independent prognostic factor of LRFS and OS (p<0.05). pN stage had no significant effect on LRFS or OS (p>0.05). In subgroup analysis, the LNR identified groups of patients with different survival rates based on pN stage. Conclusions LNR is superior to pN staging as a prognostic factor in lymph node-positive breast cancer after mastectomy, and should be used as one of the indications for adjuvant radiation therapy.


Introduction
Studies have shown that radiation therapy improves locoregional control of axillary lymph node-positive breast cancer, and thereby benefits survival [1][2][3]. The positive lymph node status has been used as an indicator for adjuvant radiotherapy after mastectomy [4,5]. However, overall outcomes can be variable depending on the extent of axillary lymph node removal. Additionally, the decision to perform radiation therapy is in part physician dependent.
The lymph node ratio (LNR) is defined as the ratio of the number of positive axillary lymph nodes to the number of removed axillary lymph nodes, and has attracted a great deal of attention. Veronesi et al. [6] has suggested that use of the LNR may minimize the difference between clinical judgment and the real status of the lymph nodes that arises due to differing physician practices. Currently, studies on the LNR have been mainly focused on patients with 1-3 positive nodes [7,8]. The reliability of the LNR in predicting the prognosis in patients with greater than 3 positive nodes has rarely been addressed. In this retrospectively study, we compared the prognostic values of the LNR and number of involved nodes (pN) staging in 1068 patients with axillary lymph node-positive breast cancer without radiation therapy after mastectomy to determine the value of the LNR as an indicator for adjuvant radiation therapy in these patients.

Study population
The study was performed in accordance with the Declaration of Helsinki and was approved by the ethics committee of Sun Yat-Sen University Cancer Center. Written consent was given by the patients for their information to be stored in the hospital database and used for research. A total of 1068 female stage II-III breast cancer patients treated between January 1998 and May 2007 at the Sun Yat-sen University Cancer Center were included in this study. All patients were diagnosed with unilateral breast cancer without initial distant metastasis, and underwent mastectomy and axillary lymph node dissection. Staging was based on the 2009 7th edition of the American Joint Committee on Cancer (AJCC) staging system, and patients with a post-mastectomy pathological stage of T1-4N1-3M0 were included. In all cases, the tumor was completely dissected and surgical margins were negative.
No neo-adjuvant therapy was administered before surgery, and no adjuvant radiotherapy was provided after surgery. No patients had any serious comorbid conditions.

Clinical and pathological factors and lymph node status
Clinical and pathological characteristics were used to assess the risk of locoregional recurrence and death, and included age, menopausal status, T stage, pN stage, and estrogen receptor (ER), progesterone receptor (PR), and human epithelial growth factor receptor family 2 (Her-2) status. T staging and pN staging were determined according to the AJCC staging system (7th edition, 2009). LNR classifications were based on the report by Vinh-Hung et al. [9]. Patients were classified into 3 groups: LNR 0.01-0.20, LNR 0.21 -0.65, and LNR > 0.65.

Follow-up and survival endpoints
Follow-up was scheduled every 3-6 months after surgery. Locoregional recurrence-free survival (LRFS) and overall survival (OS) were the primary study endpoints. Locoregional recurrence was defined as pathologically confirmed relapse on the chest wall, supra-and infraclavicular fossa, axillary area, or internal mammary region. Mortality was defined as breast cancer-related death.

Statistical analysis
Data were analyzed using SPSS 16.0 software. Kaplan-Meier curves were generated to compare the survival rates. The statistical significance of data was analyzed by log-rank test. Cox stepwise regression analysis was used for multivariate analysis, and significant variables in univariate analysis as indicated by p<0.05 were included in the Cox model. Statistical significance was set at p<0.05.

Survival and disease progression
The median follow-up time for all patients was 62 months (5-154 months). Locoregional recurrence occurred in 155  Figure 1). The variables demonstrating statistical significance by univariate analysis were further analyzed using multivariate analysis in the Cox regression model. When pN and LNR were included as covariants, the LNR remained an independent prognostic factor for LRFS and OS (p<0.05), with a higher LNR indicating a higher risk, but pN stage exhibited no effect on LRFS and OS (p>0.0 5) ( Table 2).

Prognostic significance of LNR based on pN stage
The subgroup analysis of the prognostic significance of LNR according to different pN stages is shown in Table 3 and Figure 2. For pN1 patients, the 5-year and 10-year LRFS for a LNR of 0.21-0.65 were 80.4% and 74.8%, respectively, which were significantly lower than values of 90.3% and 88.2%, respectively, when the LNR was < 0.20 (p 0.002). The 5-year LRFS for pN2 patients with a LNR of 0.01-0.20, 0.21 -0.65, and > 0.65, were 80.0%, 82.1%, and 44.6%, respectively (p<0.001). Among pN3 patients, the LNR had no impact the prognosis, but the LRFS was lower, the 5-year LRFS was 66.7%, 59.2%, and 66.2% for patients with a LNR of 0.01-0.20, 0.21 -0.65, and > 0.65, respectively (p=0.508). The LNR was a prognosis factor with respect to OS based on pN stage.

Discussion
Although significant progress has been made in understanding molecular biomarkers of breast cancer, axillary lymph node status remains one of the fundamental prognostic factors that guides the decision for postmastectomy radiation therapy [4,5]. Presently, the tumor, regional lymph node, metastasis (TNM) staging system, established by the AJCC, is accepted and utilized worldwide. In this system, the pN staging of axillary lymph nodes is based on the absolute number of lymph nodes. Although easy to use, the accuracy of the approach may be affected by the number of removed axillary lymph nodes, and thus may be subject to unintended variability. In the present study, we explored the prognostic value of LNR in stage II-III nodepositive breast cancer patients without radiotherapy after mastectomy, and demonstrated that the LNR can better predict tumor recurrence and mortality.
The 82b and 82c randomized trials of radiotherapy conducted by the Danish Breast Cancer Cooperative Group provided evidence that postoperative adjuvant radiotherapy has therapeutic value in axillary lymph node-positive breast cancer; however, the median number lymph nodes removed was 7, suggesting that adjuvant therapy used at that time appears insufficient [10]. Nagao et al. [11] showed that the LRFS rate was 8.7% with radiotherapy and 7.3% without radiotherapy after mastectomy in lymph node-positive nodes patients, with a median number of lymph nodes removed of 18.6. In a study by Gentilini et al. [12] in which patients received no radiotherapy after mastectomy plus total axillary clearance (I/II/III region) where the median number of lymph nodes removed was 23, with the 5-year LRFS rates were 3.0%, 8.1%, and 9.9% for N0, N1 and ≥ N2 stage disease, respectively. These studies suggest that sufficient clearance of lymph nodes is helpful to reduce locoregional recurrence, and thereby affects the decision to administer adjuvant radiotherapy. Physician differences and experience can affect the accuracy of pN staging. Due to variations in the clearance of axillary lymph nodes and different physical examination findings, the accuracy of pN staging can be compromised. Furthermore, the optimal number of the axillary lymph nodes that need to be removed remains controversial [13,14]. However, Fisher et al. [7] demonstrated that use of the LNR may minimize the difference in prognosis seen among hospitals due to different degrees of lymph node clearance. Several studies have shown that use of the LNR may change pN staging based on the AJCC system, and should be considered in addition to TNM staging in order to provide better guidance regarding adjuvant therapy [7,9,[15][16][17][18][19]. Our study suggests that the LNR is an independent prognostic factor of LRFS and OS, and pN staging lost significance when LNR was included in the multivariate analysis. This suggests that LNR has better prognostic value than pN staging.
Locoregional recurrence is a determinant in the selection of adjuvant radiotherapy after mastectomy. The St. Gallen Breast Cancer Conference in 1998 recommended postoperative radiotherapy when the expected LRFS rate was > 20% [20]. In recent years, research has been concentrated on the effect of LNR on OS in patients with breast cancer [15][16][17], and the studies on LRFS have been mainly conducted in patients with 1-3 metastatic lymph nodes (pN1) [7,8]. Our study suggests that LNR is superior to pN staging as a predictor of LRFS in patients with breast cancer. We performed subgroup analysis of the prognostic value of LNR according to different pN stages, and for pN1 patients the 5-year and 10-year locoregional recurrence rates (LRR) were 20% and 25.2%, and the LRR was above 20% in stage pN2 and pN3 patients across all LNR groups. The value of adjuvant radiotherapy in 1-3 metastatic lymph nodes is still controversial. Therefore, we recommend that LNR should be employed as one of the indications for adjuvant radiotherapy after mastectomy (i.e., radiation therapy should be considered if the LNR is > 0.20), instead of a treatment decision based only on pN stage.
Our study does have several limitations. First, the conclusions are based on a single center retrospective study and may not be generalizable to other populations. However, an increasing amount of data now supports the prognostic value of LNR in breast cancer, e.g., the International Nodal Ratio Working Group is currently undertaking research to establish the prognostic significance of LNR in breast cancer [19]. Second, there is no consensus on standard cutoff points for LNR [7,9,18,19]. The LNR cutoff points used in this study were based on the report by Vinh-Hung et al., which has been validated in studies in other countries [15][16][17]. Our study suggests that the cutoff points for the LNR used by Vinh-Hung et al. are applicable to Chinese women with breast cancer, but a larger sample size is needed to confirm the results. Third, the prognostic value of Ki-67 was not analyzed due to missing data, and most of the patients did not received trastuzumab therapy.

Conclusions
In summary, our study demonstrated that LNR is a better prognostic predictor than pN stage in patients with axillary lymph node-positive breast cancer after mastectomy, and should be used as one of the indications for adjuvant radiation therapy . Further prospective studies are necessary to assess the impact of LNR on prognosis, and to define the usefulness of postoperative radiotherapy.